2002, Vol.86, Issues 3, Dementia

Med Clin N Am 86 (2002) xixiii
Preface
Dementia
James D. Bowen, MD Guest Editor
Dementia is one of the most important yet dicult conditions that physicians are asked to manage. It takes an enormous toll on patients, eventually robbing them of the accumulated wealth of their life experiences, destroying the very essence of their beings. Families likewise suer from the loss of patriarchs and matriarchs while communities lose the guidance and wisdom of seasoned leaders. With 6% to 10% of those over 65 years of age aected, dementia takes a staggering economic toll that will only worsen as the population ages. Though dementia is common, and despite the severity of its impact, physicians and families often overlook the diagnosis. Recognizing dementia is not the only challenge because identifying the correct diagnosis may be dicult. Finally, the management of these patients can be daunting even for skilled geriatricians. This issue of Medical Clinics of North America is devoted to dementia. It is divided into three sections discussing clinical aspects, recent scientic insights, and treatments. The rst article provides an overview of the diagnosis of patients with dementia. The clinical history, examination, laboratory evaluation, and dierential diagnosis are reviewed. The next ve articles review specic dementing diseases that are of particular importance today. Vascular dementia is reviewed in the second article. This represents the second most common cause of dementia, after Alzheimers disease. The third and fourth articles review frontotemporal dementia and dementia with Lewy bodies. These two conditions have recently been distinguished from other types of dementia. New criteria have been proposed, allowing
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Preface / Med Clin N Am 86 (2002) xixiii
them to be distinguished from other dementing illnesses. Correctly diagnosing frontotemporal dementia and dementia with Lewy bodies can explain otherwise baing behaviors and can provide important prognostic information to patients and families. These diagnoses also carry important implications for treatment. The fth article is devoted to AIDS dementia. Dementia in patients with HIV infections can be the result of a number of dierent causes. Correctly identifying the cause is key to providing optimal treatment. The sixth article rounds out the discussion of specic diseases with a review of human prion diseases. Prion diseases represent a new class of infectious agents that have had dramatic eects on public health policy because of their link to specic food sources. Understanding and recognizing the conditions described in these opening articles should provide the practitioner with valuable tools in evaluating dementia patients. The next section of this issue reviews some of the scientic ndings that have advanced our understanding of dementing diseases. The epidemiology of dementia is discussed in the seventh article. Epidemiology studies drive many of the public health care decisions that must be made in caring for the elderly because the incidence and prevalence of dementia point toward societys present and upcoming healthcare needs. Epidemiology also identies risk factors for dementia that may provide additional insight into the pathogenesis of dementing diseases. The eighth article describes the many advances in the genetics of dementia that have occurred during the past few years. Many families with genetic risks of dementia have now been recognized. In many cases, the responsible genes have been identied. These genes and the proteins that they encode increase our understanding of dementia at the molecular level, not only for familial dementias, but also for nongenetic dementias. Genetic advances merge into the recent advances in our understanding of the molecular basis of Alzheimers disease. We are beginning to understand the molecular causes of two of the prominent pathologic changes found in Alzheimers disease: neurobrillary tangles and plaques. The role of tau in the formation of neurobrillary tangles and Alzheimers disease is described in the ninth article. The role of beta-amyloid in the formation of plaques and Alzheimers disease is described in the tenth article. The nal two articles address the treatment of patients with dementia. The eleventh article describes some of the nonpharmacologic treatments that may be used to manage the symptoms of dementia. Successful management of these symptoms can greatly reduce the burden on patients and families. In addition, these treatments can avert or delay the need for expensive care in assisted living facilities or nursing homes. The nal article describes pharmacologic treatments of dementia. These relatively new medications are the rst treatments that can improve cognitive function. I hope this issue will provide the practitioner with the tools needed to diagnose and manage patients with dementia in their clinical practices. It should also provide a basis for understanding the recent scientic advances
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that have added so much excitement to this eld, and that provide such hope for the future. James D. Bowen, MD Guest Editor Department of Neurology University of Washington Box 356465, Room RR650 1959 N.E. Pacic Street Seattle, WA 98195-6465, USA E-mail address: jbowen@u.washington.edu
Med Clin N Am 86 (2002) 455476
The diagnosis and dierential diagnosis of dementia

G. Webster Ross, MDa,*, James D. Bowen, MDb
a
Honolulu Department of Veterans Aairs, and John A. Burns School of Medicine, University of Hawaii, Pacic Health Research Institute, 846 South Hotel Street, Suite 307, Honolulu, HI 96813, USA b Department of Neurology, University of Washington School of Medicine, Box 356465, Seattle, WA 98195, USA
Dementia is one of the most costly and disabling diseases associated with aging. The emotional impact of the disease on patients and families is devastating, and the cost to society is staggering. Annual costs for caring for a single patient with Alzheimers disease (AD) are reported to be between $35,000 and $47,000, totaling more than $140 billion dollars per year in the United States assuming there are 4 million people with AD [13]. This gure is projected to rise as the proportion of the population older than the age of 65 years increases. As treatments for AD and other dementias that can extend the period individuals have reasonably good cognitive and physical functioning become available, the accurate and early diagnosis of these disorders becomes more crucial. This article provides an overview of the bedside and clinic evaluation of patients with complaints of forgetfulness or other cognitive or behavioral disturbances and reviews distinguishing features of dementia and other conditions that may be confused with dementia. The laboratory and imaging evaluation of the patient with dementia and the various causes of dementia are described. Current clinical practice guidelines and practice parameters are reviewed as relevant for the primary care practitioner. For the most part, these guidelines are similar; however, there are important inconsistencies that are discussed.
* Corresponding author. E-mail address: ross@phri.hawaii-health.com (G.W. Ross). This work was supported by National Institute on Aging contract NO1-AG-4-2149, US Department of the Army grant DAMD17-98-1-8621, and Department of Veterans Aairs medical research funds. The information contained in this article does not necessarily reect the position or the policy of the US government, and no ocial endorsement should be inferred. 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 9 - 3
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G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476
Dementia is a clinical syndrome characterized by acquired impairment in multiple neuropsychologic and behavioral domains, including memory, language and speech, visuospatial ability, cognition (the ability to manipulate previously learned information), and mood/personality [4]. Most denitions, such as that of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) [5], require that the intellectual decits be of sufcient severity to impair social or occupational functioning. These denitions necessarily draw an arbitrary line between no dementia and dementia. Patients most often pass through stages of intellectual decline that may or may not progress to dementia. These include cognitive decits thought to occur with normal aging; mild cognitive impairment (MCI), a term used to recognize a transitional phase from normal aging to dementia; and early dementia. In practice, it is often dicult to recognize when a patient with memory complaints has a process that is likely to progress to further intellectual and functional decline. Because there is no diagnostic test to identify dementia, the clinician must rely on a careful and accurate history from the patient and a reliable informant as well as a good mental status examination. As eective treatments are developed for the common causes of dementia, it is important to diagnose patients in the earliest phases of disease, perhaps even before aected individuals recognize that a memory problem exists. According to one recently published population-based study, approximately 20% of family informants failed to recognize memory problems in elderly subjects who were found to have dementia on a comprehensive standardized examination [6]. Another study found that more than 75% of patients in a primary care group practice found to have dementia on cognitive screening had no documentation of cognitive impairment in their medical record [7]. It is thus essential that clinicians inquire about cognitive and functional changes in their elderly patients and administer a brief mental status examination if changes exist so as to identify cognitive decline as early as possible.
Clinical evaluation of patients with memory complaints History of cognitive impairment Patients who complain of memory problems and those suspected to have memory problems should give a thorough and detailed history, taken from the patient as well as from a relative or close friend. Even in the early stages of dementia, such as AD or frontotemporal dementia, patients may be unable to recall important aspects of their medical history and may even deny or not recognize signicant memory decits because of lack of insight. Family members can provide information regarding the time and character of onset as well as the pattern of progression of the memory complaints. For example, the onset of AD is insidious, and the course is slowly progressive, whereas vascular dementia (VsD) may begin abruptly and be associated with a stepwise decline [5,8,9]. Although there are exceptions to these rules, they do
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provide useful information for distinguishing these two common dementia syndromes. It is also helpful to inquire about life events temporally related to the onset of the memory complaints, such as hospitalization, stroke, head injury, new medications, or the loss of a spouse or other family member. Inquiry should be made regarding ability to learn and recall new information. Examples include recall of recent conversations and events, telephone messages, short shopping lists, appointments, and use of new appliances or electronic devices. Patients may forget to pay their bills, become lost in familiar surroundings, lose items (eg, mail or keys), or exhibit repetitive behaviors (eg, asking the same question over and over). Standardized informantbased questionnaires regarding memory and cognitive decline may be administered by trained interviewers, providing a base for a more focused history taken by the primary physician. One of these tools is the Informant Questionnaire on Cognitive Decline in the Elderly [10,11]. History of behavioral disturbances It should be recognized that memory impairment, although a hallmark of the dementia syndrome, is not always the presenting feature. Behavioral disturbances and decline in functional ability are often the triggers that lead family members to seek medical attention [6]. Behavioral disturbances include delusions, hallucinations, changes in mood (eg, depression), and changes in personality (eg, disinhibition, impulsivity, loss of interest in usual activities, excessive anxiety, uncharacteristic anger or agitation). Standardized assessments of behavioral complications are also available, such as the Neuropsychiatric Inventory [12] or the Behave-AD [13]. These assist the clinician in screening for a range of behavioral complications associated with dementia and in measuring the eect that these complications have on the caregivers well-being. History of functional impairment An important component of the history is assessing the impact that the intellectual decline and behavioral disturbances are having on the patients social and basic functioning ability. This may be a dicult task in the elderly, especially when physical ailments also contribute to inactivity or decline in functional ability. As a result, some knowledge of the patients previous activities is necessary. Standardized instruments, such as the informant-rated Blessed Dementia Scale [14], the Functional Activity Questionnaire [15], or the Instrumental Activities of Daily Living Scale [16], may be used for functional assessment. These scales assess activities of daily living (personal maintenance activities essential for good health and wellbeing), including dressing, bathing, eating, and toileting, as well as instrumental activities of daily living (higher order skills required for independent living), including managing money, preparing meals, taking
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medication, and performing household tasks. More detailed discussions of these topics are available in recently published guidelines and reviews [1720]. A review of the patients past medical and psychiatric history for conditions that may contribute to cognitive decline is always necessary. This should include questions regarding cardiovascular disease, remote head trauma, alcohol use, prescription and nonprescription medications, dietary supplements, and treatment for depression. Family history is important, because many dementing diseases have a familial component. Thorough reviews of systems and a general physical examination, including a detailed neurologic examination, are needed to identify clues to the diagnosis. A cardiac murmur or dysrhythmia along with focal neurologic signs may suggest a vascular etiology, whereas bradykinesia, rigidity, and tremor suggest one of the parkinsonian syndromes. Mental status examination The bedside mental status examination should include assessment of level of consciousness, orientation, attention, speech and language, recent and remote memory, cognition, visuospatial skills and mood/personality. Attention refers to the patients ability to maintain focus on the appropriate stimulus while avoiding distraction from irrelevant stimuli. This may be tested by digit repetition or by subtracting serial 7s or 3s from 100. In general, attention is preserved until late in most dementias. Language assessment begins with listening to the patients spontaneous verbal output and includes word list generation, confrontation naming, repetition, and comprehension. Aphasia may suggest dominant hemisphere disease; however, impoverished spontaneous verbal output with paraphasic errors (word substitutions) may also be an early indication of AD [21]. Recent memory may be tested by asking the patient to recall a list of words after 3 to 5 minutes. The minimum is three words; however, longer lists, such as eight words, allow the generation of a learning curve. During the recall phase, category or multiple choice cues may be given to determine if the words have been learned. These techniques can be helpful for dierentiating the forgetfulness (ie, intact learning, impaired retrieval) of normal aging and certain subcortical dementia syndromes from the amnesia (ie, impaired learning and retrieval) of AD and other cortical syndromes [4]. Visuospatial function is tested at the bedside by asking the patient to copy two- and three-dimensional geometric shapes. Cognition or the ability to manipulate previously learned information includes assessment of abstracting ability by interpretation of similarities, proverbs, and mental arithmetic. Performance of these tasks is highly dependent on educational level. Executive function refers to judgment and motivation as well as planning, performing, and monitoring complex behaviors. Impairment in this area is characteristic of subcortical dementia syndromes. The reader is directed to several references with excellent descriptions of the mental status examination for more detail [4,22]. The bedside mental status examination
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provides valuable qualitative information in multiple cognitive domains; however, the time and expertise to administer the full examination may make it impractical in the average primary care setting. Clinicians may prefer a brief standardized cognitive assessment instrument such as the Mini-Mental State Examination [23], the Cognitive Abilities Screening Instrument [24], the Alzheimers Disease Assessment Scale [25], or the Neuropsychological Assessment of the Consortium to Establish a Registry for Alzheimers Disease [26]. These all have the advantage of being quantitative and easy to administer. When used along with the other components of the history and examination, they are useful for determining if a patient has dementia. Because of the variable sensitivity and specicity in dierent populations and the eects of education on performance, a specic cuto score cannot be the sole method of diagnosing dementia. Scores are useful for measuring change over time [18,19]. The Mini-Mental State Examination is the most commonly used cognitive screening instrument (Table 1). It has the advantages of being brief, easy to administer, and inclusive of multiple domains, including orientation, attention, language, memory, and visuospatial ability. Published normative data allow interpretation of scores according to the patients age and education [27]. In addition to age and education, impairment in hearing and vision as well as cultural and language background may aect performance on cognitive testing [18,28]. Nonnative English speakers may have diculty with
Table 1 Mini-mental state examination Maximum score What is the (year)(season)(date)(day)(month)? Where are we (state)(country)(town)(hospital)(oor)? Registration Name three objects. Give 1 second to say each. Ask the patient all three after you have said them. Give 1 point for each correct answer. Repeat them until the patient learns all three count trials and record. Attention and calculation Serial 7s. Give 1 point for each correct. Stop after ve answers. Alternatively, spell world backwards. Recall Ask for the three objects repeated previously. Give 1 point for each correct answer. Language Names a pencil and watch. Repeat the following: No ifs, ands, or buts. Follow a three-stage command: Take a paper in your right hand, fold it in half, and put it on the oor. Read and obey the following: CLOSE YOUR EYES. Write a sentence. Copy design [two overlapping pentagrams]. 5 5 3
2 1 3 1 1 1
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cognitive function tests given in English. Individuals relatively uent in English may still perform at a higher level in their native language given the stress of cognitive function tests. Cognitive screening instruments translated into the native language should be used when available. Even when assessing cognition in the language most comfortable for the patient, culturally biased items on the screening test used may still aect performance, requiring interpretation of the test results within culture-specic norms [18,28]. Formal neuropsychologic testing may be necessary when the bedside assessment fails to dierentiate between changes associated with normal aging and early dementia. These tests may also assist with narrowing the differential diagnosis of the dementia syndrome. Diagnostic evaluation of dementia Neuroimaging Although the literature regarding indications for neuroimaging in the evaluation of dementia remains inconclusive, most dementia specialists suggest that a structural brain image be obtained for a newly diagnosed patient to assess cerebrovascular lesions, neoplasms, subdural hematomas, or hydrocephalus [17]. The recent report from the Quality Standards Subcommittee of the American Academy of Neurology on the diagnosis of dementia recommends neuroimaging at the time of initial dementia assessment under most circumstances [20]. Earlier published guidelines state that neuroimaging is optional [29], and some oer prediction rules that dictate when imaging is indicated [19,30]. A recent evaluation of six published sets of prediction rules for neuroimaging in the evaluation of dementia found that the sensitivity of these rules for identifying potentially reversible causes of dementia, such as subdural hematomas, neoplasm, or hydrocephalus, ranged from 12.5% to 100%. Depending on the rules used, it was estimated that 12% to 88% of patients with a potentially reversible cause of dementia would not be imaged [31]. Another study evaluating the usefulness of the prediction rules from the American Academy of Neurology guidelines published in 1994 [30] found that 5% of cases with a meaningful lesion found on neuroimaging had none of the clinical predictors [32]. Although the guidelines support the use of either a non-contrast-enhanced CT scan or MRI, MRI is more sensitive than CT for identifying small cerebrovascular lesions and space-occupying lesions that could cause cognitive impairment. The clinical signicance of multiple small white matter changes seen on T2-weighted MRI images in the elderly is often uncertain, however. Neuroimaging is essential for the diagnosis of cerebrovascular dementia. Clinically silent (ie, no recognized focal event) lacunar infarcts, ischemic white matter changes, and even cortical infarctions that aect cognition may be present. Imaging analysis techniques that quantify the volume of brain structures or lesions may be useful in the future for diagnosing AD [33].
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Presently, these techniques are expensive and time-consuming. Neither single photon emission CT nor positron emission tomography is recommended for routine use in the diagnostic evaluation of dementia [20]. These studies can be useful diagnostic adjuncts, however. Laboratory tests Laboratory tests should be performed to identify infectious, metabolic, toxic, and inammatory disorders that can cause neuropsychologic impairment. Required tests include a complete blood cell count; tests of electrolyte, serum glucose, vitamin B12, and folate levels; tests of liver, renal, and thyroid function; and a serologic test for syphilis [19,20]. In a recent study, the use of these tests aected patient management in 13% of consecutive patients being evaluated for dementia [32]. Further diagnostic testing should be based on clinical suspicion. This includes serum or urine tests for toxins, drugs, or heavy metals when exposure is suspected; sedimentation rate for suspected infectious or inammatory disorders; and human immunodeciency virus antibody testing. Genetic testing may be useful in those with three or more rst-degree relatives with a dementing illness. Assuming that mass lesions are absent, a lumbar puncture may help to diagnose metastatic cancer, infection, vasculitis, encephalitis, meningitis, syphilis, or hydrocephalus. Lumbar puncture may be particularly useful in dementia patients less than 55 years of age or in those with rapid progression, unusual dementia, or immunosuppression [30]. Specic tests on cerebrospinal uid (CSF), although not standard, may be helpful for diagnosis. For example, elevation of the normal brain protein 14-3-3 in the CSF of patients with progressive dementia without CSF pleocytosis has been reported to be 96% sensitive and 99% specic for Creutzfeldt-Jakob disease [20,34]. An electroencephalogram may identify the periodic sharp wave complexes associated with Creutzfeldt-Jakob disease and may be helpful in distinguishing depression or delirium from dementia [30].
Dierential diagnosis of memory and cognitive impairment Not all patients with complaints of memory loss have dementia. Some have no memory loss at all, whereas others have a mild degree of impairment insucient for a diagnosis of dementia. When evaluating the patient with complaints of memory loss, the physician must rst determine whether true memory loss is present. A number of conditions can lead to memory complaints or cognitive impairment. These are listed in Table 2. Cognitive changes with normal aging Cognitive decline related solely to aging remains a controversial topic. Normative data from cross-sectional studies examining neuropsychologic
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Table 2 Problems presenting as memory loss Dementia Worried well Normal aging Depression Delirium Stroke syndromes Bradykinesia Abulia Seizure Excessive daytime somnolence Amnestic syndrome
performance demonstrate declines in memory with age. Specically, it has been reported that new learning ability or acquisition declines with age, whereas cued recall remains stable [35]. The pattern and severity of decits across cognitive domains vary widely depending on the population studied, the tests used, and whether the data are cross-sectional or longitudinal [35 37]. A clear conclusion from studies of neuropsychologic function in the elderly is that aging-related declines are not inevitable, and that when they do occur, it is age-related diseases that are often responsible [36,38]. It should be emphasized that all patients with memory complaints need a careful evaluation. It is not appropriate to assume that memory complaints, at any age, are caused by senescence. Mild cognitive impairment One of the more important clinical concepts to emerge recently in the eld of cognitive disorders is MCI. Although exact denitions vary, MCI exists in patients with memory complaints and objective memory impairment. Because the activities of daily living are intact in these patients, they do not meet the criteria for dementia. This condition is considered to be a transitional stage between normal aging and dementia. The signicance of MCI lies in the identication of patients at high risk for developing dementia and in the potential for treating these patients so as to prevent further decline. Guidelines for the detection and management of this condition have been published recently [39]. It is reported in this evidence-based review that subjects with MCI followed for up to 4 years have a high risk of progressing to dementia, with an annual conversion rate ranging from 6% to 25%. The recommendations are made that persons with MCI be recognized and monitored for cognitive and functional decline because of their increased risk of progressing to dementia and that general cognitive screening instruments be considered for identifying dementia in patients with MCI [39]. Arguments countering these recommendations question the benet of clinical monitoring considering the fact that not all those with MCI evolve to dementia and
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suggest that the stigma attached to this label could actually work to the patients detriment [40]. Depression Memory impairment is commonly associated with major depression in the elderly and may be the presenting symptom of this common and treatable disorder [41]. In fact, memory complaints in the elderly may be more related to depression than to objective memory impairment [42]. The essential features of major depression are sadness that is persistent or anhedonia (loss of interest in usual activities) [5]. In addition to memory impairment and poor concentration, depressed patients experience sleep and appetite disturbances, loss of energy, psychomotor retardation, feelings of worthlessness or guilt, or recurrent thoughts of death. Clinical screening tools for depression are available, such as the Hamilton Scale or the Geriatric Depression Scale [43,44]. Patients with depression generally have impaired recall with relative sparing of recognition memory. The cognitive and mood symptoms can resolve completely with treatment, although response to treatment may be dicult to assess when dementia and depression coexist. Additionally, because depression with cognitive impairment may presage the development of dementia, it is important to follow patients so as to assess treatment eectiveness and track progression of cognitive decits [45]. Delirium Delirium or acute confusional state is another condition that is common in the elderly. According to the DSM-IV [5], delirium requires the following: 1. Disturbance of consciousness (ie, reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention. 2. A change in cognition (eg, memory decit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia. 3. The disturbance develops over a short period (usually hours to days) and tends to uctuate during the course of the day. Illusions and hallucinations may be seen, speech may be incoherent at times, sleep-wake cycles are often disturbed, and psychomotor activity is increased or decreased. Delirium is associated with a variety of systemic illnesses, infections, and toxic and metabolic disturbances. Hospitalized patients in general and surgical patients in particular are prone to delirium. Features that help to dierentiate delirium from dementia include rapid onset, short duration, and disturbance of consciousness that often waxes and wanes between agitation and lethargy. It is important to recognize that patients with dementia are at increased risk for delirium and that delirium and dementia may coexist [46].
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Amnestic syndromes Amnesia is dened as an inability to learn new information and is an early sign of AD. Unlike AD, however, the amnestic syndromes are characterized by isolated amnesia with preservation of other areas of neuropsychologic function, such as language and visuospatial ability. Amnestic syndromes are generally associated with conditions that aect the mesial temporal lobes and their connections with the fornix, mamillary bodies, and thalamus. Causes of amnesia include Korsakovs syndrome associated with alcohol abuse and thiamine deciency, herpes encephalitis, and head trauma [47]. It is important to recognize that patients with isolated memory loss without apparent cause are at high risk for developing dementia and should be closely monitored [48]. Aphasia Language disturbance or aphasia complicates the evaluation of the cognitively impaired patient. An aphasic patient may be unable to participate in memory testing because of an inability to comprehend instructions, repeat words or phrases, or read. Aphasia is associated with dysfunction in the dominant hemisphere, usually the left hemisphere. Anterior lesions cause nonuent aphasia with sparse verbal output, whereas posterior lesions in Wernickes area are associated with uent verbal output with word substitutions or paraphasias and impaired comprehension [49]. Dominant hemisphere strokes are the most common cause of aphasia; however, anomia may be the earliest feature of AD or frontal lobe degenerative dementia [21].
Etiology of dementia Once it has been determined that a patients complaints of memory loss are the result of dementia, the physician must determine the nature of the dementing disorder. Table 3 provides a partial list of the many causes of dementia. The following discussion highlights some of the more common and reversible causes. Detailed information on some of these conditions may be found in other articles in this issue. Comprehensive reviews of the causes of dementia are also available [4,18]. Identifying less common causes of dementia Although AD is the most common cause of dementia, the physician must be vigilant to less common causes. Clues to diagnosing less common conditions include the presence of focal neurologic ndings that suggest focal structural lesions, such as stroke, tumor, or subdural hematoma. The early onset of behavioral abnormalities, language dysfunction, rigidity, or apraxia suggests frontotemporal dementia. Parkinsonian features in early stages of the disease suggest the presence of Parkinsons disease or dementia with
G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476 Table 3 Causes of dementia Cortical degenerative dementias Alzheimers disease Frontotemporal dementia Vascular dementias Multiple large vessel infarcts Single strategic infarct Lacunar state Binswangers disease CADASILa Toxic/metabolic conditions Medication-induced dementia Alcohol-related dementia Dementia related to heavy metal exposure Vitamin B12 deciency Folate deciency Hypo- or hyperthyroidism Hypo- or hyperparathyroidism Hypo or hypermagnesemia Hypo or hypercalcemia Cushings disease Addisons disease Renal failure Liver failure Porphyria Domoic acid poisoning Paraneoplastic syndromes Limbic encephalitis Autoimmune/inammatory disorders Multiple sclerosis Behcets disease Lupus erythematosus Sarcoidosis Temporal arteritis and other central nervous system vasculitides
a
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Dementias associated with parkinsonism Parkinsons disease Dementia with Lewy bodies Progressive supranuclear palsy Multiple systems atrophy Cortical-basal ganglionic degeneration Idiopathic basal ganglia calcications Parkinsonism-dementia complex of Guam Other extrapyramidal disorders Wilsons disease Huntingtons disease Hallervorden-Spatz disease Dementias related to infections Prion diseases Creutzfeldt-Jakob Disease Gerstmann-Straussler-Scheinker Disease Kuru New-variant Creutzfeldt-Jakob Disease Neurosyphilis AIDS dementia Chronic meningitis Fungal Tuberculosis Lyme disease Viral encephalitis Whipples disease Trauma-related dementias Dementia related to closed-head injury Chronic subdural hematoma Dementia pugilistica Miscellaneous disorders Normal pressure hydrocephalus Hippocampal sclerosis Central nervous system tumors Mitochondrial encephalopathies
Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.
Lewy bodies. Fluctuations in performance, often over a period of minutes, or the presence of visual hallucinations also suggests dementia with Lewy bodies. Age of onset less than 50 years or the presence of three or more rst-degree relatives with dementia suggests a genetic dementing disorder. Alzheimers disease AD is the most common cause of dementia, comprising over two thirds of all cases in most studies [50]. There is no conrmed biologic marker for AD; however, standardized clinical criteria have improved the accuracy of diagnosis to greater than 85% [8,51]. Onset is insidious, and progression
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slow. Language disturbances may be an early feature, with anomia progressing to uent aphasia with word substitutions or paraphasias and impairment in comprehension. Recent memory and the ability to learn new information are also impaired early in AD. Other common disturbances in cortical function include apraxia (impaired ability to perform motor activities despite intact motor function), agnosia (inability to recognize objects despite intact sensory functioning), and alexia (inability to comprehend the written word). Patients with AD commonly lack knowledge of their memory problems. Delusions and hallucinations are common and occur in up to 50% of patients [52]. The results of the elementary neurologic examination are remarkably normal in most cases. Subtypes of AD include those with isolated cognitive impairments that later progress to more widespread cognitive decits. In addition, another type presents with rigid or bradykinetic symptoms resembling Parkinsons disease. When present early, extrapyramidal signs suggest a more rapid decline [53]. In those patients with three or more rst-degree aected family members, familial AD must be suspected, and appropriate testing should be undertaken. Vascular dementia The concept of (VsD) is evolving as it becomes increasingly recognized that in addition to causing cognitive decline alone, vascular lesions modify the expression of Alzheimer pathologic ndings [54]. VsD is clinically recognized in patients with a prior history of strokes, focal neurologic ndings, or strokes on neuroimaging. The classic sudden onset with stepwise deterioration of VsD probably occurs in less than half of cases. Because of these clinically silent cases, it is important to obtain neuroimaging in all cases of dementia. The cognitive decits associated with VsD depend on the lesion location. Large vessel strokes cause cortical decits, such as aphasia and focal neurologic decits, such as hemianopia and hemiparesis. Multiple small vessel strokes cause a subcortical clinical presentation with forgetfulness and prominent executive function decits. Pseudobulbar palsy, gait disturbances, and urinary incontinence are also common. Although several sets of criteria exist for VsD [5,9,55], the clinician should be concerned with stroke prevention in any dementia patient with cerebrovascular risk factors or vascular lesions on neuroimaging. Frontotemporal dementia Frontotemporal dementia consists of a clinically and pathologically heterogeneous group of disorders, including Picks disease. These have in common degeneration of the frontal and temporal lobes. Diagnostic criteria for frontotemporal dementia are listed in Table 4 [56]. Behavioral changes, including disinhibition, impulsiveness, social inappropriateness, apathy, and withdrawal, are early and prominent features. These behavioral changes provide the most important clue allowing the dierentiation of this condition
G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476 Table 4 Criteria for the diagnosis of frontotemporal dementia
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A. Dominant decits in behavior and conduct appearing early in the course Loss of personal awareness (neglect of hygiene and grooming) Loss of social graces and awareness Disinhibition (sexually provocative or demanding, inappropriate jocularity), overactivity, or restlessness, often with a stereotyped repertoire Impulsivity, distractibility Hyperorality (dietary changes, excessive eating, smoking, or alcohol consumption, preference for sweet foods or food fads, oral exploration of objects) Withdrawal from social contact, apathy or inertia Stereotyped or perseverative behaviors (wandering, repetitive clapping, humming or singing, ritualistic toileting, dressing) B. Speech output changes Progressive reduction of speech (late mutism, economy of speech) Stereotypy of speech (few repeated phrases or themes), perseveration Echolalia C. Physical signs Early or prominent primitive or frontal reexes Early incontinence Late akinesia, rigidity, tremor D. Decits in social comportment, behavior, judgment, or language are out of proportion to memory decit. Memory loss is variable, often seems to result from lack of concern or eort; frontal lobe impairments most notable: abstraction, planning, self-regulation of behavior
from AD. Language disturbances may also appear early, whereas visuospatial function remains intact until later in the illness [57]. Neuroimaging may allow the visualization of focal atrophy, but the disease can often be recognized clinically before changes on routine imaging are apparent [58]. Single photon emission CT imaging demonstrates hypoperfusion in the frontal and temporal lobes before atrophy in these regions is evident on structural imaging [58]. Dementias associated with parkinsonism Parkinsonism is a syndrome of disturbed motor function characterized by bradykinesia, muscle rigidity, rest tremor, and postural instability. Dementia is often a secondary feature. There are many diseases that cause parkinsonism. The most common of these is Parkinsons disease, which is characterized by loss of dopaminergic neurons in the substantia nigra of the midbrain. The presence of Lewy bodies, target-shaped inclusions with a dense eosinophilic core, within the degenerating neurons of the substantia nigra conrms the diagnosis of Parkinsons disease; however, these lesions may also occur in the cortex. Dementias associated with Lewy bodies comprise a spectrum of diseases, including Parkinsons disease with Lewy body pathologic changes limited to the brain stem, dementia with Lewy bodies associated with Lewy bodies in the cerebral cortex, and AD associated with cortical Lewy bodies as well as typical Alzheimer pathologic ndings. Dividing lines between these conditions are somewhat arbitrary;
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however, the practitioner should be familiar with the basic clinical distinctions, because the correct diagnosis aects patient management. Dementia occurs at some time during the course of the illness in approximately 40% of patients with Parkinsons disease [59]. Cognitive decline begins at least 1 year after the onset of the movement disorder and is associated with impaired recall that is aided with recognition cues, prominent executive function decits, and intact language [60]. Dementia with Lewy bodies, in contrast to Parkinsons disease, is identiable by uctuating cognitive performance, well-formed visual hallucinations unrelated to dopaminergic therapy, and parkinsonism that emerges simultaneously with the cognitive impairment. These features allow it to be dierentiated from AD and Parkinsons disease. It is particularly important to recognize dementia with Lewy bodies because of the severe adverse reactions that these patients may have to neuroleptic medications used to treat behavioral problems. Because of this, neuroleptics should be avoided in the treatment of this disease [61]. Diagnostic criteria for identifying dementia with Lewy bodies are listed in Table 5 [62]. Other degenerative parkinsonian syndromes are much less common. Progressive supranuclear palsy begins at the age of 40 years or older and is characterized by a rigid-akinetic form of parkinsonism, dementia, supranuclear gaze palsy, severe dysarthria, neck rigidity (usually in extension), minimal tremor, and frequent falls [63]. Multisystem atrophy refers to a group of adult-onset progressive neurodegenerative disorders (ie, striatonigral degeneration, Shy-Drager syndrome, olivopontocerebellar atrophy) characterized by parkinsonism that
Table 5 Criteria for diagnosing Lewy body dementia A. The central requirement is progressive cognitive decline of sucient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Decits on tests of attention and frontal-subcortical skills and visuospatial ability may be especially prominent. B. Two of the following are required for a probable diagnosis, and one for a possible diagnosis of dementia with Lewy bodies: Fluctuating cognition with pronounced variations in attention and alertness Recurrent visual hallucinations that are typically well formed and detailed Spontaneous motor features of parkinsonism D. Features supportive of the diagnosis are as follows: Repeated falls Syncope Transient loss of consciousness Neuroleptic sensitivity (deterioration in cognitive function, parkinsonism, drowsiness, and some features of so-called neuroleptic malignant syndrome) Systematized delusions Hallucinations in other modalities E. A diagnosis of dementia with Lewy bodies is less likely in the presence of the following: Stroke disease, evident as focal neurologic signs or on brain imaging Evidence on physical examination and investigation of any physical illness or other brain disorder sucient to account for the clinical picture
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is poorly responsive to levodopa and is associated with cerebellar dysfunction, pyramidal dysfunction, or symptomatic autonomic failure as well as dementia [64]. Vascular parkinsonism is characterized by the stepwise progression of an akinetic-rigid syndrome in the setting of clinical strokes or other vascular risk factors, such as hypertension, diabetes, or lipid abnormalities. Clinical signs may improve without the use of levodopa [65]. Cortical-basal ganglionic degeneration is characterized by a chronic progressive akinetic-rigid parkinsonian syndrome resistant to levodopa and is associated with dystonic limb posturing and focal myoclonus. There is also evidence of higher cortical dysfunction (apraxia, cortical sensory loss, or alien limb) [66]. Dementia related to chronic subdural hematoma The presenting features of chronic subdural hematoma include focal symptoms, headache, or cognitive/personality changes. Without neuroimaging, the diagnosis is rarely straightforward. A history of trauma is absent in one third of patients. The onset may be sudden with a uctuating course or may extend over weeks to months. Seventy percent of chronic subdural hematomas occur in patients more than 60 years old, and men are more commonly aected than women [6769]. Patients may have lethargy or agitation. Cognitive decits involve multiple domains, including recent memory, language, abstract thinking, calculations, and judgment [68,69]. A contrastenhanced brain CT scan may be required to recognize chronic subdural hematoma, because the density of the lesion may be the same as that of brain parenchyma. Medical management is recommended for small lesions with minimal clinical signs [70]. Surgical management is indicated for the rest. Either burr holes or twist-drill craniotomy is eective and associated with relatively few complications [71]. Dementias associated with infectious disease The prion diseases, including Creutzfeldt-Jakob disease and dementia secondary to human immunodeciency virus infection, are covered elsewhere in this issue. Creutzfeldt-Jakob disease usually presents with a dementia that progresses over weeks or months. In addition to cognitive impairment, many patients experience depression or emotional lability. Myoclonus, especially in response to stimuli, is seen later in the course of the disease in three fourths of patients. Ataxia is often seen as a late manifestation of the disease. Gait and vision may be aected. The dementia is often rapidly progressive, with the median time from onset of symptoms to death being 4.5 months. Diagnosis may be aided by the electroencephalographic nding of 1- to 2-Hz triphasic sharp waves that are often asymmetric. Elevated levels of the 14-3-3 protein in CSF in the absence of pleocytosis also support the diagnosis. Recently, variant Creutzfeldt-Jakob disease has been found after consumption of beef infected by bovine spongiform encephalopathy. These variant cases generally aect younger patients and have a more prolonged course.
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General paresis refers to the dementia associated with parenchymatous neurosyphilis. Once a common cause of institutionalization, general paresis is now rarely seen, causing some to question the utility of routinely screening for treponemal infection [20]. Onset may occur many years after the initial infection. Patients exhibit memory impairment with confabulation, dysarthria, impaired judgment, psychosis, and grandiosity [4]. Treponemal serology tests, such as the micro hemagglutination assay for treponema pallidum (MHA-TP), have fewer false-negative results than nontreponemal tests, such as the venereal disease research laboratory slide test (VDRL). Cases screening positive by serologic testing should undergo lumbar puncture. The CSF VDRL test is highly specic; however, the results may be negative in some cases. Patients with positive serology and elevated white blood cells in their CSF should be treated. Aqueous penicillin G remains the treatment of choice. Toxin-related dementias Wernickes encephalopathy, characterized by delirium, ophthalmoplegia, and ataxia, is related to thiamine deciency and is associated with prolonged heavy use of alcohol. Prompt thiamine replacement may reverse the delirium and other signs, although some patients still evolve to Korsakos syndrome, an amnestic disorder that may be permanent [72]. Although the DSM-IV recognizes alcohol-induced dementia that persists after heavy drinking, the lack of pathologic ndings in the brain related to alcohol abuse has called into question the direct toxic eect of alcohol on the brain [5,73]. The increased risk of head injury and association of heavy prolonged alcohol use with blood disorders that can lead to stroke may also cause persistent cognitive impairment. Medications are a common cause of delirium and cognitive decline in the elderly and may be responsible for 1.5% to 10% of all clinically diagnosed dementias [74]. Patients with dementia may be particularly susceptible to further cognitive impairment with medication use [7577]. Sedatives and hypnotics (eg, benzodiazepines), anticholinergic drugs (eg, trihexyphenidyl and meclizine), antidepressants (eg, amitriptyline), analgesics, and antihypertensives (eg, beta-blockers) are all commonly prescribed medications that can cause cognitive impairment reversible on withdrawal of the medication [18]. Medications used to treat the behavioral complications of dementia, such as the antipsychotics haloperidol and thioridazine, may worsen the memory impairment. The lowest possible dose should be used to control the target symptoms, and the need for continued use of the medication should be assessed at regular intervals. Dementia associated with metabolic disturbance Neurologic symptoms related to vitamin B12 deciency occur most commonly in the fourth through sixth decades and include paresthesias of the
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feet and hands, loss of vibratory and position sensation, ataxia, extremity weakness, and neuropsychiatric disturbances. Confusion, memory loss, paranoia, hallucinations, depression, and irritability are all features of the neuropsychiatric syndrome that has been described as megaloblastic madness [78,79]. Importantly, among those with cognitive and behavioral symptoms and vitamin B12 deciency, as many as one fourth do not have the megaloblastic anemia that is classically associated with pernicious anemia [80]. Focal areas of cerebral demyelination characterize the brain pathologic ndings much like the loss of myelin in the posterior and lateral columns of the spinal cord associated with this syndrome. Treatment consists of intramuscular administration of vitamin B12. This usually results in improvement in the motor and sensory decits and has been reported to improve language and frontal function in individuals with vitamin B12related cognitive impairment [81]. Folate deciency may cause a similar syndrome that can be treated with oral folic acid supplements. Dementia associated with hypothyroidism is characterized by inattention, memory impairment, and impaired abstraction. Psychosis may occur [4]. Owing partly to the common assessment of thyroid function, the myxedema syndrome of edema, weight gain, thick skin, cold intolerance, constipation, and psychomotor slowing is rarely seen. More often, clinicians encounter patients with elevated thyrotropin levels, normal thyroid hormone levels, and absent or mild symptoms [82]. Evidence from communitybased studies demonstrates an association between this condition known as subclinical hypothyroidism and cognitive impairment [83]. Furthermore, treatment with thyroxine has been associated with signicant improvement in cognitive function [82]. Normal pressure hydrocephalus Normal pressure hydrocephalus is a rare condition characterized by the triad of dementia, gait disturbance, and urinary incontinence. Onset is rare before 60 years of age. Typically, the gait disturbance develops rst, followed by dementia. Incontinence may not occur until the later stages of the disease. The gait is associated with slow and small steps akin to parkinsonism, with slow initiation giving the appearance that the feet are stuck to the oorhence, the term magnetic gait. The dementia syndrome is mild, with forgetfulness, psychomotor slowing, and impaired executive function being the predominant symptoms. The cause is unknown but is thought to be related to ischemic demyelination in periventricular white matter secondary to a combination of vascular insuciency and intermittent slight increases in CSF pressure [84]. The diagnosis is made by neuroimaging in patients with the appropriate clinical picture. MRI or CT demonstrates ventricular dilatation, especially of the frontal horns, that is out of proportion to the amount of cortical sulcal widening. Radionuclide cisternography, once the diagnostic test of choice, is an unreliable predictor of treatment response and is unlikely to contribute to the
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diagnostic certainty beyond a good history, examination, and structural brain imaging. If hydrocephalus is a serious consideration, neurologic or neurosurgical consultation is recommended for several invasive tests that do have prognostic value, such as serial lumbar punctures, continuous CSF drainage, and continuous intracranial pressure monitoring. Approximately 30% to 40% of patients have improvement in cognitive function after shunt surgery [85,86]. The elderly, however, are susceptible to complications of shunt surgery, which occur in 30% to 40% of patients, with 6% to 8% having serious complications such as death or residual neurologic decits. Predictors of good response to shunting include a short history of mental decline, known cause of hydrocephalus (eg, subarachnoid hemorrhage or meningitis), predominant gait disorder, and clinical improvement after serial lumbar CSF taps or continuous drainage [86]. Summary The initial approach to the patient with memory complaints should consist of a focused history, mental status examination, and functional assessment. Patients with MCI should be monitored every 6 to 12 months for conversion to dementia. Delirium, depression, amnestic disorders, and aphasias should be considered in the dierential diagnosis of memory impairment. Once a diagnosis of dementia is made, patients should have a brain CT or MRI scan and laboratory tests to assist with determining the cause. It is crucial that dementia be recognized and evaluated at the earliest stage so as to begin appropriate therapy and allow the patient to have a role in management decisions. In the future, therapies for MCI may prevent conversion to dementia. The need for early recognition makes the development of diagnostic tools, such as quantitative or functional neuroimaging, and genetic or clinical biologic markers essential. References
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Med Clin N Am 86 (2002) 477499
Vascular dementia revisited: Diagnosis, pathogenesis, treatment, and prevention

Gustavo C. Roman, MD*
Department of Medicine/Neurology, University of Texas Health Science Center at San Antonio, and Audie L. Murphy Memorial Veterans Hospital, 7703 Floyd Curl Drive, San Antonio, TX 78284-7883, USA
Vascular dementia (VaD) is an etiologic category that includes clinical forms of dementia caused by ischemic or hemorrhagic cerebrovascular disease (CVD) or by ischemic-hypoxic brain lesions of cardiovascular origin [1,2]. VaD is the most common cause of dementia after Alzheimers disease (AD) [3]. Among other recent developments, the recognition of the adjuvant role of vascular factors in AD, the recent identication of genetic forms of VaD, and progress in the understanding of pathogenetic mechanisms as well as new possibilities of early diagnosis, treatment, and prevention, have made VaD one of the most controversial, challenging, and rapidly evolving areas in the eld of dementia.
History Thomas Willis rst described postapoplectic dementia in the seventeenth century [4]. In 1894, Otto Binswanger and Alois Alzheimer separated VaD from dementia paralytica (neurosyphilis), a common cause of dementia at that time, and identied at least four dierent clinicopathologic forms of VaD [5]. Based on their work, Kraepelin concluded in 1910 that arteriosclerotic insanity, also known as cerebral arteriosclerosis, was the most frequent form of senile dementia [4]. This unwarranted simplication of the complexity of the eld implied that progressive narrowing and blockage of large cerebral arteries led to decreased cerebral blood ow, neuronal death, brain atrophy, and dementia. This concept persisted until the late 1970s, when the importance of AD as the main cause of senile dementia was
* E-mail address: romang@uthscsa.edu (G.C. Roman). 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 8 - 1
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recognized. Concurrently, Tomlinson, Blessed, and Roth demonstrated that the loss of more than 50 to 100 mL of brain tissue from stroke resulted in dementia [6]; the term multi-infarct dementia (MID) was then coined for this condition [7]. Nevertheless, as described later in this article, VaD includes more than MID, because a single strategic stroke may also result in VaD. Likewise, with the advent of new-generation CT and MRI of the brain, the important role of ischemic-hypoxic white matter lesions in the pathogenesis of VaD has been recognized.
Pathogenesis VaD may be caused by a number of vascular lesions and pathogenetic mechanisms as listed in Table 1 [8]. Of particular importance in the elderly is small vessel disease, which causes lacunes and white matter ischemic lesions. These ischemic lesions may interrupt the recently described frontal
Table 1 Pathological lesions capable of producing vascular dementia 1. Multi-infarct dementia Multiple large complete infarcts, cortico-subcortical in location, usually with perifocal incomplete infarction involving the white matter 2. Strategic infarct dementia A single brain infarct, often lacunar in size, damages functionally critical areas of the brain (angular gyrus, thalamus, basal forebrain, posterior cerebral artery and anterior cerebral artery territories) 3. Small-vessel disease with dementia Subcortical Binswangers disease CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) Lacunar dementia or lacunar state (etat lacunaire) Multiple lacunes with extensive perifocal incomplete infarctions Cortical and subcortical Hypertensive and arteriolosclerotic angiopathy Amyloid angiopathies (including British dementia) Collagen-vascular disease with dementia 4. Ischemic-hypoxic dementia (hypoperfusive) Diuse anoxic-ischemic encephalopathy Restricted injury due to selective vulnerability Incomplete white-matter infarction Border-zone infarction 5. Hemorrhagic dementia Traumatic subdural hematoma Subarachnoid hemorrhage Cerebral hematoma Venous thrombosis 6. Other mechanisms Modied from Brun A. Pathology and pathophysiology of cerebrovascular dementia: pure subgroups of obstructive and hypoperfusive etiology. Dementia 1994;5:1457; with permission.
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cortical-subcortical circuits that underlie executive functions, motivation, and socially responsive behaviors [9,10]. There are ve parallel anatomic circuits that link regions of the frontal cortex to the striatum (caudate nucleus), globus pallidus/substantia nigra, and thalamus, with thalamocortical connections closing the loop [1115]. These frontal circuits originate in the supplementary motor area, frontal eye elds, dorsolateral prefrontal region, lateral orbitofrontal area, and anterior cingulate cortex [11,16,17]. The last three are the primary behaviorally relevant circuits [1215,18], as follows (Table 2): (1) interruption at any portion of the loop of the dorsolateral prefrontal subcortical circuit results in executive dysfunction, (2) orbitofrontal subcortical circuit lesions are manifested by disinhibited behaviors and obsessive-compulsive disorders, and (3) medial-frontal (anterior cingulate) cortex subcortical circuit lesions often result in apathy. Each segment of the circuit has dierent neurotransmitters, modulators, and receptor subtypes that may provide the basis for pharmacologic intervention [18]. Not surprisingly, executive dysfunction, apathy, mood changes, and uninhibited behaviors are frequently observed in patients with VaD [1922].
Table 2 Behavioral manifestations of subcortical vascular dementia caused by lesions interrupting prefrontal-subcortical circuits 1. Dorso-lateral prefrontal circuit lesions Lesions May include cortical strokes involving dorsolateral prefrontal cortex, infarctions at head of the caudate nucleus, lacunar lesions in putamen or thalamus, or ischemic white matter lesions involving loop segments, such as capsular genu lacunes Manifestations Executive dysfunction, poor word list generation and decreased verbal uency, impaired motor programming, perseveration, impersistence, and diculty with set shifting (loss of Lurias kinetic melody) 2. Orbito-frontal-subcortical circuit lesions Lesions May include anterior cerebral artery strokes involving lateral orbitofrontal cortical territories, or subcortical circuit lesions interrupting connections at the level of caudate, basal ganglia, thalamus or white matter loop links Manifestations Disinhibited behaviors, mania, and obsessive-compulsive disorder 3. Medial-frontal (cingulate) cortex-subcortical circuits Lesions May include anterior cerebral artery strokes involving medial frontal cortical territories, or subcortical circuit lesions interrupting connections at the level of caudate, basal ganglia, thalamus or white matter loop links Manifestations Apathy, slowing of information processing, mood changes, or vascular depression Modied from Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol 1993;50:87380; and Cummings JL. Anatomic and behavioral aspects of frontalsubcortical circuits. Ann NY Acad Sci 1995;769:113; with permission.
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Vascular and circulatory lesions In addition to acute ischemia from embolic and atherothrombotic large vessel occlusions, the elderly are also susceptible to ischemic lesions of small vessels, resulting in lacunes, cortical microinfarcts (granular atrophy), and ischemic periventricular leukoencephalopathy of the Binswanger type. Repeated episodes of brain ischemia from chronic hypoperfusion aect the deep white matter territories that are perfused by small vessels (medullary arterioles) [23]. Ageing produces tortuosity and elongation of these arterioles [2426], leading to dilatation of the perivascular spaces of Virchow . Robin [27] and etat crible Also, narrowing of the lumen is produced by senile arteriolosclerosis [28], diabetes, and hypertension. The end result of these morphologic changes is the loss of the normal autoregulation of cerebral blood ow [29] and hypoperfusion of gray matter and white matter [30]. For these reasons, orthostatic hypotension, cardiac arrhythmias, and congestive heart failure in the elderly increase the risk for the development of cognitive loss and eventual VaD [3133]. Other mechanisms responsible for VaD include cortical disconnection from ischemic white matter lesions [34], such as those present in Binswangers disease (BD) [21], and diaschisis. For instance, a single small thalamic stroke may cause extensive hypometabolism and decrease of blood ow in the frontal cortical territories and cerebellum as a result of diaschisis [3537]. The multiple mechanisms capable of producing VaD, and the syndromes resulting therein, represent a major challenge when formulating diagnostic criteria for VaD as well as for case ascertainment in epidemiologic studies and recruitment of subjects participating in controlled clinical trials.
Epidemiology AD and VaD are the most common causes of senile dementia, with VaD ranking second after AD [3,3840]. Cerebrovascular pathologic ndings and heart disease are common in the elderly, and their prevalences increase with age; as a result, histologic changes of AD in the elderly often coexist with stroke and vascular pathologic changes [41,42]. Somewhat more unexpected was the observation of the adjuvant role of cerebral infarction in AD [43], whereby elderly subjects with the presence of one or two lacunar strokes seem to require a lesser amount of senile plaques and neurobrillary tangles to manifest signs of dementia. Recently, Henon and her colleagues [44,45] demonstrated that careful questioning can separate patients with preexisting memory loss and probable AD from pure cases of poststroke VaD. About one third of poststroke VaD patients harbor this dual pathologic prole. These cases should be classied as AD plus CVD instead of the commonly used but incorrect
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denomination of mixed dementia. Henon et al [44] found a 16% prevalence of prestroke dementia in possible cases of poststroke dementia. Prevalence Jorm et al [40] performed a meta-analysis of 47 international studies on VaD prevalence and found that prevalence increases exponentially with age up to the age of 95 years. Prevalence rates double every 5.3 years compared with every 4.5 years for AD. Prevalence rates range from approximately 1.5 per 100 persons from the age of 70 to 75 years to 14 to 16 per 100 persons at the age 80 years and above. In Europe, VaD was more prevalent than AD in 85-year-olds in Italy and Gothenburg (Sweden) [46]. VaD seems to be more common in men in contrast to AD, which predominates in women. Also, VaD has a peculiar geographic (racial) variation, being more prevalent in Asian populations than in white populations. This is probably a result of the preponderance of small vessel disease in Oriental races. The prevalence of AD versus VaD tends to increase among ethnic Japanese who migrated to Hawaii, however, indicating environmental interaction on genetic susceptibility [47]. Incidence Incidence data for VaD from longitudinal cohort studies are rather limited. Jorm and Jolley [48] performed a meta-analysis of 11 studies of VaD with age-specic incidence data. More recently, Dubois and Herbert [49] used age-based standardized incidence ratios to analyze data from 10 incidence studies of VaD in comparison to the Canadian Study of Health and Aging. Age-based standardized incidence ratios ranged from 0.42 to 2.68, conrming the geographic variation of VaD. These variations may be a result of genetic, environmental, or methodologic dierences between studies. Poststroke dementia The most common form of VaD is probably poststroke dementia (also known as MID when dementia develops after multiple strokes). The incidence of poststroke dementia is relatively easy to ascertain when cognitive tests are performed after stroke (typically, at 3 months after ictus). There are methodologic variations that depend on the denition of dementia and test cutos used. In Helsinki [50], the gures ranged from 6% to 25.5%, whereas in New York City [51,52], poststroke dementia ranged between 27% and 41%. This means that in the United States alone, approximately 125,000 new cases of VaD after ischemic stroke occur every year (approximately one third of the estimated 360,000 incident cases of AD) [39,53]. Based on these gures, the prevalence of poststroke VaD would be above 1 million elderly people currently suering from poststroke VaD [53]. It should be noted, however, that most cases of poststroke VaD remain undiagnosed.
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Risk factors for vascular dementia One of the long-time paradoxes of VaD has been why it is that some patients develop dementia after a single stroke, whereas others seem to tolerate large or recurrent strokes without decline of intellectual function. Risk factor quantication in case-control studies of poststroke dementia have begun to provide an answer [54,55]. Pohjasvaara and colleagues [50] conrmed that the most important risk factors for poststroke VaD are older age, lower educational level, recurrent stroke, and left hemisphere stroke (associated with a vefold increase in the risk of developing poststroke dementia, an eect not explained by aphasia) as well as the presence of dysphagia, gait limitations, and urinary impairment. Demented patients were more often current smokers and had lower blood pressure and orthostatic hypotension. Larger periventricular white matter ischemic lesions as detected by MRI are also predictive of poststroke dementia [56,57]. Moroney et al [58] recently found that hypoxic and ischemic complications of acute stroke (eg, seizures, cardiac arrhythmias, aspiration pneumonia) are strong and independent risk factors for poststroke dementia, increasing more than fourfold the risk of developing poststroke dementia (odds ratio 4.3 and 95% condence interval: 1.99.6, after adjustment for demographic factors, recurrent stroke, and baseline cognitive function). Hypoxic and ischemic complications of acute stroke may result in border zone infarcts [59] but also cause Binswanger-type ischemic periventricular white matter lesions [60]. Orthostatic hypotension has been correlated with these lesions in a large population-based MRI study of elderly subjects [61]. Consequently, dementia is a predictor of poor outcome in patients with stroke [52].
Clinical forms of vascular dementia Roman [62] has simplied the clinical syndromes of VaD into two main groups, acute and subacute, according to the temporal prole of clinical presentation. Acute-onset vascular dementia This group includes patients with new-onset dementia after a clinically eloquent acute ischemic event as a single strategic stroke resulting from occlusion (or rupture) of a large-sized vessel, from recurrent strokes (MID), or after a symptomatic lacunar stroke caused by small vessel disease. Poststroke multi-infarct dementia The risk factors for poststroke MID have been presented and are summarized in Table 3.
G.C. Roman / Med Clin N Am 86 (2002) 477499 Table 3 Principal risk factors for poststroke vascular dementia 1. 2. 3. 4. 5. 6.
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Age: older age Education: lower educational level Personal factors: lower-income, current smokers Genetic factors: family history of dementia Stroke type: recurrent strokes Stroke location: left-sided lesions, strategic strokes (ie, posterior association areas such as gyrus angularis; posterior cerebral artery territories including paramedian thalamic artery territory, inferomedial temporal lobes, and hippocampus; watershed or border-zone infarcts mainly involving superior frontal and parietal regions; bilateral anterior cerebral artery territories, anterior choroidal artery strokes, and basal forebrain lesions; and frontal white matter lesions); inferior capsular genu stroke producing diaschisis of frontal lobes and cerebellum 7. Stroke volume: lesions larger than 50100 ml of tissue destruction, larger peri-lesional incomplete ischemic areas involving white matter, larger periventricular white matter ischemic lesions 8. Stroke complications: hypoxic and ischemic complications of acute stroke (ie, seizures, cardiac arrhythmias, aspiration pneumonia, hypotension) 9. Stroke manifestations: dysphagia, gait limitations, urinary impairment
Dementia caused by a single cortical-subcortical infarction A single large vessel stroke in the following locations may produce VaD: 1. Posterior cerebral artery territory involving the ventral-medial temporal lobe, hippocampus, occipital structures, and thalamus and presenting with anterograde amnesia, aphasia, visuospatial difculties, or constructional apraxia [63]. 2. Infarction in the anterior cerebral artery territory and medial-frontal lobe lesions, often from an anterior communicating artery aneurysm rupture [64]. 3. Infarctions of the left angular gyrus presenting with right-to-left disorientation, nger agnosia, acalculia, dysgraphia, aphasia, and constructional difculties and on the right side with hemispatial neglect and visuospatial or visuoconstructive disturbances [65]. 4. Bilateral involvement of the basal ganglia and thalamus. This is the socalled thalamic dementia of vascular origin [66] caused by butteryshaped bilateral paramedian thalamic polar infarcts [66,67]. Some cases of caudate stroke may also result in VaD [68]. Dementia from capsular genu infarction In 1992, Tatemichi and his colleagues [69,70] called attention to this characteristicalthough relatively uncommonsyndrome manifested by sudden change in cognitive function and often associated with uctuating attention, memory loss, confusion, abulia, striking psychomotor retardation, inattention, and other features of frontal lobe dysfunction but with mild focal ndings, such as hemiparesis or dysarthria. The usual cause is a lacune involving
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the inferior genu of the internal capsule, causing ipsilateral blood ow reduction to the inferomedial-frontal cortex by a mechanism of diaschisis [71]. This is considered a thalamocortical disconnection syndrome [69]. An unusual case of subcortical dementia resulting from a giant lacune with a unilateral left-sided mammillothalamic tract lesion has been recently reported [72]. Subacute (subcortical) vascular dementia The temporal prole of presentation of these forms of VaD is typically subacute, with a chronic course marked by uctuations and progressive worsening. This group is characterized clinically by a subcortical dementia (subcortical VaD) with frontal lobe decits, executive dysfunction, slow information processing, impaired memory, inattention, depressive mood changes, motor involvement, parkinsonian features, urinary disturbances, and pseudobulbar palsy. As mentioned previously, this is one of the most common forms of VaD and results from small vessel disease with lacunes and white matter lesions that damage structures (caudate nucleus, globus pallidus, thalamus, and connecting bers) of the prefrontal subcortical circuits [22]. The main forms of subacute subcortical VaD are lacunar state (etat lacunaire), BD, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), and some forms of cerebral amyloid angiopathy (CAA). Diagnostic criteria for subcortical VaD have been proposed recently [73]. Lacunar state (etat lacunaire) In 1901, Pierre Marie [74] described this clinical syndrome in the elderly, emphasizing the presence of multiple lacunes in the basal ganglia, pons, and white matter. In addition to lacunes, ventricular dilatation and Binswangertype lesions of the white matter caused by recurrent ischemia-hypoxia frequently coexist. The latter are also called leukoaraiosis (Greek for white rarefaction) [75]. Senile dementia of the Binswanger type In 1894, Binswanger [76] described as the hallmark of this condition the presence of an ischemic periventricular leukoencephalopathy that typically spares the arcuate subcortical U bers [21]. Small vessel disease and multiple lacunes often coexist in BD, and it has been postulated that this condition and the so-called lacunar dementia of patients with a lacunar state may represent a single entity [77]. Their clinical manifestations are similar, [21,7679] and are discussed jointly. A lacunar state and BD produce a cognitive and motor syndrome with characteristics of subcortical dementia, including executive dysfunction, loss of verbal uency, slowing of motor function with perseveration, impersistence, inattention, diculties with set shifting, and abnormal Lurias kinetic melody test results [12,13,1721,7880]. Memory loss is characterized by
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poor retrieval and intact recognition. Apathy, depression, and behavioral problems are common. Mild residual hemiparesis or other discrete focal ` ndings are often found as well as a peculiar short-stepped gait (marche a petits pas), dysarthria, pseudobulbar palsy, and, in some cases, astasia-abasia. Extrapyramidal features, such as inexpressive facies, slowness of movement, axial rigidity, loss of postural reexes, frequent falls, increased urinary frequency, and nocturia are also common ndings [80,81]. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy One of the most important recent developments in the eld of VaD has been the clinical and genetic description of CADASIL [8284]. Originally called familial BD [85], this condition oers a natural model for the study of subcortical subacute forms of VaD, particularly BD. Numerous pedigrees have been described in Europe and North America [82,84,86,87]. CADASIL is an autosomal dominant disorder of cerebral small vessels mapped to chromosome 19q12 [83]. Clinical manifestations include transient ischemic attacks and strokes (80%), cognitive decits and VaD (50%), migraine with focal decits (40%), mood disorders (30%), and epilepsy (10%). Onset is usually in early adulthood (mean age of 46 years) [87] in the absence of risk factors for vascular disease, culminating in dementia and death usually approximately 20 years after the onset of symptoms [82,84,87]. The dementia is slow in onset, subcortical, frontal in type, and accompanied by gait and urinary disturbances and pseudobulbar palsy clinically identical to that of sporadic BD. MRI reveals a combination of small lacunar lesions and diuse white matter abnormalities; these are often present in asymptomatic relatives [88]. Also, cerebral blood ow reactivity to inhaled carbon dioxide is impaired. The underlying vascular lesion is a unique nonamyloid and nonatherosclerotic microangiopathy involving arterioles (100400 lm in diameter) and capillaries, primarily in the brain but also in other organs. The diagnosis may be established by skin biopsy [89] and conrmed by immunostaining with a Notch3 monoclonal antibody [90]. The vessels show deposits of eosinophilic periodic acidSchi-positive material in the arterial media that consists of granular osmiophilic deposits and accumulation of the ectodomain of the Notch3 receptor in the basal lamina of degenerated smooth muscle cells on electron microscopy. The brain lesions are ischemic infarcts, mainly lacunar strokes, localized in the basal ganglia, thalamus, centrum ovale, and pons, and are associated with extensive conuent areas of frontal ischemic leukoencephalopathy, particularly in periventricular regions. The disease is caused by highly stereotyped mutations in the Notch3 gene, which encodes a phylogenetically old transmembrane cell surface receptor that regulates cell fate during embryonic development. The large extracellular domain of Notch3 contains 34 tandem epidermal growth factorlike repeats, where the mutations result in gain or loss of a cysteine residue [91].
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Cerebral amyloid angiopathy This is a heterogeneous group of disorders characterized by deposition of amyloid in the walls of leptomeningeal and cerebral cortical blood vessels and demonstrated clinically by recurrent or multiple lobar hemorrhages, cognitive deterioration, and ischemic strokes. MRI displays diuse white matter abnormalities along with ischemic or hemorrhagic focal brain lesions. On histologic examination, the vessels show amyloid deposition, microaneurysms, and brinoid necrosis. There are several autosomal dominant forms of CAA with dierences in their clinical, genetic, biochemical, and pathologic ndings. Amyloid b, the major amyloid component in the Dutch, Flemish, and Iowa type of familial CAA, is also the major amyloid component in sporadic CAA and AD. Familial British dementia with amyloid angiopathy (FBD) is an autosomal dominant condition characterized by VaD, progressive spastic paraparesis, and cerebellar ataxia with onset in the sixth decade [92]. A point mutation in the BRI gene has been shown to be the genetic abnormality. On brain MRI, Binswanger-type deep white matter hyperintensities and lacunar infarcts are seen, but no intracerebral hemorrhages are apparent. The corpus callosum is severely aected and atrophic plaques and tangles are present, but the amyloid subunit found in FBD brains is entirely dierent and unrelated to other amyloid proteins. FBD combines neurodegeneration and dementia with systemic amyloid deposition [93].
Diagnosis of vascular dementia Although a number of diagnostic criteria for VaD have been proposed, the National Institute of Neurologic Disorders and Stroke-Association Internationale pour la Recherche et lEnseignement en Neurosciences (NINDS-AIREN) criteria [94] (Table 4) oer an operative approach to the three basic elements needed to reach a diagnosis of VaD: cognitive loss, frequently a subcortical form of dementia; cerebrovascular lesions demonstrated by brain imaging (CT, MRI); and exclusion of other causes of dementia, such as AD. These criteria also require a logical link between the vascular lesions and the dementia. A temporal relation (ie, development of dementia within 3 months after stroke) has proven to be more dicult to fulll, particularly in patients with silent strokes. The NINDS-AIREN criteria require objective proof of dementia validated by neuropsychologic tests. In practical terms, internists usually have suspected patients perform a Mini-Mental State Examination (MMSE) [95]. This test is more suitable for patients with cortical forms of dementia, particularly AD. VaD requires the use of tests for subcortical dysfunction, including executive function testing [22]. Some of the bedside tests available include clock drawing [96], the Trail Making Test Part B [97], and the Behavioral Dyscontrol Scale [98] based on Lurias kinetic melody.
G.C. Roman / Med Clin N Am 86 (2002) 477499 Table 4 NINDS-AIREN diagnostic criteria for vascular dementia
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I. The criteria for the diagnosis of probable VaD include all of the following: 1. Dementia: Impairment of memory and two or more cognitive domains (including executive function), interfering with ADLs and not due to physical eects of stroke alone. Exclusion criteria: Alterations of consciousness, delirium, psychoses, severe aphasia or decits precluding testing, systemic disorders, Alzheimers disease, or other forms of dementia. 2. Cerebrovascular disease: Focal signs on neurological examination (hemiparesis, lower facial weakness, Babinski sign, sensory decit, hemianopia, dysarthria) consistent with stroke (with or without history of stroke, and evidence of relevant CVD by brain CT or MRI including multiple large-vessel infarcts or a single strategically placed infarct (angular gyrus, thalamus, basal forebrain, or PCA or ACA territories), as well as multiple basal ganglia and while matter lacunes or extensive periventricular white matter lesions, or combinations thereof. Exclusion criteria: Absence of cerebrovascular lesions on CT or MRI. 3. A relationship between the above two disorders is manifested or inferred by the presence of one or more of the following: A. Onset of dementia within 3 months following a recognized stroke. B. Abrupt deterioration in cognitive functions or uctuating, stepwise progression of cognitive decits. II. Clinical features consistent with the diagnosis of probable VaD include the following: ` 1. Early presence of gait disturbances (small step gait or marche a petits pas, or magnetic, apraxic-ataxic or parkinsonian gait). 2. History of unsteadiness and frequent, unprovoked falls. 3. Early urinary frequency, urgency, and other urinary symptoms not explained by urologic disease. 4. Pseudobulbar palsy. 5. Personality and mood changes, abulia, depression, emotional incontinence, or other decits including psychomotor retardation and abnormal executive function. III. Features that make the diagnosis of VaD uncertain or unlikely include: 1. Early onset of memory decit and progressive worsening of memory and other cognitive functions such as language (transcortical sensory aphasia), motor skills (apraxia), and perception (agnosia), in the absence of corresponding focal lesions on brain imaging. 2. Absence of focal neurological signs, other than cognitive disturbances. 3. Absence of CVD on CT or MRI. Abbreviations: ACA, anterior cerebral artery; ADLs, activities of daily living; CT, computerized tomography; CVD, cerebrovascular disease; MRI, magnetic resonance imaging; PCA, posterior cerebral artery; VaD; vascular dementia. From Roman GC, Tatemichi TK, Erkinjuntti T, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDS-AIREN International Workshop. Neurology 1993;43: 25060; with permission.
Demonstration of the presence of vascular lesions by brain MRI or CT is required. Lesions range from a single strategic lacunar stroke, to multiple cortical-subcortical strokes, to periventricular ischemia. Mungas et al [99] determined by MRI that hippocampal atrophy, volume of cortical gray matter, and volume of white matter lesions (but not lacunes) were strong and independent predictors of vascular cognitive impairment. The neuropathologic substrate of these lesions in patients with VaD seems to be widespread ischemia from microvascular disease, including ischemic hippocampal injury
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pathologically resembling mesial temporal lobe sclerosis [100]. By denition, absence of vascular lesions by brain imaging excludes VaD. Inclusion and exclusion criteria as well as stratication into levels of diagnostic certainty are also provided in Table 4. Chui [39] has recently reviewed other available diagnostic criteria for VaD. The dierent criteria are not interchangeable, and the criteria for subcortical VaD are yet to be validated. Separating Alzheimers disease from vascular dementia A practical problem that frequently confronts the internist is the elderly patient with cognitive and behavioral disturbances presenting with an abnormal MMSE and the presence of vascular lesions on brain imaging. Does the patient have MID, AD plus CVD, or simply AD? The ischemic score (Table 5) may provide additional elements for the diagnosis of the MID form of VaD [101]. A score greater than or equal to 7 is consistent with MID, a score less than or equal to 4 is consistent with AD, and a score of 5 to 6 is suggestive of AD plus CVD. In a recent metaanalysis [101], the following features were found more often in VaD than in AD: stepwise deterioration, uctuating course, history of hypertension, history of stroke, and focal neurologic symptoms. As discussed previously, it is possible to successfully diagnose prestroke dementia by means of a careful interview of relatives and caregivers [45]. In most instances, probable AD is a likely etiology for the progressive memory loss occurring before the ictus. Another related method is the application of the concept of mild cognitive impairment [102]. The amnestic form of MCI is easily identiable and carries a risk of conversion to clinically probable AD at a rate of 10% to 15% per year compared with 1% to 2% per year in healthy age-matched
Table 5 Items of the ischemic score Item Abrupt onset Stepwise deterioration Fluctuating course Nocturnal confusion Preservation of personality Depression Somatic complaints Emotional incontinence History of hypertension History of stroke Associated atherosclerosis Focal neurological symptoms Focal neurological signs Score (total: 18) 2 1 2 1 1 1 1 1 1 2 1 2 2
Modied from Hachinski VC, Zilhka E, DuBoulay GH, McAllister VL, Marshall J. Cerebral blood ow in dementia. Arch Neurol 1975;32:6327; with permission.
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control subjects. The frequency and severity of CVD in older patients with AD point to the possibility that vascular risk factors may predispose not only to VaD but to the development of AD [103]. Population-based epidemiologic data [104,105] have shown that vascular risk factors, such as hypertension, carotid artery wall thickness, cholesterol, and peripheral vascular disease, often occur in patients who develop AD. The vascular role of the apolipoprotein E e4 allele [105,106], a risk factor for AD, may partially explain this interaction. Treatment and prevention Secondary prevention Patients with VaD have higher morbidity and mortality than age-matched control subjects and patients with AD [52]. Coronary artery disease and recurrent strokes are among the common complications in these patients. Secondary prevention of recurrent stroke must be undertaken in patients with poststroke VaD. Although age, gender, ethnicity, and genetic factors are nonmodiable stroke risk factors, there is clear class I evidence that treatment of hypertension reduces the risk of recurrent stroke by 28% [107]. Likewise, the use of statins to decrease low-density lipoprotein cholesterol by 25% reduces stroke risk up to 30% [108]. Antiplatelet medications reduce the risk of recurrent stroke by 17% with aspirin and 25% with ticlopidine. Clopidogrel is a safe and eective alternative to ticlopidine but is not superior to aspirin; dipyridamole in combination with aspirin seems to be superior to aspirin alone [109]. Anticoagulation with warfarin [International Normalized Ratio (INR): 23] in patients with atrial brillation is highly ecacious in preventing recurrent stroke (approximately 70% risk reduction) [110]. For patients with more than 75% carotid artery stenosis, surgery reduces recurrent stroke by 51% [111]. Primary prevention Of signicant public health interest are the observations that the treatment of hypertension [112115] and the use of statins [116119] have been associated with decreased incidence of dementia in the elderly. Other risk factors Treatment of other risk factors for subcortical VaD is also indicated; these risk factors include smoking, hyperbrinogenemia, orthostatic hypotension, cardiac arrhythmias, congestive heart failure [32,33,120], and obstructive sleep apnea [121]. Not infrequently, nocturnal hypertension (nondippers), a risk factor for Binswanger-type VaD, frequently occurs in patients with obstructive sleep apnea. Finally, control of hemorheologic factors that increase blood viscosity becomes important in subjects with small vessel
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disease and disturbances of the microcirculation. Blood glucose control in patients with diabetes and lowering of brinogen and lipids should be benecial. In patients with hyperhomocystinemia, the use of oral folate is recommended. Increased homocysteine levels may have a role in the pathogenesis of CADASIL [122]. Drug treatments for vascular dementia A large number of medications of purported ecacy for VaD have been available for many years [123]. These drugs responded to prevailing notions about pathogenesis, however, and have been found to be ineective. For instance, vasodilators (nicotinic acid, cyclandelate, papaverine, isoxsuprine, cinnarizine, buomedil, naftidrofuryl, and ergoloid mesylates among others) were widely used to counteract hardening of the arteries. As pointed out by Cochrane [124], their alleged ecacy was based on open-label trials that lacked masking, controls, randomization, clear inclusion and exclusion criteria, and appropriate outcome measures and endpoints. A comprehensive review by Roman [125] of pharmacologic agents for VaD is available elsewhere. Here, only those agents with demonstrated ecacy in randomized controlled clinical trials (class I evidence) are presented. Calcium channel blockers Nimodipine (Nimotop) and nicardipine have demonstrated moderate ecacy in tests of attention and psychomotor performance in the subcortical (small vessel) form of VaD [126,127]. These agents have eects on autoregulation of cerebral blood ow and block L-type calcium receptors, providing some degree of neuroprotection. Neuroprotective (Nootropic) agents Piracetam [128], oxiracetam [129], and nicergoline [130] seem to be safe and modestly eective in the MID form of VaD as well as in elderly hypertensive patients with leukoaraiosis [131]. Citicoline has been shown to have positive short-term eects on memory and behavior in patients with VaD [132,133]. Citicoline activates the biosynthesis of structural phospholipids in the neuronal membranes, increases cerebral metabolism, and increases noradrenaline and dopamine levels in the central nervous system [134]. Memantine This agent is a potent noncompetitive antagonist of the N-methyl-Daspartate receptor with nootropic properties [135]. Memantine has been shown to be well tolerated and useful in severe dementia [136]. A recently completed pivotal 28-week trial of memantine in patients with mild to moderate VaD enrolled 321 patients who received 2 10 mg/d or placebo. The study demonstrated good tolerance and improvement in cognitive tests, including the Alzheimers Disease Assessment ScaleCognitive Subscale (ADAS-Cog) and MMSE [137].
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Pentoxifylline (Trental) This is a xanthine derivative with hemorheologic and immunomodulatory properties [138]. The multicenter European Pentoxifylline Multi-infarct Dementia Study demonstrated signicant cognitive improvement in the MID form of VaD in comparison with placebo [139]; these ndings conrmed previous results [140]. Recently, Solerte et al [141] described hemorheologic alterations in patients with AD but not in age-matched controls or in patients with VaD. Abnormalities included hyperviscosity, increased sedimentation rate, hyperbrinogenemia, and increased acute-phase reactants; these changes were correlated with increased levels of tumor necrosis factor-a and interferon-c. Pentoxifylline treatment lowered brinogen and tumor necrosis factor-a levels and corrected these abnormalities. Antiplatelet agents Aspirin [142], triusal [143], and Ginkgo biloba [144] have been used in patients with MID or with AD plus CVD with modest positive results. It should be noted that the MMSE was the primary endpoint for cognitive evaluation in most of these patients. Cholinesterase inhibitors The encouraging results obtained with the use of cholinergic agents in VaD may give some clinicians the mistaken impression that VaD is really AD or, at best, a mixed dementia [145]. It seems clear that (at least in the oldest patients) both vascular and degenerative mechanisms contribute to AD dementia [146]. This overlap occurs, however, only in one third of patients diagnosed with VaD [147]. Sometimes, such as in the case of an anterior choroidal artery occlusion, the patients fulll the criteria for AD [148]. Cholinergic drugs are eective in VaD because these patients have cholinergic decits related to ischemic involvement of basal forebrain neurons (nucleus basalis of Meynert) or their projections. Wallin et al [149] found pronounced disturbances of the serotoninergic and cholinergic systems in subcortical and cortical gray matter at postmortem brain examination of patients with VaD. These widespread neurotransmitter decits probably are not caused by localized brain infarcts per se. Likewise, Tohgi et al [150] found acetylcholine concentrations in the cerebrospinal uid of patients with BD and MID to be signicantly lower than in controls, whereas choline concentrations were higher than in controls or AD patients. Recently, using postmortem brain tissue materials, Martin-Ruiz et al [151] demonstrated the relative integrity of nicotinic receptors in denite cases of VaD. Nicotinic receptors control cerebral vasodilatation. Of the available cholinergic agents approved for the treatment of AD, donepezil hydrochloride (Aricept), rivastigmine tartrate (Exelon), and galantamine hydrobromide (Reminyl) have been used in patients with VaD. A large, 24-week, multicenter, randomized, placebo-controlled international trial of donepezil in VaD has been completed recently [152]. The trial
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randomized 1219 subjects with mild to moderate VaD selected according to the NINDS-AIREN criteria. Patients were randomized to placebo (n 330), to low-dose donepezil at 5 mg/d (n 329), or to high-dose donepezil at 10 mg/d (n 310). Compared with placebo, signicant improvement was noted on the ADAS-Cog and MMSE cognitive tests, with benecial eects on activities of daily living and global scores. Patients on the 5-mg/d dose tolerated the drug better than those on the high dose of 10 mg/d. Rivastigmine tartrate was evaluated in patients with mild to moderately severe AD with or without concurrent vascular risk factors [153]. Patients were randomized to placebo (n 235), low-dose rivastigmine (14 mg/d, n 233), or high-dose rivastigmine (612 mg/d, n 231) for 26 weeks. Signicant improvement was found on the ADAS-Cog and MMSE in patients treated with high-dose rivastigmine compared with controls treated with placebo. Rivastigmine has also been found to be eective and safe in a study of 16 patients with subcortical VaD [154]. Galantamine is also being tested in a large, multicenter, controlled clinical trial of patients with VaD identied by NINDS-AIREN criteria [155]. The results of the trial are awaited with interest. Other agents Atypical antipsychotic drugs, such as risperidone and olanzapine, have been useful in the treatment of agitation and disruptive behaviors. The use of cholinergic medications often controls these problems. For some patients with depression and anxiety, the use of antidepressants, such as the selective serotonin reuptake inhibitors citalopram or sertraline, may be required. The use of tricyclic antidepressants in the elderly patient with VaD is discouraged because of anticholinergic eects and orthostatic hypotension.
Summary VaD is the second most common cause of dementia in the elderly after AD. VaD is dened as the loss of cognitive function resulting from ischemic, ischemic-hypoxic, or hemorrhagic brain lesions as a result of CVD and cardiovascular pathologic changes. Diagnosis requires (1) cognitive loss (often predominantly subcortical), (2) vascular brain lesions demonstrated by imaging, and (3) exclusion of other causes of dementia, such as AD. VaD is excluded by brain imaging showing no evidence of vascular lesions. VaD may be caused by multiple strokes (MID or poststroke dementia) but also by single strategic strokes, multiple lacunes, and hypoperfusive lesions such as border zone infarcts and ischemic periventricular leukoencephalopathy (Binswangers disease). Primary and secondary prevention of stroke and cardiovascular disease decreases the burden of VaD. Genetic advice is needed in patients with familial forms, such as CADASIL. Treatment
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involves control of risk factors (ie, hypertension, diabetes, smoking, hyperbrinogenemia, hyperhomocystinemia, orthostatic hypotension, cardiac arrhythmias). Anticholinergic medications used for AD are also useful in VaD, and atypical antipsychotic agents and antidepressants (eg, selective serotonin reuptake inhibitors) may be required in some patients.
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[141] Solerte SB, Ceresini G, Ferrari E, Fioravanti M. Hemorheological changes and overproduction of cytokines from immune cells in mild to moderate dementia of the Alzheimers type: adverse eects on cerebromicrovascular system. Neurobiol Aging 2000; 21:27181. [142] Williams PS, Spector A, Orrell M, Rands G. Aspirin for vascular dementia. Cochrane Database Syst Rev 2000;2:CD001296. [143] Lopez-Pousa S, Mercadal-Dalmau J, Marti-Cuadros AM, et al. Triusal in the prevention of vascular dementia [in French]. Rev Neurol (Barcelona) 1997;25146:15258. [144] Oken BS, Storzbach DM, Kaye JA. The ecacy of Ginkgo biloba on cognitive function in Alzheimer disease. Arch Neurol 1998;55:140915. [145] Gorelick PB, Nyenhuis DL, Garron DC, Cochran E. Is vascular dementia really Alzheimers disease or mixed dementia? Neuroepidemiology 1996;15:28690. [146] Aguero-Torres H, Winblad B. Alzheimers disease and vascular dementia. Some points of conuence. Ann NY Acad Sci 2000;903:54752. [147] Kalaria RN, Ballard C. Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord 1999;13(Suppl 3):S11523. [148] Sarangi S, San Pedro EC, Mountz JM. Anterior choroidal artery infarction presenting as a progressive cognitive decit. Clin Nucl Med 2000;25:18790. [149] Wallin A, Alafuzo I, Carlsson A, et al. Neurotransmitter decits in a non-multi-infarct category of vascular dementia. Acta Neurol Scand 1989;79:397406. [150] Tohgi H, Abe T, Kimura M, et al. Cerebrospinal uid acetylcholine and choline in vascular dementia of Binswanger and multiple small infarct types as compared with Alzheimer-type dementia. J Neural Transm 1996;103:121120. [151] Martin-Ruiz C, Court J, Lee M, et al. Nicotinic receptors in dementia of Alzheimer, Lewy body and vascular types. Acta Neurol Scand 2000;176(Suppl):S3441. [152] Pratt RD, Perdomo CA. Results of clinical studies with donepezil in vascular dementia. Am J Geriatr Psychiatry 2002;10(Suppl 1):889. [153] Kumar V, Anand R, Messina J, et al. An ecacy and safety analysis of Exelon in Alzheimers disease patients with concurrent vascular risk factors. Eur J Neurol 2000;7: 15969. [154] Moretti R, Torre P, Antonello RM, Cazzato G. Rivastigmine in subcortical vascular dementia: a comparison trial on ecacy and tolerability for 12 months follow-up. Eur J Neurol 2001;8:3612. [155] Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damarajn CR. Ecacy of galantamine in probable vascular dementia and Alzheimers disease combined with cerebrovascular disease: a randomized trial. Lancet 2002;359:128390.
Med Clin N Am 86 (2002) 501518
Frontotemporal dementia
Andrew Kertesz, MD, FRCPCa,*, David G. Munoz, MD, FRCPCb,c
Department of Clinical Neurological Sciences, St. Josephs Hospital, University of Western Ontario, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada b Department of Pathology and Clinical Neurological Sciences, University of Western Ontario, London, Ontario, Canada c Banco de Tejidos para Investigacion Neurologica, Universidad Autonoma, Madrid, Spain
a
Frontotemporal dementia (FTD) is a new name for clinical Picks disease (PiD). The eponymic PiD has been increasingly restricted to the pathologic variant with Pick bodies. The clinical picture of frontal lobe dementia (FLD) or, as later renamed, FTD, has been described with emphasis on the personality and behavioral changes [13]. The Lund and Manchester Groups [4] described the core symptoms as personality change, apathy, blunting of emotions, lack of insight, and disinhibition. The pathologic prole was characterized by gliosis, neuronal loss, and spongiform degeneration in a supercial area of the frontal and temporal cortex [5]. Similar cases were described as dementia lacking distinctive histology (DLDH) [6]. Less than 25% of the patients with this syndrome had Pick bodies [5]. Neuropsychologic testing showed poor performance on tests of mental exibility and executive function. Nevertheless, most clinicians make the diagnosis on the basis of the striking behavioral and personality changes, neuroimaging evidence of often asymmetric frontal and temporal atrophy, or decreased activity on isotope single photon emission CT [3,7]. At the same time, when dementia of the frontal lobe type was described as a behavioral and personality disorder, cases of primary progressive aphasia (PPA) were distinguished as a unique entity [8]. Subsequently, it was recognized that PPA is related to FTD, and it was also suggested that corticobasal degeneration (CBD) belongs to this group of various overlapping clinical presentations and underlying pathologic ndings called Pick complex [9]. Later, a consensus meeting agreed that PPA and semantic dementia
* Corresponding author. E-mail address: andrew.kertesz@sjhc.london.on.ca (A. Kertesz). 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 1 1 - 1
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A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518
should be part of the frontotemporal lobar degenerations [2]. It was recognized that FTD or Pick complex could have a number of pathologic substrates, including PiD, CBD, and motor neuron type inclusions [10,11]. The recent discovery of autosomal dominant inherited chromosome 17 linked FTD with parkinsonism (FTDP-17) and subsequent description of tau mutations in several families with this linkage created considerable interest [12,13]. The phenotypic and pathologic variations of these mutations closely match sporadic disease and provide powerful evidence for the cohesion of the complex. FTD is still underdiagnosed and underestimated, partly because the individual components of the complex are considered separately or considered heterogeneous, a favorite and sometimes misleading adjective in many descriptions. In this review, the considerable overlap is emphasized in addition to the distinctive features.
Picks disease Arnold Pick [14] described behavioral and aphasic symptoms associated with frontotemporal atrophy more than 100 years ago. Several of his subsequent articles dealt with progressive aphasia and progressive apraxia on the basis of focal atrophy. Picks initial cases only had gross examination without any microscopic data, but the clinical pattern and its relation to focal atrophy are the basis of the syndrome. Gans [15] suggested the eponymic term and considered a predilection for the phylogenetically younger frontal and temporal lobes in the etiology. Subsequently, PiD was dened on the basis of histology as initially described by Alzheimer [16]. Onari and Spatz [17] re-examined the cases of Pick and cases from others emphasizing Pick bodies and Pick cells (large ballooned neurons). Later, it became apparent that cases of clinical PiD with frontal lobe and temporal lobe symptomatology often do not show this typical histologic picture on autopsy [1820]. Most series of PiD were based on postmortem examination, and the clinical features were often incompletely described because of the retrospective nature of these studies. A dichotomy of nosology arose, because some people use the term Picks disease on the basis of histologic criteria, whereas others describe the clinical picture of focal atrophies as Pick did originally. This gave rise to the notion that PiD is dicult to diagnose in vivo. Many of the clinical descriptions had dramatic frontal lobe decits. Schneider [21,22] described several stages of PiD: rst, a disturbance of judgement and asocial behaviour, followed by aphasia and, later, by more generalized dementia. The temporal lobe variety of PiD presenting with progressive aphasia was described quite early [14,18,2326], and these descriptions are similar to those of PPA appearing later. Caron [27], in his review of PiD, stated that the most common form is characterized by early development of aphasia, and others also emphasized early speech disturbance or aphasia in PiD [2830].
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There have been several case descriptions of PiD in which the patients had prominent extrapyramidal features [19,24,31,32]. Ferraro and Jervis [33] stated that extrapyramidal symptoms were common in PiD. Sometimes, unilateral rigidity and parkinsonism were the rst symptoms to attract attention. It was recognized that subcortical changes occur in PiD even without extrapyramidal symptomatology [19]. Constantinidis et al [20] described extrapyramidal involvement particularly in group B patients, and Mann et al [34] described extrapyramidal involvement in 8 of 12 of FLD patients. Changes in the basal ganglia, especially in the striatum and substantia nigra in addition to cortical pathologic changes, occurred in most of 30 cases in one review [35]. Many of the subcortical varieties of PiD are similar to corticonigral and CBD clinically and pathologically. Munoz-Garcia and Ludwin [36] dierentiated the generalized variety of PiD from the cortical variety because of the subcortical extent of the pathologic ndings. The clinical description of these patients is quite similar to the description of the cortical variety of PiD. None of these patients had prominent extrapyramidal symptoms, but some had features of the Kluver Bucy syndrome [37]. The relatively early age of patients has been observed by authors describing the subcortical or generalized varieties of PiD [19,36,38]. PiD generally has a presenile onset below the age of 65 years in contrast to the age at onset of most AD patients. In addition, familial cases tend to have an even earlier onset. It was recognized that the disease sometimes occurred in families [39]. More than half of autopsy-diagnosed cases of PiD were familial [40]. A large family with PiD, where 25 of 51 examined members were aected [41] with a mostly behavioral presentation, was subsequently found to have a genetic linkage to chromosome 17 [42]. Several other families were described with various tau mutations with classic PiD pathologic ndings [4346]. There were larger series of PiD described in the literature in the early 1950s from Europe [4750]. Frontotemporal atrophy was the most common form of the disease (54%). Frontal atrophy only occurred in 25% of cases, and temporal atrophy only occurred in 17% of cases. The brunt of the atrophy was most often in the medial orbital, the inferior frontal gyri, and the anterior third of the superior temporal gyrus. More than half of the cases showed atrophy on the left side more than on the right side, and in 20% of the cases, right frontal atrophy was more prominent than left frontal atrophy. Constantinidis et al [20] classied PiD as (1) with Pick bodies, (2) only with swollen neurons, and (3) only gliosis. They believed that in spite of the dissimilarities between these forms, considering the absence of sucient knowledge about pathogenesis, it seems prudent at present to maintain the uniqueness of Picks entity [20]. They thought the clinical dierences between these forms were not related to the nature of histologic alterations but rather to the temporal lobe or frontal predominance of the abnormality. With the development of neuroimaging, frontotemporal lobe atrophy was demonstrated with increasing frequency in vivo, rst, with air studies;
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then, with CT scans in the 1970s; and more recently, with MRI and single photon emission CT scans. The in vivo diagnosis of PiD continued to be made sporadically on the basis of frontal and temporal symptomatology supported by the focal atrophy on imaging and a normal electroencephalogram [51]. Instead of shifting the diagnosis of PiD back to the clinic, however, the in vivo studies applied new labels, such as FLD, FTD, and PPA, to clinical PiD, while reserving the diagnosis of PiD to increasingly restricted histologic criteria. The pathologic denition of PiD, as dened by pathologists, is characterized as round argyrophilic inclusions in the neuronal cytoplasm called Pick bodies. They are best demonstrated with traditional silver stains, such as Bodian or Bielchowsky stain, but do not stain with the Gallyas method [11]. There is variable labeling with tau antibodies, ubiquitin, and chromogranin A. Electron microscopy has revealed bodies made up of 15-nm straight brils [36,52] and long-period twisted brils [53]. Neocortical Pick bodies are preferentially located in small neurons, and they are pathognomonic in the dentate gyrus [53], whereas traditional silver stains and tau antibodies identify scattered Pick bodies in the neocortex in CBD as well [54]. Large ballooned neurons (Pick cells), supercial cortical spongiosis neuronal loss, and gliosis occur in the atrophied areas, and these features are common in CBD, DLDH, and other forms of the Pick complex. Complement proteins and complement inhibitors are detected in the neuronal cytoplasm, suggesting that complement activation is interrupted before reaching completion and causing neuronal lysis [55]. Additionally, Pick bodybearing neurons (but not Pick cells) are surrounded by activated microglial cells and T lymphocytes [56]. Progressive subcortical gliosis [38,57] is clinically similar to PiD but, so far, only remains a pathologic diagnosis. More than 30 cases have been described in the literature, with the largest series being those of Verity and Wechsler [58] and Bergeron et al [59]. Because white matter gliosis is common in other varieties of Pick complex pathologic entities, the separation of this variation is hardly justied [11].
Frontotemporal dementia In the second half of the 1980s, two European groups described FLD as a distinct entity and contrasted the clinical features with those of AD [13,5]. They estimated its relative incidence to be 15% to 20% of degenerative dementias. Both groups recognized that even though some of the cases had Pick bodies and most did not, the clinical syndrome was the same. They called the pathologic entity without Pick bodies frontal lobe dementia type, which consisted of neuronal loss and gliosis in the frontal cortex with or without spongiform changes or ballooned neurons [5]. At the same time, Knopman et al [6] described a similar clinicopathologic picture as DLDH.
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The groups that described dementia of the frontal lobe type changed the terminology to FTD [4]. The term frontotemporal degeneration or frontotemporal dementia [60] does not include the frequent subcortical involvement, parietal pathologic ndings, or extrapyramidal symptomatology. Furthermore, it does not distinguish between the clear-cut behavioral presentation of FTD and aphasic presentation of PPA, which is one of the most valuable contributions of the recent descriptions of the clinical picture in these conditions. It does reect, however, the frequent combination of frontal and anterior temporal atrophy originally described by Pick. The striking alterations in personality and behavior have become synonymous with FTD. The hallmark of this distinctive form of dementia is the combination of disinhibition with apathy, although at dierent stages of the disease, one or the other symptom may be predominant. Disinhibition often refers to social inappropriateness ranging from childish rude behavior to exposure and kleptomania. It overlaps with impulsivity, poor judgment, irresponsibility, and irritability. Other manifestations, such as restlessness, pacing, wandering, and aggression, are also seen. One of the characteristic groups of behaviors is characterized by perseveration of words, gestures, and actions as well as obsessive stereotypic routines. These patients are inexible, insisting on eating, buying, or doing the same thing at the same time; hoarding objects, clothes, or even garbage; perseverating with stories; and telephoning people inappropriately. Patients may be preoccupied with germs, pills, money, sex, types of clothing, or clock watching while they carry out their stereotypic routines. If attempts are made to restrain these behaviors, anger and violent resistance often occur. In more advanced stages, echolalia, incessant clapping, singing, and laughing are observed. Other disinhibition phenomena, such as hypersexuality, hyperorality, and utilization behavior, are sometimes grouped under the term Kluver-Bucy syndrome, which originated from the observation of monkeys with bilateral temporal lobectomy [37]. The hypersexuality may be only verbal and gestural in middle-aged or older individuals. Hyperorality often manifests in gluttony and overeating, and many patients develop food fads, particularly for sweets. Patients may consume large quantities of candy or cookies in one sitting. We had patients who would eat in the same chicken restaurant day in and out. Others insisted on a diet of milk and bananas or had plum sauce with everything. Some patients grab food o the serving plate before anybody else starts or even take food o the plates of others. The compulsive eating and drinking sometimes extends to inedible objects as in coprophagia. Utilization behavior is the need to touch, feel, examine, or pick up objects within reach and sight, similar to what others called environmental dependence or hypermetamorphosis [61]. The nal stages of disinhibition manifest in urinary and stool incontinence, although this may occur early in FTD patients who are still oriented. There is a group of behaviors that can be characterized as negative, consisting of apathy, aspontaneity, indierence, and emotional atness.
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Patients are unable to recognize the extent of their own behavioral disturbance and most often insist there is nothing wrong. A striking disinterest in family matters or in the plight of others is sometimes the presenting feature. More apparent extremes of indierence and apathy culminate in personal neglect, for example, not washing or changing underwear. Another negative behavior is the lack of ability to plan complex activity or pay attention in a sustained manner so as to complete a task, which is often called the dysexecutive syndrome. Decreasing language and communication is also part of this negative cluster of symptoms, which may eventually resemble progressive aphasia resulting in mutism. Lately, several anatomic correlations with the behavioral variants of FTD have been attempted. Snowden et al [62] distinguished the disinhibited overactive variety of FTD. These patients are impulsive and distractible. Their social and personal disinhibitions are embarrassing to families. The pathologic changes tend to be in the orbital surface of the frontal lobes and the temporal neocortex. The apathetic inert subtype may be seen at presentation or subsequent to the disinhibited behavior. These patients have pathologic changes in the dorsal lateral convexity as well as in the temporal neocortex. The stereotypic rigid subtype of FTD is associated with perseverative and ritualistic behavior and tends to be associated with akinesia and rigidity early in the disease. Pathologic changes are considered to involve the basal ganglia and temporal neocortex, with relative sparing of the frontal lobes. Others emphasize the loss of self, a serial criminal behavior, and obsessive copying or coloring behavior with right temporal atrophy [63]. Progressive aphasia was also renamed the left temporal variety of FTD. In our experience, these variants tend to overlap a great deal, and their separation may not be clinically or pathologically feasible. Patients may perform surprisingly well on neuropsychologic tests, although impulsiveness, distractibility, and lack of cooperation tend to interfere with testing rather early in the disease. Sometimes, only the results of complex executive tests of shifting sets, such as the Wisconsin Card Sorting Test, interference (the Stroop Test), or planning (the Tower of Hanoi), are abnormal. There are patients, however, whose behavior is grossly abnormal, yet they can perform well on the traditional frontal lobe tests. A behavioral inventory, such as that designed in our clinic, seems to be more helpful in the clinical diagnosis and even in the quantitation of severity of the illness [64]. Similar behavioral inventories for FTD have been used at other centers [65,66]. The more general Neuropsychiatric Inventory has also been used to dierentiate AD from FTD but has less specic items for FTD [67]. The pathologic prole of FTD was originally described as a separate entity, consisting of focal atrophy with supercial cortical spongiosis, gliosis, and neuronal loss, but this is generic to all the varieties of Pick complex pathologic ndings [11]. Several families with FTD have been described with linkage to chromosome 17 [68]. The combination of phenotypes in these families suggests that the various clinical manifestations in the much more
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common sporadic illness are also related. Some of these families have taupositive pathologic ndings and tau mutation, but tau-negative families with motor neuron type inclusions are also described [69]. An association of FTD with motor neuron disease (MND) has been increasingly recognized [70,71]. Ubiquitin-positive and tau-negative inclusion bodies in the dentate gyrus and nonmotor cortex were described as a marker of this MND type of FTD [72,73]. Strong et al [74] reviewed the neuropsychologic decit in amyotrophic lateral sclerosis, which tends to be the frontal type. When MND supervenes, however, the rapid course precludes development of full-blown FTD.
Primary progressive aphasia PPA was described as a distinct clinical entity [8]. It is dened as progressive language impairment without dementia for at least two years [75], although it is recognized that other modalities are aected subsequently, particularly behavioral changes suggesting frontal decit. In the original series, only one patient had a biopsy showing nonspecic pathologic changes with lipofuscinosis. Many subsequent (and preceding) cases of PPA were described with classic PiD [9,23,25,26,76], however. Other cases had histologic ndings characterized by gliosis, neuronal loss, layer II and III spongiosis in the cortex [77] identical to that described in FLD, and subcortical involvement with neuronal achromasia similar to that in CBD [9,78]. Although much has been made of the heterogeneity of the underlying pathologic changes, Mesulam and Weintraub [79] found that most cases have a PiD or Pick variant pathologic prole. If one includes the cases with only focal atrophy and supercial cortical spongiform degeneration or those with motor neuron type inclusions in this group, the pathologic ndings become far less heterogenous. There are a few cases with underlying focal AD, but the pathologic or clinical features may not be typical [80]. Mesulam [81] also recently argued that the syndrome is connected to FTD clinically, pathologically, and genetically. Several varieties of PPA have been described, with the more common nonuent variety leading to mutism (most of the published cases), the aphemic variety with verbal apraxia and stuttering initially, and semantic aphasia (dementia) in which speech output remains preserved, whereas the naming and comprehension of objects seem to be lost [82]. The major distinction is the early loss of comprehension in semantic dementia and the early loss of uency in primary nonuent aphasia. It must be kept in mind that the uency-nonuency distinction is relative and greatly depends on when the patient is seen in the course of the illness. Progression of the illness results in eventual mutism in all varieties, but even those patients who are mute may have relatively well-preserved memory and visuospatial orientation and may function surprisingly well in the community if they do not develop
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the behavioral disturbance in contrast to aphasia in AD, which is usually superimposed on memory and visuospatial loss. Sometimes, isolated progressive aphasia can be seen for a decade before other symptoms develop. Semantic dementia or aphasia deserves to be described separately, although the features overlap with primary progressive nonuent aphasia and FTD. These cases often begin with diculty in naming and comprehending single nounsin other words, losing the meaning of words; thus, the term semantic dementia [82,83]. Similar cases were described as loss of semantic memory [84]. Aected patients retain good articulation and syntax, and their speech remains quite uent, but they begin asking stereotypic questions, such as What is a steak? or What is a vehicle? At rst, this occurs for relatively low-frequency words, but common words seem to be involved later on. The loss of comprehension and naming and the retained uency and repetition are distinct and could be classied as transcortical sensory aphasia. Some cases have associated visual agnosia, indicating a multimodality loss of meaning for objects. Patients with semantic dementia become nonuent later in their illness, and they also develop behavioral disturbances relatively frequently. At times, extrapyramidal complications [9,85,86] and even MND supervene in PPA [87]. The variety associated with MND tends to be more rapidly progressive [87]. FTD and CBD, in turn, frequently have a progressive language disturbance. As a result, not only the pathologic ndings but the symptomatology of PPA overlaps among the entities belonging to the Pick complex. Corticobasal degeneration When Rebeiz et al [88] described corticodentatonigral degeneration, they considered it to be a distinct entity characterized by an akinetic extrapyramidal syndrome, apraxia, alien hand, and vertical gaze palsy, but they recognized the similarity of the pathologic ndings to those of PiD (alien hand refers to one hand interfering with the other among other phenomena). The syndrome was ignored for 20 years and then resurrected using the term corticobasal degeneration or corticobasal ganglionic degeneration [89,90]. Most of the literature concerning this condition acknowledges the clinical and pathologic overlap between CBD and PiD [9193]. In addition to the ballooned neurons (Pick cells) and supercial layer (cortical spongiosis), CBD has certain distinctive features. The cortical neuronal inclusions are positive by Gallyas stain, and the hippocampus is usually spared. Most of the pathologic changes are subcortical, and the inclusions often have a ring or kidney shape and are less homogenous than in Pick bodies; however, without the Gallyas stain, they may be dicult to distinguish. The abundance of tau-positive oligodendroglial inclusions and astrocytic plaques is characteristic. CBD patients suer from a dichotomy similar to that of PiD patients in that the pathologic and clinical descriptions do not fully overlap. There are
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some case reports describing patients who presented clinically with CBD as dened by unilateral rigidity, apraxia, and alien hand syndrome but had the pathologic ndings of PiD with Pick bodies [31,94,95]. Other cases, pathologically typical of CBD, have a frontal type of dementia without the presenting extrapyramidal features [91,96,97]. Typical CBD pathologic ndings can be seen with a clinical picture of PPA [9,78,98100]. In a recent study, we suggested that the clinical syndrome of prominent apraxia unilateral extrapyramidal syndrome with the alien hand phenomenon should be designated as CBD syndrome, regardless of the pathologic ndings. Further evidence of the clinical and neuropathologic overlap between CBD, FTD, and PPA has been accumulated. The evidence is overwhelming that CBD is also part of the Pick complex [101]. There is also a signicant overlap between CBD and progressive supranuclear palsy (PSP) clinically and pathologically, suggesting that PSP may be considered in the same biologic spectrum as CBD [102105]. Typically, unilateral presentation of extrapyramidal symptoms in combination with apraxia leads to the diagnosis of CBD; axial dystonia, falls, and bilateral rigidity are considered more typical of PSP [106]. Nevertheless, these distinctions are not mutually exclusive. The increasingly frequent recognition of gaze palsy in CBD also contributes to the clinical similarities of these entities.
The Pick complex Because FTD is used to designate the behavioral abnormality of disinhibition dementia in most instances and the use of PiD has been accepted by many to designate a specic histopathologic prole with Pick bodies, we suggested the term Pick complex to avoid the confusion that continues to surround the term Picks disease [9]. Pick complex designates both the pathologic and clinical overlap between the variations. It has an advantage over FTD in that it avoids the restriction of pathologic and clinical symptomatology to the frontotemporal cortex and acknowledges the relation of PiD. Pick complex is a unifying concept of the overlapping clinical syndromes of FTD, PPA, and CBD with the underlying neuropathologic ndings, emphasizing the commonalities rather than dierences between them. An alternative is to use the lengthy and redundant term frontotemporal lobar degeneration [62], but this term does not consider the extrapyramidal or subcortical manifestations or CBD [107]. The third alternative is to return to the term Picks disease; however, to date, this has been done with a degree of equivocation [108]. Conditions combining several features of the Pick complex continue to be published under dierent names, such as dementia with nonspecic pathologic ndings, atypical presenile dementia or DLDH [6], hereditary dysphasic dementia [85], and disinhibition dementiaparkinsonismamyotrophy
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complex [109], with a variable amount of discussion and reference to the clinical and pathologic overlap. Table 1 summarizes the terms used to describe similar conditions. If one considers all the cases of FTD, PPA with and without MND, and CBD as part of the Pick complex, the entity becomes much less of a rarity. According to some estimates, including all pathologic variants, the incidence of FTD may be as high as 20% of degenerative dementias [2,40,110], and PPA reports may represent another 10%, even considering the substantial overlap with FTD. The percentage is higher if only presenile cases are considered [108]. This number would be further increased by the inclusion of CBD cases. We have now examined over 150 patients with Pick complex in our clinic compared with 600 patients with probable AD, and we frequently continue to see suspected cases. Approximately half of these patients have FTD (behavioral), half have PPA (language) presentation, and a smaller number (7%) start with the movement disorder of CBD. The numbers match or surpass those of patients with vascular dementia. The ratio of Pick complex to AD may turn out to be 1:4 or approximately 25% of degenerative dementias rather than the estimates of PiD based on autopsy material using restrictive histologic criteria. Admittedly, epidemiologic studies are lacking, and a selection bias is playing a role in centers with an interest in the disease. Nevertheless, a revision of the mistaken belief that the disease is rare and dicult to diagnose should result in increased recognition; hopefully, successful treatment will follow.
Table 1 Glossary of Pick complex 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. Circumscribed cerebral atrophy Picks disease (PiD) Lobar atrophy Progressive subcortical gliosis (PSG) Corticodentatonigral degeneration Generalized Picks disease Frontal lobe dementia (FLD) Primary progressive aphasia (PPA) Corticobasal degeneration (CBD) Dementia lacking distinctive histology (DLDH) Semantic dementia Frontal lobe dementia with motor neuron disease Frontotemporal dementia (FTD) Primary progressive apraxia Nonspecic familial dementia Atypical presenile dementia Spongiform encephalopathy of long duration Hereditary Dysphasic Dementia Pallido-Ponto-Nigral Degeneration Disinhibition-Dementia-Parkinsonism-Amyotrophy
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Neuropathologic ndings The underlying commonality of Pick complex neuropathologic ndings is the initially asymmetric focal atrophy of the frontotemporal regions. There is also underlying neuronal loss, gliosis, and supercial linear spongiosis in aected cortical areas. Ballooned neurons or Pick cells occur with variable frequency in all varieties. They appear swollen pink on hematoxylin-eosin staining, lack Nissl substance (neuronal achromasia) of the cytoplasm, and express phosphorylated neurolament episodes. There is tau reactivity in the oligodendroglial cells and astrocytic processes. The supercial layer spongiosis is seen in layers II and III of the cortex in contrast to the spongiform changes of Creutzfeldt-Jakob disease, which tend to be visible throughout. Various distinctive features, such as Pick bodies, astrocytic plaques in CBD, tufted astrocytes in PSP, and ubiquitin-positive and tau-negative inclusions in MND type dementia, have been described, but they, in turn, can occur with each of the other clinical varieties. Cases lacking any of these distinctive features are often labeled dementia lacking distinctive histology, but we have found ubiquitin-positive and tau-negative inclusions of the amyotrophic lateral sclerosis type in many of these cases previously considered to represent DLDH [69]. There is substantial overlap between all varieties of the Pick complex, although their distinctiveness is also argued [111]. As mentioned previously, the clinical varieties do not predict the histologic variety, but they strongly predict the complex.
Biochemistry Pathologic tau proteins (PTPs) are biochemical markers of various forms of degenerative dementia, including AD, PiD, CBD, PSP, the parkinsonismdementia of Guam (Lytico-Bodig), and dementia pugilistica, which are collectively called tauopathies. Tau mutations have been discovered only in FTDP-17, however. Neurobrillary tangles of AD contain all six human tau isoforms. Abnormally phosphorylated PTPs form three bands on Western blot studies with a molecular weight of 55, 64, and 69 kd using certain immunologic probes in AD. Other monoclonal antibodies label other bands indicating variously phosphorylated amino acids [112]. PiD has 64-kd and 55-kd doublets, and CBD and PSP have 69-kd and 64-kd doublets. The amount of abnormal tau can be low in FTD, and PTP is sometimes absent. At times, FTD has a tau triplet as in AD [112]. Sometimes, dierent band compositions are obtained from dierent parts of the brain [113]. In some studies, two bands were seen in brain stem neurons, and triplets were seen in the hippocampal neurons of PSP. Tau-negative hereditary dysphasic disinhibition dementia and some sporadic cases of DLDH with prominent language and behavioral decits have been more recently attributed to the loss of tau in the brain, with the same eect as the tauopathies with tau-positive pathologic ndings [114].
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Genetics Wilhelmsen et al [12] discovered a linkage to chromosome 17 q2122 in a large family with variable symptomatology of FTD, aphasia, parkinsonism, and amyotrophy [109]. A consensus conference summarized the clinical features of 12 families and the pathologic characteristics resembling those of the sporadic cases. Although each family was described under dierent terminology (see Table 1), the term frontotemporal dementia with parkinsonism linked to chromosome 17 was accepted [68]. The microtubular-associated protein tau was suspected as the candidate gene for mutation. A few years later, several tau mutations were discovered [13,115,116]. Normal tau proteins contribute to axonal transport by binding to microtubular protein. Six tau isoforms are created by the dierential splicing of exon 10, making three or four repeats of the microtubular binding domain of tau. To date, more than 20 tau mutations in more than 50 families have been identied [117]. The exon 10 splice mutations alter the ratio of fourrepeat to three-repeat tau isoforms, most often resulting in pathologic ndings resembling those of CBD or PSP. The phenotypes range from FTD, to PiD, to CBD, with the same mutation often resulting in a dierent clinical presentation [43]. The missense mutations disrupt the interaction between tau and microtubules, and unbound tau becomes abnormally phosphorylated and polymerized into laments and inclusions. Mutations in exons 9, 12, and 13 lead to accumulation of all six isoforms of tau, resulting in Alzheimer-type tangles, or to a predominance of three-repeat tau and Pick body dementia. Although dierent tau mutations dierentially alter biochemical properties of tau isoforms [118], these mutations do not predict the clinical presentations, but they do predict the overall clinical morphologic picture resembling sporadic FTD or Pick complex. Tau polymorphisms from the two main haplotypes of tau were also associated with various phenotypes. The AO allele is overrepresented in both PSP and CBD [119]. The allele is more common in AD with an interaction with apolipoprotein E4; a similar interaction was found in FTD, but the association of apolipoprotein E4 with FTD is controversial [120].
Treatment There is evidence that cholinergic receptor binding is decreased in PiD in aected cortical regions [121123]. Serotonin and Imipramine binding were decreased in the hypothalamus and frontal and temporal lobes associated with PID [124]. The decreased serotonin binding could correlate with the overeating and weight gain observed in some patients with PiD/FTD/Pick complex. Other behavioral impairments, such as depression, irritability, and apathy, with relative preservation of memory are also compatible with serotoninergic dysfunction [125]. Selective serotonin reuptake inhibitors and
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Trazodone have been tried in an o-label application in FTD patients and did result in improvement of some of the symptoms [126]. We have tried Lithium, Selegiline, Donepezil, and Cerebrolysin for possible disease-modifying properties in a few patients without observable eect. Lithium has been shown to dephosphorylate tau in vitro, but the few patients we have tried to treat tolerated it poorly. Trazodone may help agitation and compulsive behavior, and antipsychotics may have to be used for aggressive behavior when behavioral modication fails. Patients may become aggressive when their disinhibited, stereotypic, perseverative behavior is opposed by caregivers or if they are restrained in any manner. Distracting patients and providing them with alternative routines to socially unacceptable behavior seems to work better than verbal attempts to dissuade them. The disease is often misdiagnosed and treated with excessive sedation, however. Acknowledgment The authors thank Bonita Stevenson for secretarial assistance. References
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Med Clin N Am 86 (2002) 519535
Dementia with Lewy bodies

James B. Leverenz, MDa,b,c,*, Ian G. McKeith, MD, FRCPsychd
Department of Veterans Aairs, Northwest Network Mental Illness and Parkinsons Disease Research, Education and Clinical Centers, 116MIRECC, 1660 S. Columbian Way, Seattle, WA 98108, USA b Department of Neurology, University of Washington, 1959 NE Pacic Street, Box 356465, Seattle, WA 98195, USA c Department of Psychiatry and Behavioral Sciences, University of Washington, 1959 NE Pacic Street, Box 356560, Seattle, WA 98195, USA d Department of Old Age Psychiatry, Institute for the Ageing and Health, Wolfson Research Centre, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne, NE4 6BE, UK
a
Historical perspective Parkinsons disease James Parkinsons classic monograph of 1817 is generally considered the rst full description of the clinical disorder now bearing his name, Parkinsons disease (PD) [1]. Physicians prior to Parkinson had described various patients with components of the syndrome, such as tremor and gait disturbance, but his description was signicant in bringing together the major motor manifestations of this disease. Interestingly, his initial description of PD specically notes the senses and intellects being uninjured. This failure to recognize any intellectual impairment may have been, in part, caused by the fact that three of his six cases were noticed casually in the street or were only seen at a distance. The French physicians Trousseau and Charcot appear to have been the rst to recognize the cognitive impact of PD. Trousseau noted, in his Lectures on Clinical Medicine, that The intellect is at rst unaected, but gets
* Corresponding author. Department of Veterans Aairs, Northwest Network Mental Illness and Parkinsons Disease Research, Education and Clinical Centers, 116MIRECC, 1660 S. Columbian Way, Seattle, WA 98108, USA. E-mail address: leverenz@u.washington.edu (J. Leverenz). This work was supported by NIA U01AG06781, RO1-AG10845, Department of Veterans Aairs (JBL), and University of Newcastle upon Tyne, and NNNT Mental Health NHS Trust (IGM). 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 1 2 - 3
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weakened at last; the patient loses his memory precocious caducity set in [2]. Charcot also recognized that in the later stages of disease the mind becomes clouded and memory is lost [3,4]. The English physician Sir Edward Gowers later noted that there could be mental weakness and loss of memory [5]. In addition, he reported a tendency to delusions, perhaps the rst description of the now well-recognized propensity for psychotic symptoms in patients with PD and dementia with Lewy bodies (DLB). Lewy bodies (LB) are the characteristic pathology associated with idiopathic PD. Friederich H. Lewy rst described these intracytoplasmic inclusions in the basal forebrain (substantia innominata) [6]. He did not describe, however, any LB pathology in other regions such as the substantia nigra or cortex. Tretiako appears to have been the rst to describe LB in the substantia nigra [7]. Subsequent reports by Foix, Hassler, Klaue, and Greeneld and Bosanquet fully characterized the substantia nigra lesions in the brains of PD patients, including neuronal loss, gliosis, and LB inclusions [811]. LB in the substantia nigra and other brainstem nuclei, such as the locus coeruleus, have a characteristic spherical appearance with an eosinophilic core and clear halo on standard hematoxylin and eosin staining (Fig. 1a). In extra-brainstem regions, such as the cortex, LB are often elliptical or irregularly shaped and are without a halo. This appearance of extra-brainstem LB makes them dicult to identify using standard pathological stains, such
Fig. 1. Lewy body inclusion (arrow) in a pigmented neuron of the substantia nigra (a, hematoxylin and eosin). Immunohistochemical staining of multiple Lewy body inclusions (arrows) in substantia nigra neurons using antibodies to ubiquitin (b) and alpha-synuclein (c). Lewy neurites detected by antibody to alpha-synuclein (c, small arrows). Lewy body inclusions detected using alpha-synuclein antibodies in CA-3 neurons of the hippocampus (d, arrows).
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as hematoxylin and eosin. Many neuropathologists now use antibodies to protein components of LB, such as ubiquitin or alpha-synuclein, to detect extra-brainstem LB (Fig. 1d) [12,13]. Research utilizing biochemical analysis and highly specic antibodies have found a number of potential protein constituents of LB [1417]. Antibodies raised against neurolaments, ubiquitin, and alpha-synuclein have been found to label inclusions and other LB-associated pathologies, such as neurites (Fig. 1b, c, and d), throughout the nervous system. The discovery of alpha-synuclein mutations in familial Parkinsons disease and the nding of distinct alpha-synuclein pathology in diseases such as multiple system atrophy and DLB has suggested to many investigators that these comprise a group of disorders characterized by synuclein abnormalities, and they have been classied as synucleinopathies [18]. Dementia with Lewy bodies As previously noted, nineteenth-century French and English physicians recognized that late-stage PD patients often developed neuropsychiatric symptoms. Subsequent reports by Lewy in 1923, Hassler in 1938, and Woodard in 1962 also noted dementia or psychiatric disorders associated with LB pathology [10,19,20]. In fact, Woodard labeled cases with LB and psychiatric disease as having Lewy body disease. The Japanese in the 1960s were the rst to recognize that some patients who present with a dementia syndrome have a predominant LB pathology at autopsy [21,22]. Because of the diuse distribution of LB pathology in these cases, both in brainstem and cortical regions, the cases were diagnosed with Diuse Lewy body disease. These cases often had only modest, and occasionally no, AD pathology (senile plaques and neurobrillary tangles) to account for the dementia. Clinical parkinsonism was also variably present. In the 1970s, several groups reported signicant numbers of clinically diagnosed AD cases as having clinical parkinsonism. Subsequent neuropathological reports conrmed a seemingly high frequency of LB pathology in cases of AD [23,24]. Because most of these cases had concomitant AD pathology, these cases were frequently interpreted as being patients with a variant of AD, the Lewy body variant [25]. Others found, however, that these cases with AD and LB pathology generally had less severe AD pathology than that observed with AD alone [26]. In addition, the report of Lewy neurites in the CA2 region of the hippocampus of only LB-containing dementia cases suggested that these cases with combined pathology were pathologically dierent and therefore a pathophysiologically unique and separate disorder from Alzheimers disease, Diuse Lewy body disease [27]. Although it was suggested that the dierence in the diagnostic labeling of these cases with combined AD and LB pathology was semantic [28], the correct classication of cases has important implications for research on the fundamental pathogenesis of the disorders characterized by LB pathology.
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In 1995, the First International Workshop of the Consortium on Dementia with Lewy Bodies met in the United Kingdom. The results of this conference were published in 1996 by McKeith et al, who outlined the consensus guidelines for the clinical and pathological diagnosis of DLB [13]. Pathologically, DLB required only the presence of LB pathology with a history of dementia. Some of these cases would also fulll pathological criteria for AD and thus would have that additional classication. Because of the unclear pathophysiological relationship between DLB and AD, the consensus group was unable to come to an agreement on a single disease classication of cases with both LB and AD pathology. The clinical criteria for DLB will be reviewed in the next section. It is an ongoing research objective to more fully understand the pathophysiology of DLB and thus improve the appropriate diagnostic classication scheme. Despite the lack of diagnositic clarity inherent in any disease process that is not yet fully understood, it is clear that the pathology and clinical symptoms of DLB comprise a large proportion of dementia cases, second perhaps only to AD [13]. Thus, DLB is an important focus for both research and clinical care.
Clinical diagnosis of DLB Clinical-pathological studies have revealed a complex set of clinical signs and symptoms in DLB. We will outline the cognitive, behavioral, and motor signs and symptoms observed in pathologically conrmed cases of DLB patients and will then review the current consensus criteria used by many researchers to make a clinical diagnosis of DLB. Cognitive The primary clinical feature of DLB is progressive loss of cognitive function and associated decline of social or occupational function [13]. This progression generally occurs over years, although it may proceed more rapidly than typically observed in AD. The cognitive prole of patients with DLB, however, can be very similar to AD and in fact accounts for the frequent misdiagnosis of DLB patients as having AD [29]. Similar to AD, memory impairment can involve loss of ability to encode new memories (short-term or recent memory), although this type of memory impairment is generally less severe than that observed in AD patients [30,31]. Loss of the ability to retrieve already encoded information (long-term memory) may be more severe in DLB than AD [30]. DLB patients will also generally have more severe visuospatial dysfunction than observed in AD patients [30,31]. Clinically, this can manifest as the loss of the ability to navigate in well-known locations (eg, getting lost in ones own neighborhood) or on examination by the inability to perform tasks such as clock drawing or copying gures.
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Similar to patients with Parkinsons disease, patients with DLB can also have signicant problems with frontal lobe-associated cognitive skills such as executive function. This latter problem might present clinically with loss of ability to problem-solve or plan and successfully execute a task. On neuropsychological testing, this may appear as a decline in the ability to perform tests such as the Wisconsin Card Sorting and Trail Making Tests [30,31]. Although there is some overlap with the cognitive impairments in AD, this pattern of neuropsychological dysfunction should increase the clinicians suspicion of DLB. Thus, although the bedside neuropsychological testing (eg, Mini-Mental State Exam, Short Blessed) is important, formal neuropsychological testing can provide a more detailed prole of cognitive decits that may be helpful in dierentiating DLB from other disorders such as AD. Finally, it is important to recognize that these cognitive dierences may be most evident in the early stages of disease. Neuropsychological distinctions between DLB and other neurodegenerative dementias are less clear as a patient moves into a more severe stage of disease and cognitive decits become much broader. Besides specic neuropsychological decits, patients with DLB can exhibit marked uctuation in attention and cognition with cognitive impairment alternating from near-normal performance to severe confusion within periods ranging from minutes to days and weeks [13,32]. This is distinct from normal variations in function observed in all patients with neurodegenerative disorders in which the severity of the uctuations are less severe and more predicable. In addition to uctuations in cognition, alterations in levels of attention and vigilance are also seen. Patients with DLB can have episodes of severely reduced levels of arousal and also may have histories of increased somnolence. Recent work with computerized attention and vigilance tasks in DLB patients have conrmed this increased frequency of uctuation in performance on some tasks on a second-by-second basis [33]. For clinicians, it is worth noting that these uctuations can be helpful diagnostically and can also account for visit to visit variability in patient cognitive and functional performance. Behavioral Behavioral and psychiatric disturbances in dementia are a signicant source of morbidity and increase the risk for institutionalization [34]. Psychotic symptoms are more frequent, persistent, and tend to occur earlier in DLB patients, when compared with patients with AD [3537]. Recurrent visual hallucinations (VH) are one of the hallmarks of DLB and are one of three core symptoms in the consensus criteria for DLB (Table 1). VH are characteristically well formed in DLB, with patients able to describe ne details. Emotional responses can vary, ranging from indierence to signicant distress and agitation. Level of insight may be an important factor in the emotional response. As will be discussed in the treatment section, the
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Table 1 Consensus criteria for the clinical diagnosis of probable and possible DLB 1. The central feature required for a diagnosis of DLB is progressive cognitive decline of sucient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages but is usually evident with progression. Decits on tests of attention and of frontal-subcortical skills and visuospatial ability may be especially prominent. 2. Two of the following core features are essential for a diagnosis of probable DLB, and one is essential for possible DLB: a. Fluctuating cognition with pronounced variations in attention and alertness b. Recurrent visual hallucinations that are typically well formed and detailed c. Spontaneous motor features of parkinsonism 3. Features supportive of the diagnosis are: a. Repeated falls b. Syncope c. Transient loss of consciousness d. Neuroleptic sensitivity e. Systematized delusions f. Hallucinations in other modalities 4. A diagnosis of DLB is less likely in the presence of: a. Stroke disease, evident as focal neurologic signs or on brain imaging b. Evidence on physical examination and investigation of any physical illness or other brain disorder sucient to account for the clinical picture From McKeith IG, et al: Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47:1114.
emotional response can be used as a guide to help determine whether psychotropic medications are required. Unlike VH in delirium, those in DLB are recurrent and not associated with a systemic illness [37]. Other types of hallucinations, such as auditory hallucinations, are less frequent and less specic for DLB. Delusions are also less unique to DLB than VH. When delusions occur, however, they are frequently complex and bizarre, in contrast with AD where delusions are less well formed or related to misidentication or memory impairment (eg, delusions of theft) [13]. Other behavioral symptoms are also common in DLB. A large crosssectional study of behavioral symptoms in DLB has revealed high frequency of apathy, anxiety, and depression [38]. As with other dementias, these symptoms are important as a source of morbidity and eects on caregiver burden. It is not clear, however, that these latter behavioral symptoms are suciently unique to DLB to warrant use in diagnosis. Motor The four major motor symptoms of PD (resting tremor, rigidity, bradykinesia, and postural instability) can be observed in DLB, but with lesser frequency and with a distribution of symptoms that diers from typical PD [39]. In particular, patients with DLB can be bradykinetic, rigid, and
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have signicant gait disturbance, whereas resting tremor is a comparatively uncommon motor symptom. The gait disturbance can include slow shuing steps, en bloc turns, and decreased arm swing, in addition to postural instability. Unlike PD, these motor symptoms may be less responsive to dopaminergic agents [39]. The reasons for this discrepancy in patterns of motor symptoms and response to treatment are unclear, although dierences in the nigrostriatal dopaminergic systems in DLB and PD may be important [40]. It is worth noting that PD symptoms are relatively common in the later severe and terminal stages of several other dementias including AD and fronto-temporal dementia. Thus, the timing of onset of motor symptoms may be an important feature in helping to distinguish DLB from other dementias. On the other hand, it has also been reported that some autopsyconrmed DLB patients never exhibited motor symptoms of PD [41]. Good prospective studies of the parkinsonian symptoms in DLB and other degenerative disorders are needed to further our understanding of the timing of these motor symptoms and their diagnostic utility. Consensus criteria for the diagnosis of DLB Currently, most investigators utilize the consensus guidelines provided by the First International Conference on Dementia with Lewy Bodies for the clinical diagnosis of DLB [13]. In these guidelines, the clinical diagnosis of DLB is based on a set of required core symptoms and assisted by the presence of supportive signs and symptoms (Table 1). The rst required feature is the presence of dementia. Second, two of three core features are also required for a diagnosis of probable DLB, and one of three for a diagnosis of possible DLB. These core features include uctuating cognition with pronounced variations in attention and alertness, VH, and spontaneous motor features of parkinsonism. Included in the consensus guidelines are a series of supportive features, such as falls and neuroleptic sensitivity, whereas other clinical features such as a focal neurological decit or stroke make a diagnosis of DLB less likely. Supportive symptoms have not, as yet, been shown to clearly improve on the diagnostic accuracy of DLB [13]. Multiple studies have examined the diagnostic accuracy of the published clinical criteria for DLB [4249]. Most of these studies have demonstrated high specicity and positive predictive value of the criteria for the diagnosis of DLB. Thus, when a case of dementia is clinically diagnosed with DLB, there is a high likelihood (greater than 80%) that there will be LB pathology at autopsy. In most retrospective studies, and one recent prospective study, however, the consensus criteria were found to have a relatively low sensitivity (the clinical criteria correctly identifying pathologically conrmed DLB cases) [4245,48,49]. Two other prospective studies have found higher sensitivity rates for the diagnostic criteria, though still lower than the specicity rates [46,47]. These results would suggest that the consensus DLB criteria
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are, in general, very good at correctly identifying patients who will have LB pathology at autopsy (high positive predictive value). The lower sensitivity values would suggest that DLB is under-diagnosed clinically. This lower sensitivity is likely, in part, because of the inconsistent presence of clinical parkinsonism and is exacerbated by the criterias exclusion of patients who present with parkinsonism more than 12 months before dementia (these patients are currently classied as PD with dementia). Exclusion of these latter patients lowers the ability of the presence of this core feature to identify patients with dementia and LB pathology [13,50]. Additionally, reliable identication of uctuating confusion and cognition may also be a problem, as these symptoms are dicult to operationalize. More systematic approaches to identifying uctuating cognition may improve the clinical diagnosis of DLB. At this point, additional prospective investigations into the clinical characteristics of DLB should help improve our ability to accurately diagnosis DLB. Ancillary studies including special imaging studies (eg, PET and SPECT imaging) may be particularly helpful in the future. Several MRI studies have emphasized the relative preservation of medial temporal lobe volume in DLB compared to AD [51,52], although there is no signicant difference in the overall rate of brain atrophy in DLB compared with other dementia syndromes [53]. Postmortem pathological assessment of temporal lobe volume provides a clear correlate of this with in vivo imaging data [54]. PET and SPECT studies show consistent evidence of occipital hypometabolism (reduced O2 uptake and reduced glucose utilization) compared with AD [55,56]. The degeneration of the nigrostriatal dopaminergic projection in DLB is demonstrable by FP-CIT SPET imaging of the pre-synaptic dopamine uptake site [57,58]. This investigation has been proposed as a diagnostic procedure to distinguish DLB from AD [59]. Whether other ancillary studies such as spinal uid testing will be helpful is less clear [60]. From a clinicians point of view, it is important to look prospectively for the core and supportive signs and symptoms of DLB and to know that once a patient fullls these criteria, the patient is likely to have DLB pathologically.
Clinical management of DLB Clinical management of DLB patients can be very challenging. In addition to their dementia, patients develop frequent behavioral disturbances that are a source of signicant morbidity for patients and are quite problematic for their caregivers. Appropriate clinical management can lead to substantial improvement in the quality of life for both the patient and caregiver. Dementia A focus of treatment of dementia in AD has been the reversal of the wellcharacterized loss of cholinergic activity in the brain. In the United States,
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there are currently four medications (three of these in Great Britain) available to clinicians for treatment of the cholinergic decit in mild to moderate AD (see also Bonner and Peskind, in this issue) [97]. All are cholinesterase inhibitors that increase availability of central nervous system acetylcholine by blocking its metabolism by the cholinesterases. Tacrine was the rst available cholinesterase inhibitor approved for use in AD in the United States in 1993. Since that time, three additional cholinesterase inhibitors (donepezil, rivastigmine and galantamine) have become available with improved ease of administration and more favorable side eects proles than tacrine [61]. All of these second generation cholinesterase inhibitors have been shown, in double-blind placebo-controlled studies, to have signicant positive cognitive and behavioral eects in AD (see Bonner and Peskind, Chapter 12). Examination of the cholinergic system in DLB has also demonstrated a signicant reduction in activity that appears to be more severe than that observed in AD [62]. These ndings in DLB suggest that this group of patients may also respond well to cholinesterase inhibitors [63]. Several open-label trials have suggested that patients with DLB can tolerate cholinesterase inhibitors, with few reports of worsened parkinsonism, and can have a positive clinical response [6472]. In the rst and, thus far, only double-blind study of cholinesterase inhibitor treatment in DLB, McKeith et al found a signicant positive treatment eect of rivastigmine [73]. DLB patients treated with rivastigmine had signicantly better performance on a computerized cognitive assessment system examining attention, working memory, and episodic memory. Neuropsychological tests for executive function and planning also showed signicant improvement with treatment. The Neuropsychiatric Inventory (NPI), a systematic behavioral assessment scale, was administered as a primary outcome measure and demonstrated signicant improvement with rivastigmine treatment on ratings of apathy, indierence, anxiety, delusions, hallucinations, and aberrant motor behavior. Given the signicant morbidity associated with behavioral disturbance in dementia and the high frequency of these symptoms in DLB, this latter nding has particular importance in the treatment of patients with DLB. Further evaluation of the cholinesterase inhibitors for patients with DLB and PD with dementia will hopefully be available in the future. Psychiatric features Psychotic symptoms present a common and challenging clinical problem in the treatment of DLB. As with other behavioral disturbances, psychotic symptoms are associated with signicant morbidity and early nursing home placement. Double-blind placebo-controlled treatment trials of psychotic symptoms in DLB are nonexistent (however, note rivastigmine trial in previous section [73]). Only case reports or small case series are available. There does exist, however, a more extensive literature investigating treatment of psychosis in PD, which suggests that the newer atypical antipsychotic agents
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may be the most useful ones [7477]. Unfortunately, studies in PD suggest that even some atypical antipsychotic agents, such as risperidone and olanzepine, can have signicant associated extrapyramidal and cognitive side eects [74,78]. Treatment of psychotic DLB patients with atypical antipsychotics can be successful but can also be associated with either signicant side eects, such as confusion or parkinsonism, or a lack of response. Based primarily on the PD literature, clozapine may be the most eective atypical antipsychotic medication available for patients with psychosis and parkinsonism, whereas quetiapine needs further study [76]. The results from the rivastigmine trial would suggest that treatment with cholinesterase inhibitors might be an eective treatment for not only cognitive but also behavioral disturbances in DLB [73]. The Lewy body cluster of symptoms from the NPI (delusions, hallucinations, apathy, and depression) was signicantly improved with treatment. In contrast with most antipsychotics, rivastigmine was not associated in treatment with a signicant increase in extrapyramidal symptoms (except for the appearance of new tremor in 4 of 59 subjects). In addition, cognitive symptoms were improved with treatment, rather than impaired, as can be observed with antipsychotic use. Despite the encouraging ndings in the rivastigmine study, the treatment of psychosis in DLB remains problematic. Further blinded and controlled studies of atypical antipsychotic medications and cholinesterase inhibitors are needed to guide treatment strategies. As a nal caveat, in some patients, psychotic symptoms do not appear to be a signicant stressor to the patient or caregivers. In this latter circumstance, it generally wise to avoid medications that specically target psychotic symptoms. Motor symptoms As with psychosis, treatment of parkinsonian motor features in DLB has been incompletely studied. Motor symptoms in DLB patients are somewhat unique, in that there tends to be less resting tremor than observed in PD, while there are similar levels of rigidity, bradykinesia, and postural instability [39]. In addition, the clinical response of motor symptoms to levodopa is modest in DLB, in comparison with the almost universal response in PD [39]. A randomized and blinded prospective study of levodopa, or other antiparkinsonian agents, in DLB has not been performed and is clearly needed. Unfortunately, given the unique motor prole of DLB patients, studies of treatments in PD are not necessarily applicable.
Research in DLB Clinical The focus of much of the clinical research in DLB has been on diagnostic and clinical characterization. As elaborated in previous sections, the consensus
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criteria for DLB have been successful in accurately identifying patients with DLB pathology, but not as successful in identifying clinically subtle cases. This latter problem has led to continued eorts to improve characterization of the clinical symptoms of DLB patients and to identify biomarkers that may help in improving diagnostic sensitivity of DLB clinical criteria. Pathological Pathological characterization of DLB using new histological techniques has been a major focus of recent clinical-pathological studies [7981]. The clinical and pathophysiologic signicance of the high frequency of alphasynuclein lesions in the amygdala of AD patients remains unclear. Further evaluation of alpha-synuclein pathology and examination of other pathological markers are needed (See also Neurobiology below). Neurobiological Neurochemistry Neurobiological investigations have focused on understanding the pathophysiological basis of the unique clinical symptomatology of DLB. As already mentioned, it has been established that DLB patients have substantial loss of cholinergic function [62]. Recent evidence suggests that specic alterations in cholinergic receptors also occur in DLB and that regionally specic alterations in receptor density are associated with delusions and hallucinations [82,83]. The well-established cholinergic disturbance in DLB and the benecial response to cholinesterase inhibitors are important ndings and clues to future directions of DLB research. As would be expected, alterations in the substantia nigra-based dopaminergic system have been demonstrated in DLB, with reduction in dopamine transporter sites and dopamine levels in the striatum [40,84,85]. There is some evidence that dopaminergic changes in DLB dier from those observed in PD and may account for the dierential clinical response of DLB patients to dopaminergic agents [40]. Of course, alterations in the dopamine system have been implicated in psychotic disorders, and disruption of this system in DLB may also be important in the development of hallucinations and delusions. In addition to the abnormalities of the dopaminergic and cholinergic systems in DLB, the locus coeruleus and its neurotransmitter norepinephrine are also aected. Neuronal counts of the locus coeruleus in DLB show a substantial loss of neurons [86]. Norepinephrine levels are also signicantly reduced in the striatum of DLB, and receptors for norepinephrine are abnormally increased in locus coeruleus projection sites [85,86]. Neurotransmitter system alterations in dementia, and particularly in DLB, are complex and incompletely understood. Understanding of the alterations of these systems including potential compensatory mechanisms
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will be important, however, in advancing the understanding of the pathophysiology of clinical symptoms. Biology of alpha-synuclein The discovery of alpha-synuclein mutations in a subset of cases with familial PD and the presence of this protein in LB has led to an exploration of synuclein biology in both normal brain function and in disease. Alpha-synuclein appears to play an important role in normal vesicular function in the presynaptic terminals of neurons [87]. Mutation in the gene is associated with a form of familial PD characterized by LB inclusions [88,89]. Interestingly, in at least one of these families with an alpha-synuclein mutation, PD motor symptoms are also associated with a dementing syndrome [90]. Further work in PD and DLB has also suggested a more widespread dysfunction of all of the synuclein proteins (alpha-, beta- and gamma-synuclein) [91]. There may, in fact, be critical interactions between alpha- and beta-synucleins that inuence the development of LB pathology [92]. Interactions between alpha-synuclein and other proteins implicated in the synucleinopathies, such as parkin and synphilin, may also play a role in the development of LB pathology [93]. Additional recent investigations have suggested an abnormal posttranslational modication of alpha-synuclein in synucleinopathies [94]. Transgenic mouse models are currently under development; these mice have the mutated form of alpha-synuclein inserted into their genome and have shown associated alpha-synuclein abnormalities in the brain [95]. It is unclear at this time whether these animals will serve as useful models for the clinical-pathologic components of DLB; however, they certainly should provide important, more general, insights into the pathophysiology of the synucleinopathies. Genetics Mutations in alpha-synuclein and parkin genes in familial PD would appear to be important in helping understand the pathophysiology of PD and its relationship to DLB. In these families with alpha-synuclein and parkin mutations, individuals have presented with PD symptoms and/or dementia, suggesting that the same mutation can lead to a variety of clinical phenotypes [90]. These ndings also appear to blur the distinctions between DLB and PD. The frequent presence of AD and LB pathology together in familial AD would also suggest a possible pathophysiologic connection between AD and DLB [80]. In contrast to PD and AD, only a few families with familial DLB have been described [96]. In these families, dementia was the predominant presenting symptom and LB pathology was conrmed at autopsy. At this time, there is no mutation that has been associated with DLB. Identication of additional cases of familial DLB and of mutations could be critical to our understanding of the etiologic processes that lead to the development of this disease.
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Summary DLB is a complex disorder with important associations with PD and AD. As clinicians, it is important for us to identify these patients because of their unique responses to medical interventions and to help patients and caregivers more fully understand this disease process and its implications. Further research is needed to improve our understanding of the pathophysiology of this important dementing disorder, with the ultimate goal of improving clinical management of this disease.
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Med Clin N Am 86 (2002) 537550
AIDS dementia
David B. Cliord, MD*
Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Street, St. Louis, MO 63110, USA
Human immunodeciency virus type 1 (HIV-1)associated complications were rst reported in 1981, and the virus was identied in 1983 [1]. The subsequent scientic battle that has been a major part of medicine in the past 20 years has expanded knowledge in many areas of medicine, including but not limited to infectious diseases, oncology, immunology, nephrology, gastroenterology, ophthalmology, metabolism, and neurology. Worldwide, this infection aects in excess of 36 million people, and its rapid growth in the poorest parts of the world, notably in Africa and Asia, threatens profound economic and political consequences while causing unthinkable human suffering. A detailed understanding of the manifestations of the infection is thus of considerable importance. This tragic epidemic also represents an opportunity for mankind. As a model of the interaction between viral infections and hosts, it provides insights into human pathobiology that may assist in the development of treatments for many other aictions. Further, the complicated ramications of this infection in society seem to require that broad societal improvements be included in the response to the infection. Improvements in general health care and in the social and economic status of the worlds peoples are required to control this epidemic. The neurologic impact of HIV-1 has been recognized since quite early in the development of the clinical description of HIV infection [2] and includes opportunistic complications as well as those primarily associated with the HIV infection itself. Clinical diagnosis of HIV-infected subjects must always include careful exclusion of opportunistic complications. Cryptococcal meningitis, toxoplasma encephalitis, cytomegalovirus (CMV) encephalitis and radiculomyelitis, progressive multifocal leukoencephalopathy, neurosyphilis, and primary central nervous system (CNS) lymphoma are the most prominent of the serious secondary neurologic complications. Primary HIV-associated conditions include peripheral neuropathy, myelopathy, and
* E-mail address: cliordd@neuro.wustl.edu (D.B. Cliord). 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 5 - 6
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D.B. Cliord / Med Clin N Am 86 (2002) 537550
encephalopathy. The latter is associated with clinical dementia that has been called AIDS dementia complex (ADC) [3]. Other names for this condition are HIV-associated cognitive motor complex and HIV-associated dementia. A milder clinical presentation that may be a precursor of full-blown dementia is minor cognitive motor disorder, which is recognized by a complaint of neurologic dysfunction accompanied by changes in neuropsychologic test performance. Systematic classication of these HIV-associated cognitive processes is most widely performed using the American Academy of Neurology criteria [4].
Human immunodeciency virus HIV-1 is an RNA virus that is spread by person-to-person tissue transfer, most commonly during sexual intercourse, during blood transfusion, from mother to child, in maternal milk, or on contaminated needles. Although the epidemic in the United States began with a preponderant cohort of male homosexuals, globally, the infection is spread predominantly through heterosexual contacts and by contaminated needles most commonly used in illicit intravenous drug abuse. In the United States, the spread of the virus has gradually been decreasing in the initial male homosexual cohort and more heavily aecting drug abusers and persons of both sexes. The social stigmas of homosexual lifestyles and drug abuse have compounded the medical problems associated with the disease. Behavior modication in the face of drug abuse has been particularly challenging, and this sector of the epidemic has been especially hard to stem. HIV-1 has several important characteristics that have an impact on the natural history of the infection. After introduction of the virus, most hosts experience a viral illness, including fever, myalgia, headaches, and sometimes a rash. As the host immune response develops, serologic tests for HIV become positive, and viral load in the serum declines to a variable degree. The success of the host immune response governs the course of untreated infection. Where hosts generate a good immune response, viral loads fall to low levels, and clinical progression is absent or slow, leading to more than a decade of asymptomatic infection in some nonprogressors. In others, less complete control of the infection results in higher viral loads and more rapid onset of clinical symptoms associated with increasing immunodeciency. The CD4 lymphocyte count declines over time in infected hosts and is a useful indicator of the degree of immunosuppression. When this count falls below 200 cells per cubic millimeter, a notable increase in opportunistic infections is more commonly encountered, and clinical signs with weight loss, diarrhea, fever, and thrush often develop. Characterization of the clinical state and outlook has been rened by the development of routine monitoring of CD4 counts and HIV RNA viral loads in the plasma. Eective therapy generally results in signicant increases in CD4 counts (rarely to
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normal levels, however) and decline of viral loads to levels that are not detectable by current RNA assays. A second important aspect of HIV is the rapid and persistent rate of viral replication that typies this infection [5]. The virus has a half-life of only a few days in the plasma compartment, implying that the large amount of virus correlates with a huge synthesis rate estimated at 109 to 1010 virions per day. Replication requires a viral reverse transcriptase step in which viral RNA is transcribed to DNA, which may then be inserted into the host DNA. This step is a critical target for antiretroviral therapy. Also important is a high mutation rate that allows rapid change in the genetics of the virus even in the same individual over time. With the high mutation rate and high turnover rate, it is possible for this virus to generate resistant versions in a distressingly rapid and ecient manner. Presumably, this modulating characteristic of the virus explains in part why the immune response alone is unable to control the infection and why antiviral medications cannot eradicate it.
Clinical characteristics of acquired immunodeciency syndrome dementia complex The full manifestations of ADC are characteristic of a subcortical dementia in which cognitive decline and motor slowing are the predominant characteristics, colored by a variable degree of behavioral change. Cognitive decline is subacute with a course of at least 6 months in most cases. Abrupt changes in cognition are generally not attributable to HIV itself. In questioning subjects, one nds that there is often insight into the progressing cognitive decline. Patients often discover that they have increased problems with concentration interfering with their ability to perform tasks, enjoy reading, and eventually concentrate on hobbies and avocations. Language involvement is variable but generally not prominent. Patients often compensate by writing reminders and making lists. Motor slowing is a virtually uniform feature of this process, to the extent that clinical trial testing can be heavily weighted to timed motor tasks that reliably monitor the severity of the disorder. Motor slowing aects patients ability to get around and to accomplish tasks as well as their independence. It generally involves the arms and legs. Symmetric involvement is typical of ADC, and any major degree of lateralized asymmetry should arouse serious suspicion that additional opportunistic processes are involved. Behavioral changes are variable. A depressed aect may be particularly pronounced in this setting, but the performance decits can generally be clearly separated from an aective disorder. Rarely, frank psychotic changes are observed, generally for relatively brief intervals. Other neurologic manifestations that accompany ADC include some increase in the frequency of seizures and increased complaints of headache.
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Epidemiology ADC is seen primarily in advanced HIV patients in whom immunodeciency has developed. Although it may be the presenting complaint leading to the diagnosis of AIDS, this is rarely the case. Instead, it complicates the disease course of subjects who often have multiple medical problems because of the broad impact of immunodeciency. Before eective antiviral therapy was developed, ADC developed in more than 60% of patients developing AIDS [3]. The introduction of zidovudine (ZDV) therapy and, subsequently, dual nucleoside therapy resulted in a decline in ADC to the range of 20% [6]. The more recent introduction of highly active antiretroviral therapy (HAART) has further reduced the incidence to considerably less than 10% of AIDS patients. In HAART-treated patients, ADC has declined less than other complications, however, now representing a greater proportion of AIDS-dening clinical events [7]. Further, it is notable that ADC is now encountered more commonly in patients with a higher CD4 count. Dore et al [7] report that the median CD4 count in subjects with ADC rose from 70 to 170 cells per cubic millimeter after the introduction of HAART. Additional factors that are associated with an increased risk of dementia include anemia, constitutional symptoms, and wasting [8]. Advancing age has been suspected as a risk but has not been clearly demonstrated as such. Similarly, it has not been clear that exposure through intravenous drug use is associated with a risk dierent from that of sexual exposure for the development of ADC [9]. The impact of viral replication is clearly important; this is supported by the declining incidence of ADC with increasingly eective treatment and by the observation that ADC patients have a higher HIV viral load in the cerebrospinal uid (CSF) than patients without ADC [10].
Pathologic characteristics and mechanisms The pathologic characteristics of HIV infection in the brain often seem to be less impressive than the functional impact would predict, but careful analysis of the brain reveals many pathologic changes [1113]. The onset of neurocognitive dysfunction in HIV is likely associated with modication of synaptic architecture in the cortex [14,15]. In the hippocampus, a stereologic study demonstrated cell atrophy without loss of cell numbers [16]. Cortical atrophy develops as HIV infection progresses. In advanced stages, this is grossly apparent and is obvious in loss of thickness of the cortical mantle [17]. Quantitatively, neuronal cell loss has been demonstrated in frontal [18] and temporal regions [19]. Not all neuronal types are equally likely to be killed [17,20,21]. Apoptosis [22,23] is probably a common pathway for cell loss and is somehow accelerated in the setting of HIV. Because ADC has the appearance of a subcortical dementia, it is not surprising that there is ample evidence of involvement in subcortical structures.
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From the earliest descriptions of the brain in HIV, notable involvement of the subcortical white matter has been described, with the presence of multinucleated giant cells often loaded with the virus and change in the staining characteristics of white matter being prominently described. The subcortical gray matter also seems to be preferentially involved. Early positron emission tomography scans demonstrated the earliest stages of ADC associated with hypermetabolism in deep gray structures [24], and this is followed by loss of volume that is notable in MR scans when basal ganglia atrophy develops in association with ADC [25]. HIV is primarily replicated in monocytes and macrophages in the brain [26]. In groups, the presence and severity of ADC correlates with the levels of productive HIV replication within the brain [27]. In individual cases, however, high viral load is sometimes found without dementia, and some patients with dementia have low brain viral loads. In ADC, there is an association with multinucleated macrophages and leukoencephalopathy seen on pathologic examination, but, again, these ndings are not uniformly seen in patients with ADC. Although astrocytes may be infected, they do not seem to be a source of replicative infection. This does not mean that viral-induced changes in astrocytic function, so critical to maintaining the brain environment, may not be an important aspect of the clinical syndrome. Neurons are rarely, if ever, infected. It is thus implied that the changes in neuronal performance that must underlie behavioral changes are indirect rather than direct. Indirect mechanisms that may be responsible for this changed neuronal behavior are probably myriad. Portions of the HIV virus have been postulated to have critical importance, with most evidence accruing to the impact of the envelope glycoprotein, gp120 [28]. Recent evidence has linked Tat with neurotoxicity by a number of mechanisms [2931], including a recent report linking it to the metabolic balance of low-density lipoprotein receptorrelated protein ligands as well as to direct activation of neuronal genes [32]. Cytokines have also been implicated in the indirect mechanisms resulting in neuronal dysfunction in ADC. When messenger RNA was analyzed in brains of ADC patients, tumor necrosis factor-a message was found to be most closely associated with the development of dementia [33]. b2-microglobulin [34,35], neopterin [36,37], and quinolinic acid [38] have been demonstrated to be elevated in CSF in proportion to progressing ADC when other causes of activation are excluded. Although therapeutic drug activity within the CNS seems to be of critical importance to understanding AIDS dementia treatment, it has been surprising that even with regimens that penetrate the CNS and CSF compartments relatively poorly, the protective CNS benets for HIV therapy remain. The hypothesis that the development of dementia may be initiated outside the brain would be consistent with this observation. Pulliam et al [39] reported signicant elevations of peripheral CD14/CD16 and CD14/CD69 monocytes associated with the development of AIDS dementia. Gartner [40] has proposed the hypothesis that peripheral events may be primary in triggering
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AIDS dementia. It could be that bone marrow populations are activated in late-stage disease, leading to the development of monocyte subsets associated with ADC. The activated cells probably transmigrate into the brain, readily setting up the physiologic changes leading to dementia. If this were true, peripheral control of the disease should protect subjects from dementia. The alternative scenario that remains of great concern to investigators is that the CNS represents a distinct compartment in which HIV infection can develop less impeded by drug treatments and that it becomes the nidus of treatment failure, manifesting neurologic complications particularly in late disease. Longitudinal data to assess the peripheral and CSF compartments (and the brain after death) are critical to a more certain understanding of the dynamic interaction between peripheral and central viral infection in the genesis of neurologic disease.
Diagnosis and monitoring Diagnosis of ADC is made by recognition of a compatible clinical picture in the setting of HIV infection and exclusion of alternative causes for these clinical changes. Research criteria have been articulated in the report of the American Academy of Neurology AIDS Task Force [4]. Ideally, an informant should assist in corroborating the change in cognitive and motor functions typifying ADC, whereas neuropsychologic testing may be used to quantify performance measures. Most HIV neurology studies have used widely available neuropsychologic tests, including representative measures of attention/working memory, speed of information processing, learning, and motor skills. Ancillary measures that are essential include brain imaging studies and CSF evaluation. Brain imaging is not diagnostic, but it is a critical means of helping to rule out alternative diagnoses. MR brain scanning detects more lesions than CT, with its greater sensitivity for pathologic changes, particularly in the white matter. Recent reports suggest that focusing on white matter by the use of diusion tensor imaging might further enhance the ability of MR to detect the subtle white matter changes caused by HIV [41]. MR scanning is optimal for screening for other diagnoses, although CT scanning allows reliable exclusion of most mass lesions, including toxoplasma encephalitis and lymphoma. CNS complications such as toxoplasma encephalitis, progressive multifocal leukoencephalopathy, and primary CNS lymphoma have notable abnormalities on MRI that should turn the clinicians attention to these alternative causes of neurologic abnormality. Absence of massive space-occupying CNS lesions also augments the safety of performing lumbar puncture. CSF evaluation is important. Cryptococcal meningitis may mimic ADC and is best excluded when cryptococcal antigen is absent from the CSF. CMV encephalitis is one of the most serious considerations in the dierential diagnosis, and it can be excluded by absence of
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CMV DNA on polymerase chain reaction testing of CSF [42]. Neurosyphilis should also be considered when sexually transmitted diseaserelated dementia is being considered. CSF testing for syphilis is important in excluding this consideration. CSF cannot conrm the diagnosis of ADC, because ndings are nonspecic. Typically, a few mononuclear cells are found (as they are throughout HIV infection), and CSF protein may be slightly elevated, although glucose is generally in the normal range. Oligoclonal bands may be found in the CSF in the setting of HIV infection but are not limited to ADC patients. In advanced disease, elevations of neopterin and b2-microglobulin correlating with increasing dementia have been reported [37]. HIV viral loads have been studied in the CSF. Overall, ADC subjects have higher viral loads than undemented controls [10,43], but elevated viral loads are not necessarily associated with dementia, and dementia is sometimes seen in the absence of elevated viral loads. Correlates of ADC in the CSF include b2-microglobulin [34,35], neopterin [36,37], and quinolinic acid [38]. Elevated levels of soluble Fas and Fas ligand in the CSF [44] were recently described. These elevated levels associated with ADC declined with successful treatment and decreasing viral loads. Fas is involved in the execution of apoptotic programs and thus may be a rationale link to neuronal loss causing neurologic impairment. One of the promising means of tracking HIV brain involvement uses MR spectroscopy [4547]. This MR-based technique allows noninvasive measurement of several brain metabolites reecting neurons and glia. Advancing ADC has been accompanied by declining N-acetylaspartate and early elevations in choline reecting neuronal loss and gliosis, respectively [48]. Recent studies with perfusion MR scanning also suggest that MR techniques allow monitoring of cerebral blood ow, which seems to diminish as ADC progresses [49].
Therapy HIV therapy has evolved rapidly over the past decade, propelled by the urgent need to address this devastating viral disease. Improvements in general therapy for HIV have led to marked improvements in life expectancy and quality of life and have been accompanied by improvements in the neurologic complications. The unique aspects of the brain and CSF compartment, which involve barriers to drug penetration and a dierent immunologic milieu, make it critical to maintain additional vigilance for incongruity of response in these compartments compared with plasma, where most observations informing drug development occur. Further, inability to completely clear this viral infection and the potential of indirect mechanisms to cause complications even when the replicative viral infection is largely controlled make it critical to continue to study the evolution of ADC in the HAART era.
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HIV therapy is rapidly evolving. Some of the drugs required have complicated and important drug interactions. It is thus best for HIV patients to be managed by clinicians with extensive practice in this area. HIV specialists have the incentive and opportunity to stay abreast of current therapeutic knowledge. Without this investment, care is often suboptimal, leading to inferior clinical outcomes. The best point after infection for initiation of therapy remains uncertain. This therapeutic decision must balance the rational desire to treat infections early when involvement may be minimal and complications have not occurred with the recognition that current therapy has substantial long-term toxicities, is expensive, and inevitably results in evolution of resistant virus over long periods of use. The current trend in academic centers is moving toward delayed initiation of drug therapy because of these concerns. Current recommendations suggest initiation of therapy in acute infection or symptomatic infection. For asymptomatic subjects, therapy should be oered when viral loads are high (>55,000 copies per milliliter) or the CD4 count has fallen to levels less than 350 cells per cubic millimeter. Evolving recommendations may be studied as they are developed by a panel of experts working with the International AIDS SocietyUSA (http://www.hivatis.org). Once therapy is undertaken, the goal is to achieve maximal viral suppression with minimal toxicity. Most subjects should reach undetectable levels of HIV virus in the plasma with currently available HAART therapy. Ongoing research probes the ability of resistance testing to improve drug selection by genotypic or phenotypic techniques, the role of therapeutic drug monitoring in dose selection, and tools to enhance compliance, which is absolutely essential to therapeutic success. Currently, three classes of antiretroviral medications are approved, with 15 approved drugs available as follows: Nucleoside reverse transcriptase inhibitors (NRTIs) Abacavir (Ziagen) Didanosine (Videx) Lamivudine (Epivir, Combivir) Stavudine (Zerit) Zalcitabine (Hivid) Zidovudine (Retrovir, Combivir)
Nonnucleoside reverse transcriptase inhibitors (NNRTIs) Delavirdine (Rescriptor) Efavirenz (Sustiva) Nevirapine (Viramune) Protease inhibitors (PIs) Amprenavir (Agenerase) Indinavir (Crixivan)
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Lopinavir / ritonavir (Kaletra) Nelnavir (Viracept) Saquinavir (Fortovase) Ritonavir (Norvir)
The rst class of drugs developed was the NRTI class, which includes ZDV (also known as AZT), didanosine (ddI), zalcitabine (ddC), lamivudine, stavudine (d4T), and abacavir (ABC). These drugs are important components of most standard treatment combinations, and exploration of a triplenucleoside HAART regimen also seems to be acceptable [50]. Because resistance tends to develop within classes of drugs, delaying exposure to other classes of drugs has a signicant theoretical benet. Major toxicity of NRTI drugs includes bone marrow toxicity (ZDV), pancreatitis (d4T, ddC, ddI), rashes (most serious hypersensitivity reaction with ABC), distal sensory peripheral neuropathy (ddI, d4T, ddC), and lactic acidosis. Other less common neurologic toxicities include myopathy (ZDV) and headache (especially ZDV). The second class of drugs developed was the NNRTI class. These drugs specically block the active site of HIV-1 reverse transcriptase. These are potent compounds that are highly specic for HIV-1 alone. They are drugs useful only in combinations, because resistance develops quite rapidly in monotherapy. They are extremely important components of HAART, however. The chief toxicities of this class are hypersensitivity reactions with rashes, and hepatic toxicity. Approved drugs in this class include nevirapine, delavirdine, and efavirenz. Neurologic toxicity has been the most common issue with efavirenz, with more than half of subjects reporting a detectable change in sleep, dreaming, attention, or alertness [51]. Fortunately, this is mild in most cases and tolerated well enough to allow continuation of the therapy. Symptoms tend to recede over the initial weeks of therapy. The third class of antiretroviral agents is the PI class. These drugs, including saquinavir, ritonavir, indinavir, nelnavir, amprenavir, and lopinavir, revolutionized HIV therapy when they were introduced. Their marked ecacy when combined with NRTI drugs vastly increased the ability to achieve prolonged viral inhibition, resulting in fewer opportunistic complications, longer life, and improved quality of life. The combination therapies originally including PIs were referred to as HAART. As potent NNRTI and NRTI drugs have been introduced, the concept of HAART has been broadened to include the numerous triple or more drug-containing regimens that typically can achieve undetectable HIV RNA viral loads. Improvements in the overall health of HIV patients associated with HAART are not without a price in toxicity. Long-term complications associated with these drugs in conjunction with the other antiretroviral agents are a growing source of concern. Gastrointestinal toxicity with nausea, diarrhea, and hepatic toxicity has been seen with drug regimens that contain PI drugs. Metabolic complications, including insulin resistance and the
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development of diabetes, elevated cholesterol, and elevated triglycerides as well as osteopenia and lipodystrophies, are active areas of research associated with the use of HAART. Some of these complications may combine to accelerate atherosclerosis with the risk of premature cardiovascular and cerebrovascular disease. Because ADC seems to be triggered by HIV replication in the CNS, selection of optimal antiretroviral therapy is an important consideration. Comparative trials of dierent antiviral regimens have not been undertaken for neurologic disease. At present, optimizing the ecacy of the treatment for full control of the plasma viral load would appear to be the primary goal of therapy. Many neuroAIDS specialists are monitoring the response of HIV viral load in the CSF as a part of such therapy. Generally, a successful response in plasma is accompanied by a decline in CSF viral load as well [52]. If this did not occur and ADC were suspected, eorts to enhance CSF and CNS penetration would be appropriate. PIs are highly protein bound and enter the CSF and CNS only in low concentrations. The least protein bound of these drugs is indinavir, and its CNS ecacy is better established than that of the other PI drugs [53]. Use of NNRTI drugs may be of advantage in the setting of neurologic disease. Nevirapine seems to cross the blood-brain barrier quite eectively [54], whereas efavirenz has been documented to at least achieve therapeutic free drug concentrations in the CSF [55]. In the NRTI class, ZDV has the best evidence of ecacy against ADC [56], but d4T [52] also seems to be ecacious in lowering viral load in the CSF [52]. ABC is potent, has good CSF penetration, and thus is seen as a good drug to use in this situation. Nevertheless, a placebo-controlled trial of this drug in patients with ADC failed to demonstrate ecacy when it was added to optimal therapy in the setting of ADC. The study did provide evidence of ABC antiretroviral activity in CSF studies, however [57]. Consequently, construction of a treatment program with these specic drugs is probably optimal. Design of antiviral therapy for ADC should consider other criteria as well. Achieving strict compliance with therapy is crucial to success for HIV therapy, because the rapid turnover of the virus means that even brief lapses of therapeutic ecacy allow time for viral replication and selection of resistant mutants. With cognitive function impaired, the needed focus on compliance goals may threaten therapeutic success. A supportive environment designed to ensure compliance should be sought for ADC patients. As with other patients, simplied drug regimens are easier to follow and may be of particular value with cognitively impaired populations or where directly observed therapy is tried. Extended-release forms of some of the drugs are in development, and the once-a-day dosing of efavirenz should make these formulations of particular value if they are otherwise satisfactory. Finally, side eects routinely encourage noncompliance; thus, working closely with patients to achieve the most tolerable set of medications may also pay handsome dividends in clinical success.
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At present, clinical evidence primarily supports eorts to optimize antiretroviral therapy without clear evidence that other forms of therapy improve the outcome for patients with ADC. The belief that indirect mechanisms are important in developing the neurotoxicity underlying ADC suggests that other forms of therapy might be quite helpful. Mechanisms of toxicity for which there is at least in vitro evidence include calcium-mediated toxicity, excitotoxicity mediated by N-methyl-D-aspartate, oxidative stress, cytokine-mediated damage, platelet activating factormediated neuronal injury, nitric oxidemediated toxicity, and toxicity of viral components, including gp120 and Tat [28,5860]. A substantial group of small clinical trials have explored some of these mechanisms, including trials of nimodipine [61], lexipafant [62], peptide T [63], selegiline [64,65], CPI-1189 [66], and memantine [67]. The most promising results to date have been seen in the small trials of selegiline, and a larger trial is currently enrolling subjects sponsored by the Neurologic AIDS Research Consortium and the AIDS Clinical Trials Group to further investigate this drug. Selegiline is to be administered transdermally in this trial (A5090). Updates on clinical trials for ADC may be obtained by consulting the web site of the Neurologic AIDS Research Consortium (www.neuro.wustl.edu/narc). Major questions HIV infection has resulted in many opportunities to learn more about medicine and neurology. The treatments devised have already resulted in longer and healthier lives for our patients. We still are challenged by an incomplete understanding of the pattern of tracking of the virus across the blood-brain barrier and by the potential pathologic mechanisms resulting in ADC and other neurologic consequences of infection. Because the CNS compartment represents a challenge to treatment, it remains a concern that over the extended survival time now achieved by our patients, the brain may become a recurrent source for infection or that accelerated degenerative processes may result in more serious and common neurologic disease later in the course of infection. Ongoing studies focusing on the CNS and CSF are continuing to unravel the virology, pharmacology, and pathologic consequences in the brain and CSF. References
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Med Clin N Am 86 (2002) 551571
Human prion diseases

Man-Sun Sy, PhDa,*, Pierluigi Gambetti, MDb, Boon-Seng Wong, PhDb
Division of Neuropathology, Institute of Pathology, and Cancer Research Center, Room 933 Biomedical Research Building, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44120-1712, USA b Division of Neuropathology, Institute of Pathology, School of Medicine, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44120-1712, USA
a
Transmissible spongiform encephalopathy (TSE) is a group of rare, subacute, fatal neurodegenerative diseases in human beings and animals [13]. In human beings, TSE includes Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal familial insomnia (FFI), and kuru. CJD and GSS have been known since the 1920s [2]. Kuru, a disease conned to the Fore linguistic group, a tribe in PapuaNew Guinea, was rst reported in the 1950s by Gajdusek [1]. In Fore language, kuru means to tremble or shake and graphically describes a symptom of the disease. FFI is a much more recent disease that was rst described in 1986 by Goldfarb and colleagues [4]. From the onset, it was recognized that some of these spongiform diseases, such as GSS, occur in clusters in an inherited familial manner [2]. Some histopathologic features of this group of diseases are spongiform vacuolation, astrocytic proliferation, and neuronal loss [2]. GSS has a unique phenotype with the presence of multicentric amyloid plaques. The clinical presentations of these diseases as well as the levels of histopathologic lesions and their distribution in the central nervous system (CNS) vary from case to case. It has been suggested that there are variants in each disease [5,6]. These variations hampered earlier histopathologic and clinical diagnose of these diseases. In recent years, human TSE diseases have been classied on the basis of pathogenic mechanisms instead of histopathologic and clinical observations [2]. Human TSE diseases were divided into three basic categories: the
* Corresponding author. E-mail address: mxs92@po.cwru.edu (M.-S. Sy). 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 4 - 4
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familial form, as in GSS and FFI cases and some CJD cases; the infectious form, as in kuru and iatrogenic CJD; and the sporadic form, as in 85% of human TSE cases, which occurs sporadically via unknown mechanisms (Table 1). In animals, major TSE diseases include scrapie in sheep and goats, transmissible mink encephalopathy in mink, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease (CWD) in deer and elks (see Table 1). TSE has also been found in captive animals in the zoo as well as in domestic cats. A major breakthrough in our understanding of these diseases was the serendipitous discovery of histopathologic similarities between the brains of kuru patients and the brains of sheep and goats with scrapie, a TSE disease [1]. Scrapie has been known in the United Kingdom for more than 200 years. It was commonly thought to be a genetic disease [7], that is, some herds of sheep were susceptible, whereas others were resistant. In 1936, however, Cuille and Chelle demonstrated that scrapie was a transmissible disease [8]. Based on this lead, Gibbs and Gajdusek demonstrated the transmissibility of kuru and then of CJD in the 1960s, followed by that of GSS in 1981, from human beings to primates [1,3]. Experimental transmission was most eciently achieved by injecting homogenates into the brain of recipient animals. The homogenates were prepared using brains from aected subjects. Subsequent studies revealed that the natural transmission of kuru most likely occurred through cannibalism, which was practiced as part of the funereal ceremony common to the Fore linguistic group [1]. The incubation period of kuru could be as long as four to ve decades [1]. Cessation of
Table 1 Transmissible spongiform encephalopathy diseases in human beings and animals Form Human beings Sporadic Inherited Phenotype Creutzfeldt-Jakob disease Fatal familial insomnia Creutzfeldt-Jakob disease Fatal familial insomnia Gerstmann-Straussler-Scheinker disease Undened or mixed Iatrogenic Creutzfeldt-Jakob disease (tissue grafts, surgical instruments, hormones) Kuru (contaminated food) Variant Creutzfeldt-Jakob disease (contaminated food?) Scrapie Bovine spongiform encephalopathy Chronic wasting disease Transmissible mink encephalopathy Transmissible spongiform encephalopathy of domestic and captive animals
Acquired by infection
Animals Probably all acquired by infection
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cannibalism since the 1950s has gradually eliminated the disease. Like other infectious diseases caused by microbes or viruses, kuru can be acquired exogenously, specically by the ingestion of contaminated foods. The infectious agent spreads from the digestive tract to the CNS, a process known as neuroinvasion. The mechanisms of neuroinvasion are not clear. It is believed that the infectious agent can travel from the peripheral to the CNS either via the peripheral nervous system or via the circulatory system [3]. Scrapie has a 200-year history in the United Kingdom and is endemic [7]. No transmission of scrapie to human beings has yet been reported, however. In the past, experimental animal models showed that the infectious agent is highly species specic [3]. Hence, transmission of scrapie was thought to be impossible because of the existence of this species barrier between the agent and the host. It is now clear that this species barrier can be violated in experimental animals, and it can also be penetrated outside the laboratory [8]. The barrier is not permanent, because the agent of TSE can cross the species barrier after repeat passages in the host. Recently, a novel form of CJD called variant CJD (vCJD) that is believed to be acquired from cattle aected by BSE (commonly known as mad cow disease) has emerged in the United Kingdom [9]. The development of BSE in England in the 1980s has been traced to the consumption of meat and bone meal fed to cattle [9]. This dietary supplement was contaminated by scrapieinfected ovine. It became infectious in the 1980s when rendering plants abandoned the use of organic solvents that inactivated the infectious agent. By jumping the species barrier, the infectious agent has transmitted scrapie from sheep to cattle and from cattle to human beings. Dietary supplement contaminated with scrapie-infected ovine is also the culprit for transmissible mink encephalopathy in mink and for most of the TSE cases in captive animals in the zoo. Despite the relative rarity of the cattle-to-human transmission route, TSE diseases have captured considerable attention because of their unique pathogenic mechanism and their potential threat to public health. Overall, TSE diseases are rare in human beings. The annual rate is approximately 1.5 per 1 million people per year, a rate that has remained stable over the last few decades [2,10]. Many case-control studies have attempted to identify the risk factors in these diseases [8]. So far, there is no conclusive evidence to suggest that the frequency of the disease is linked to gender, occupation, geographic location, or environmental factors. The exception occurs in cases where there is a familial link between aected individuals. These cases represent the familial form of the TSE diseases. All patients with sporadic TSE diseases suer from cognitive decits, including psychiatric and behavior abnormalities. For sporadic diseases, the onset of disease most frequently occurs between the fth and seventh decades of life. Clinical laboratory results reveal no evidence of inammation, abnormal blood chemistry, or malfunctions of hepatic or renal systems. Immune responses also have not been detected in aected individuals. The mean survival time for patients with sporadic diseases is approximately
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5 months, and most patients die within 1 year. The inherited form of the diseases has an earlier age of onset and a more protracted disease course than the sporadic form [2]. At variance with other neurodegenerative diseases, human TSE diseases have been acquired via infectious mechanisms, as most vividly demonstrated by kuru. Physicians have also inadvertently transmitted the disease to patients as a result of medical procedures. These cases are commonly referred to as iatrogenic CJD [2]. Human transmission was most convincingly demonstrated when TSE disease developed in two young patients who underwent stereotactic electroencephalographic exploration with silver electrodes. The electrodes had previously been implanted in a patient with TSE disease [2]. The electrodes were sterilized with 70% alcohol and formaldehyde vapor, which was sucient to eliminate microbes and viruses but did not destroy the TSE agent. Furthermore, more than 80 cases of iatrogenic diseases have been reported after neurologic transplants of human cadaverderived dura mater. More than 100 cases of iatrogenic diseases have also been linked to injection of cadaver-derived growth hormone and gonadotropic hormone [2]. It is presumed that the dura maters and the hormones were harvested from donors who might have died of unrecognized TSE diseases. More recently, a cluster of seven TSE cases surfaced in a small village with a population of approximately 70,000 in Australia (C.L. Masters, personal communication, 2001). All seven patients are unrelated, and the common feature of the group is that three of the seven patients have visited the same ophthalmologist. It is clear that TSE can be transmitted by invasive medical procedures under some conditions. Nevertheless, based on the number of surgical procedures that have been carried out and the number of iatrogenic TSE cases that have been reported, the risk of contracting TSE as a result of surgery must be low. The onset, frequency, and duration of the iatrogenic form of the diseases are much more variable than those of either the sporadic form or the inherited form. The incubation period for iatrogenic diseases ranges from 6 months to 19 years. These variations reect dierences in the levels of exposure as well as in the route of infection. Intracranial infections, as in the cases of electrode implantation or dura mater transplants, have a shorter incubation period. Extracranial infections, as in the cases of growth hormone injection, tend to have a much longer incubation period. Similar to patients with sporadic disease, patients with iatrogenic disease develop ataxia and movement disorders followed by dementia. Human TSE is clearly transmissible, but the rate of transmission from human beings to primates varies from disease to disease. Based on studies carried out over a span of 30 years involving 300 cases of human TSE and close to 2000 primates, Brown and colleagues [11] found that the transmission rates were higher for iatrogenic CJD (100%), kuru (95%), and sporadic CJD (sCJD) (90%) and lower for the familial form of diseases (68%). Transmission best correlated with the presence of spongiform pathologic ndings
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(80%). The absence of spongiform change was a better indicator of nontransmissibility, however. The brain, spinal cord, and eye consistently have the highest infectivity [11]. In contrast, infectivity in other tissues was much lower and was only detectable in a limited number of inoculated animals. No infectivity has ever been detected in any body uids, including the transfusion of full units of blood from CJD donors into chimpanzees, the most susceptible host. This observation is consistent with the ndings of epidemiologic studies, which have failed to uncover any link between blood transfusion and human TSE to date [9]. Neither patients with hemophilia nor intravenous drug users have increased risk. A number of CJD patients have been known to donate blood over extended periods of time. The tracking of the blood recipients has failed to uncover any development of CJD in this group so far [9]. Therefore, although the infectious agent has been reported to be present in non-CNS locations, including blood, in experimentally infected animals, there is no evidence to suggest that the agent is present in the blood of aected human beings. It has been known since 1936 that scrapie is a transmissible disease. The nature of the etiologic agent remained elusive and controversial until the mid-1980s, however. Many attempts to isolate the pathogen were unsuccessful, and many positive reports were never conrmed [3]. The infectious agent was too small to carry nucleic acid and tended to copurify with proteins [3]. Accumulated evidence suggested that the infectious agent in scrapie was highly unusual. It was resistant to agents that destroy nucleic acids but was sensitive to agents that destroy protein [3]. The confusion and frustration are best summarized by the names assigned to this elusive pathogen (eg, slow virus, virino, virods [plant virus] or, simply, unconventional viruses) [3].
Prion concept and protein-only hypothesis In 1967, Grith [12] was the rst to propose that the agent for TSE is a self-replicating protein rather than a bacteria or virus. Prusiner [3] made the fundamental discovery that led to our current understanding of these diseases, however. In 1982, Stanley Prusiner and his colleagues isolated and tentatively identied the infectious pathogen, which they termed a proteinaceous infectious particle or prion. Since then, the name prion disease has been used synonymously with TSE. Later, the same group found that the prion is an aberrant isoform of a protein that is normally expressed and highly conserved in all mammals [13]. The normal human cellular prion protein (PrPC) is encoded by a single gene in the short arm of chromosome 20 [13]. All three forms of prion diseases (hereditary, sporadic, and infectious) are believed to share the same pathogenic mechanism, which is based on the conversion of the normal PrPC into the pathogenic prion protein (PrP), commonly called scrapie PrP (PrPSc). As a result, PrPSc has the unique and fundamental property of being
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a self-replicating and infectious agent that lacks nucleic acid. Although the conversion hypothesis provides a mechanism for the propagation of PrPSc, the mechanisms by which PrPSc causes neurodegeneration remain unclear. In addition to the CNS, PrPC is expressed at high levels in many non-CNS tissues, including the heart, lymphoid tissues, and muscle [3]. In all human prion diseases, with the exception of vCJD, no PrPSc has ever been detected in non-CNS tissues. Therefore, the brain is the only site where the conversion from PrPC to PrPSc could occur. Alternatively, conversion may occur in other tissues, but only the CNS has the capacity to accumulate PrPSc. The mechanism by which PrPSc targets the CNS is not known. Two dierent lines of evidence provide the strongest support for the prion concept. The rst line of evidence came from studies in transgenic animals. PrPC knockout mice that do not express PrPC are resistant to infection [14]. Therefore, the presence of the PrPC is essential for PrPSc propagation. The second line of evidence came from clinical studies in human beings. It has been known for decades that some human spongiform diseases, such as GSS and, more recently, FFI, can be inherited in an autosomal dominant fashion [2]. The identication of the prion gene suddenly permits investigators to determine whether any of the inherited forms of human prion disease are linked to the PrP gene. Indeed, more than 20 pathogenic mutations have been found in the coding sequence of the PrP gene in patients with the inherited form of the diseases [3]. Pathogenic mutation represents approximately 15% of the human prion diseases. Pathogenic mutations are broadly divided into those that cause point mutations and those that cause insertion mutations in the coding region. Whereas it is generally accepted that normal cellular PrPC is critical for the pathogenesis of prion diseases, it should be noted that the prion concept or the protein-only hypothesis is not universally accepted. Some skeptical investigators still question whether prion by itself is sucient for the pathogenesis of the diseases [15]. Normal cellular prion protein In human beings, PrPC is a small glycoprotein bound to the cell surface by a glycosyl-phosphatidyl-inositol (GPI) anchor [16]. The full-length PrPC, which includes 209 amino acids (residues 23231), can be arbitrarily divided into three subregions: (1) the N-terminus region, which encompasses approximately the rst 90 amino acids and has a highly conserved motif of ve repeating octapeptides; (2) the central region, which is located approximately between amino acids 110 and 125; and (3) the C-terminal region, which has two highly conserved nonobligatory N-linked glycosylation sites and a disulde bridge between residues 179 and 214 (Fig. 1) [3]. In the human brain, PrPC is expressed in three glycoforms [5]. It is believed that these three glycoforms represent: (1) the diglycosylated form, which migrates at 33 to 42 kd; (2) the monoglycosylated form, which migrates at 29 kd; and (3) the unglycosylated form, which migrates at 27 kd
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Fig. 1. Diagrammatic representation of human prion protein after posttranslational modications. The normal cellular prion protein can be divided into three regions: the N-terminus region, the central region, and the C-terminus region. Most of the secondary structure elements, the a-helices, and b-sheet structures are located in the C-terminus as well as two potential Nlinked glycosylation sites and the disulde bonds.
(Fig. 2). The N-link glycans are complex, as exemplied by the murine PrPSc, which has over 60 dierent carbohydrate structures [17]. This variety indicates that the glycans play a complex role in the physiology of PrPC and may be important in the pathogenesis of the diseases [18]. Nuclear magnetic resonance analysis of recombinant PrPC shows that the N-terminus region is highly exible. It also shows that the central region is partially structured and hydrophobic. In contrast, the C-terminus region includes three a-helices and two short antiparallel b-strands, which form a well-structured core domain when combined (see Fig. 1) [19,20]. PrPC knockout mice are normal; thus, expression of PrPC is not obligatory for survival in mice [21]. Recent in vitro and in vivo studies suggest that PrPC is a metalbinding protein and may be important in oxidative stress responses [22].
Pathogenic mechanism: conversion of normal cellular prion protein to scrapie prion protein The PrPC-to-PrPSc conversion is based on a conformational change from the predominantly a-helical structure of PrPC to the predominantly b-sheet structure of PrPSc (see Fig. 2) [23]. PrPC has 42% a-helix content and 3% b-sheet content. In contrast, the b-sheet content of infectious PrPSc increases to 43%, and the a-helix decreases to 30%. According to the most recent model, the PrP is inherently unstable, uctuating between the dominant native state, PrPC, and other intermediate conformers, one or more of which can self-associate to produce a supramolecular structure, PrPSc. This structure then acts as a seed, recruiting the unstable PrP forms, which leads to the formation of new PrPSc through an autocatalytic process [3]. The exact cellular compartment where the conversion processes takes place is not clear. The initial interaction between infectious PrPSc and PrPC
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Fig. 2. Ribbon models of the tertiary structures of hamster cellular prion protein (PrPC) (A) and scrapie prion protein (PrPSc) (B) based on nuclear magnetic resonance studies of PrP108 231 and major biochemical dierences between PrPC and PrPSc. The PrPC-to-PrPSc conversion is based on the change in conformation from the predominantly a-helical form of PrPC (light ribbons) to the predominantly b-sheet structure of PrPSc (dark ribbons). (From Prusiner SB. An introduction to prion biology and diseases. In: Prusiner SB, editor. Prion biology and diseases. Cold Spring, NY: Cold Spring Harbor Press; 1999. p. 168; with permission.)
is believed to occur rst in the plasma membrane and then in the endosome [24]. The presence of the GPI anchor is important for the conversion processes to occur [16]. The GPI anchor may be needed, because GPI-anchored proteins occupy microdomains on the cell membrane known as detergentinsoluble complex in a concentrated and multimeric form, and the detergent-insoluble complex may facilitate the initial interaction [25]. Disulde bonding is also important in the conversion process [26] and seems to be inversely related to the glycosylation in PrPC [18]. Extensive cell model stud ies support this interpretation [27]. Indirect evidence suggests that the conversion process requires PrPSc to interact with PrPC either directly or through the help of protein X or chaperones [28]. To date, a molecular chaperone has not been identied. Conversion of PrPC by exogenous PrPSc has been demonstrated in vitro in a cell-free system [29]; however, the process is inecient because of the absence of cofactors or the chaperone protein [30]. The conformational changes in PrPSc also result in drastic alterations in its biochemical properties. Some of these changes are summarized in Table 2. One of the consequences of the conformational change is that although the N-terminal region of PrPSc remains sensitive to treatment with proteases, the C-terminal region from residues 80 to 231, also known as PrP2730, becomes protease resistant. In contrast, the entire PrPC is protease sensitive. The accumulation in the brain of PrPSc that is resistant to proteases has
M.-S. Sy et al / Med Clin N Am 86 (2002) 551571 Table 2 Dierences between normal human cellular prion protein and scrapie prion protein PrPC Monomer More a-helix Relatively more soluble in detergent Sensitive to in vitro digestion with proteinase K Noninfectious Present in CNS and many non-CNS tissues PrPSc
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Oligomeric or polymeric More b-sheet Less soluble in detergent Relatively more resistant to proteinase K Infectious Only in CNS
Abbreviations: PrPC, normal human cellular prion protein; PrPSc, scrapie prion protein; CNS, central nervous system.
provided a useful diagnostic test for prion diseases [6,31]. The commonly used protease is proteinase K (PK) (Fig. 3). Resistance to PK is the only in vitro test by which one can distinguish PrPSc from PrPC. Sensitivity to PK in vitro is relative rather than absolute, and the levels of PK-resistant PrPSc vary greatly between dierent prion diseases. In a small number of cases, no PK-resistant PrPSc was detected [32]. Therefore, the presence of PKresistant PrPSc might not be required for pathogenesis in some situations. Brown and colleagues [11] have also evaluated the relation between transmissibility of diseases and the presence of PK-resistant PrPSc in human
Fig. 3. Resistance of scrapie prion protein (PrPSc) but not cellular prion protein (PrPC) to proteinase K (PK) digestion in vitro. Brain homogenates were prepared from two nonCreutzfeldt-Jakob disease (CJD) cases and two conrmed CJD cases. Each sample was divided into two tubes: one sample was either not treated (lanes 1 and 2 from non-CJD, lanes 5 and 6 from CJD) or treated with PK (lanes 3 and 4 from non-CJD, lanes 7 and 8 from CJD). After treatment, all samples were separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis and immunoblotted with an anti-PrPC monoclonal antibody as described [47]. No immunoreactivity is detected in non-CJD samples after PK digestion (lanes 3 and 4). In contrast, strong immunoreactivity remained detectable after PK treatment of samples from CJD cases (lanes 7 and 8) (unpublished results) [47].
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prion diseases. Approximately 80% of the transmissible cases contain PKresistant PrPSc. This discrepancy may be a result of the presence of variable amounts of PrPSc in the dierent parts of the brain that were used for in vivo transmission and in vitro immunoblots. Alternatively, the in vivo bioassay may be much more sensitive than the in vitro immunoblots, a fact that has been demonstrated in animal models. Although resistance to PK is a reliable diagnostic test for human prion diseases, it is time-consuming and technically demanding. Only laboratories with the necessary expertise can perform the test. All three forms of prion diseases (hereditary, sporadic, and infectious) are believed to share the same fundamental pathogenic mechanism, which is based on the conversion of the endogenous PrPC (or its conformational variants) into PrPSc [2]. Accumulated evidence also suggests that the conversion involves one or more intermediate conformers [32]. In the hereditary form, which represents about 15% of human prion diseases, the disease is believed to be triggered by the presence of a germline mutation in the PrP gene. This mutation destabilizes the mutant PrP and facilitates its inevitable conversion to PrPSc [2]. More than 20 pathogenic mutations have been found in the human PrP gene. Most of the point mutations are located in the C-terminal regions of the PrP protein (Fig. 4). A pathogenic point mutation in residue 145 has been found to result in the generation of the stop codon and in premature termination of the PrP. Another pathogenic mutation has been identied in the GPI anchor signaling peptide at residue 231. This residue is normally removed during the
Fig. 4. Diagram of prion protein (PrP), including mutations, polymorphisms, secondary structures, and posttranslational modications. Mutations resulting in Creutzfeldt-Jakob disease and fatal familial insomnia as well as polymorphisms (long arrows) are indicated above the diagram. Mutations resulting in the heterogeneous and Gerstmann-Straussler-Scheinker disease phenotypes are indicated below the diagram. b b-sheets, H a-helix, S-S disulde bond, CHO N-glycans. (From Gambetti P, Petersen RB, Parchi P, Chen SG, Capellari S, Goldfarb L, et al. Inherited prion diseases. In: Prusiner SB, editor. Prion biology and diseases. Cold Spring, NY: Cold Spring Harbor Press; 1999. p. 168; with permission.)
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attachment of the GPI anchors to the protein and is absent in the mature protein. Collectively, these results suggest that there are multiple pathways in the pathogenesis of the inherited form of human prion diseases. Sixty percent of pathogenic mutations found in human prion diseases involve residue 200, which results in a change from glutamine (E) to lysine (K). Microsatellite analysis searching for E200K mutationassociated haplotypes reveals that this mutation is derived from two families, one in Spain and the other in Slovakia. All E200K cases reported in the United States and Canada are descendants of the Slovakia family, whereas the Spanish family is the origin of the cases in Europe (L.G. Goldfarb, personal communication, 2001). Conversely, insertion mutations have only been found in the octapeptide repeat region [33]. The number of insertions ranges from one to nine octapeptide repeats. It is interesting to note that although insertion mutations in the octapeptide repeat region cause diseases, deletion mutation in the same region does not. As a matter of fact, a single octapeptide repeat deletion is a polymorphism in 1% to 2.5% of the population [2]. Also noteworthy, transgenic mice lacking the N-terminus are susceptible to infectious PrPSc, albeit at a reduced eciency [34]. One of the most intriguing ndings regarding the inherited form of prion diseases comes from studies revealing that a common polymorphism in aminoacid residue 129 of the human PrP gene can greatly modulate disease phenotypes [4]. An individual can be homozygous with methionine (M/M) or valine (V/V) or heterozygous (M/V). Two groups of patients were identied with an identical mutation in residue 178 with a change from aspartic acid to asparagine. The clinical presentations and histopathologies of the two groups diered dramatically, however. In the group with the 129 V/V genotype, the phenotype was more consistent with CJD, with extensive spongiosis, neuronal loss, and astrogliosis in the cerebral cortex region. Lesions were less severe in the thalamus. In the group with the 129 M/M genotype, the phenotype was that of FFI, with preferential thalamic and olivary atrophy. These ndings show that a dierence in one amino acid can drastically alter disease phenotype. The mechanisms by which residue 129 inuences the disease phenotype are not clear. Experimental mutations of the PrP gene in some transgenic mice have led to neurodegeneration in the absence of detectable PrPSc [35]. It is unclear whether PrPSc is solely responsible for all aspects of the pathogenesis and whether all hereditary prion diseases share the same pathogenic mechanism. It should be noted that another transgenic mouse line bearing the same human pathogenic mutation failed to develop neurodegeneration [36]. The reason for this discrepancy is not known. These results suggest that a mutation in the PrP gene may not be sucient to cause neurodegeneration and that other factors unique to human brain may be required for the manifestation of the disease. Sporadic prion diseases are thought to be triggered by a rare and stochastic change of the PrPC conformation, which leads to the formation of PrPSc.
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Even so, one cannot rule out the possibility that some sporadic prion diseases may be caused by non-germline mutations or by unrecognized infectious mechanisms. Interestingly, the 129 polymorphism also inuences the incidence of sCJD in Caucasian patients. Most of the sCJD patients are homozygous with M/M or V/V [10]. In the general population, the frequency of M/M is 37%, V/V represents 12% of cases, and the remaining 51% of cases are heterozygous (Table 3). Accumulated results suggest that homozygosity at residue 129 predisposes an individual to prion diseases. Homozygosity presumably provides more PrPC substrates with similar conformation for conversion. In contrast, heterozygous individuals have two dierent PrPCs with dierent conformations. If this interpretation is correct, it suggests that residue 129 is important either directly or indirectly in the overall conformation of PrPC. Prion diseases contracted by an infectious mechanism are believed to result from exposure to exogenous PrPSc, which binds to endogenous PrPC, causing its conversion to PrPSc [3]. Accumulated evidence in animal models suggests that the successful transmission of a prion disease depends on several factors: (1) the degree of homology between the exogenous PrPSc and the PrPC of the recipient, which may be necessary for the initial binding; (2) the dose of the PrPSc; and (3) the expression of PrPC at the portal entry of the exogenous PrPSc as well as in the various intermediate stations between the portal entry and the CNS of the recipient. The mechanism by which the PrPSc travels from the peripheral to the CNS is not clear. Some investigators believe that the peripheral nervous system is the route of PrPSc entry into the CNS. Other investigators believe that blood cells are involved in the process. Once the initial conversion occurs, it is the endogenous PrPSc that propagates and accumulates, causing the disease. Interestingly, all vCJD cases so far were from individuals homozygous with M/M at residue 129 [9]. Either individuals with M/M are uniquely susceptible to vCJD or other genotypes are also susceptible but with a much longer incubation period.
Rise of variant Creutzfeldt-Jakob disease BSE was rst reported in 1986 in England [9]. The rst conrmed vCJD case was reported in 1996, suggesting an incubation period of approximately
Table 3 Polymorphism at amino-acid residue 129 and incidences of sporadic Creutzfeldt-Jakob disease 129 Genotype Normal Sporadic M/M 37% 71.6% M/V 51% 11.7% V/V 12% 16.7%
Abbreviations: M, methionine; V, valine. Data from Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeer W, Windl O, et al. Classication of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:22433; with permission.
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10 years in vCJD. Since 1996, close to 100 conrmed cases of vCJD have been reported, most of which occurred in the United Kingdom with a few exceptions [9]. The origin of the infection in vCJD has not been rmly established, but considerable evidence points to BSE [37]. Four major lines of evidence associate vCJD with BSE: (1) the outbreak of vCJD with a time delay from and in the same geographic location as the BSE epidemic; (2) the distinct clinical features of vCJD, which set this disease apart from conventional CJD; (3) the similar histopathologic lesion prole in mice inoculated with either BSE or vCJD preparations; and (4) the similar molecular signatures shared between BSE and vCJD. The histopathologic changes seen in the vCJD cases are reminiscent of those seen in kuru, suggesting that similar pathologic mechanisms are involved in these two diseases (ie, consumption of contaminated meat or meat products). Early on, it was recognized that the clinical signs, age at onset of the disease, and CNS pathologic ndings seen in patients with vCJD diered greatly from those seen in patients with conventional CJD. The unusual clinical signs of vCJD patients are prominent behavior changes at the time of clinical presentation, followed by ataxia, dementia, and myoclonus at the terminal stage of disease. In addition, PK-resistant PrPSc is detectable in non-CNS tissues (eg, tonsils, appendix) of vCJD patients but not in patients with conventional CJD [8,38]. Interestingly, PK-resistant PrPSc is detectable in tonsil before the manifestation of clinical signs. Some of the differences between vCJD and conventional CJD are summarized in Table 4. No vCJD has been reported in the United States; however, four cases of prion disease in unusually young patients have been reported [39]. At least three of these patients (whose tissue has been examined by us) had regularly consumed deer or elk meat. Available evidence does not indicate that the prion disease was acquired via exposure to CWD through the consumption of contaminated deer or elk meat, however. CWD was rst recognized as a prion disease in deer and elks in 1980. CWD is endemic in north central Colorado and southeastern Wyoming.
Table 4 Dierences between sporadic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease sCJD Residue 129 genotype Disease onset (mean age) Mean duration of disease CNS histopathology PrPSc type PrPSc outside of CNS M/M, M/V, or V/V 60 years old 5 months No daisy plaques Type 1 or 2 None vCJD M/M only 29 years old 14 months Plaques with daisy-like feature Type 2 only In tonsil and appendix
Abbreviations: sCJD, sporadic Creutzfeldt-Jakob disease; vCJD, variant Creutzfeldt-Jakob disease; M, methionine; V, valine; CNS, central nervous system; PrPC, normal human cellular prion protein; PrPSc, scrapie prion protein.
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Can sCJD also be caused by ingestion of infected meat? Case-control studies involving 206 cases of sCJD disease identied between 1990 and 1997 in England have provided statistical evidence that the risk of CJD increases with the frequency of consumption of certain types of meat [40]. The greatest odds ratio is for venison (odds ratio 7.94), with individuals who eat venison at least once per year having an eightfold increased risk of sCJD compared with individuals who never eat venison (P 0.004). Because of the small sample size, this study should be duplicated before drawing any denitive conclusion. Molecular and biochemical typing of human prion strains Early on, it was recognized that the infectious agent of scrapie exists in multiple strains in a manner similar to microbes and viruses. When inoculated into susceptible animals, each strain of scrapie produces characteristic pathologic lesions and has a distinct incubation time. Recent reports indicate that the size of the PK-resistant PrPSc fragment and the ratio of the three glycoforms vary depending on the type of prion diseases or the strain of prion. Two major types of PrPSc have been identied in human prion diseases based on electrophoretic mobility; which, in turn, reects the size of the main PrPSc fragment generated by PK digestion in vitro [6]. After electrophoresis, type 1 PrPSc migrates at 21 kd and type 2 PrPSc migrates at 19 kd (Fig. 5).
Fig. 5. Molecular typing of human prion stains. (A) Brain lysates were prepared and separated by sodium dodecyl sulfate polyacrylamide gel electrophoresis. Separated proteins were then transferred onto nitrocellulose membranes and blotted with anti-prion protein (PrP) monoclonal antibody 8H4 as described [47]. PrP from four of the sporadic Creutzfeldt-Jakob disease cases was indistinguishable from that of the control sample. (B) Aliquots of lysates were treated with 50 lg/mL of proteinase K (PK), and immunoblots were carried out as described. After PK treatment, the unglycosylated form of scrapie prion protein type 1 migrated at approximately 21 kd, whereas that of type 2 migrated at approximately 19 kd. (From Wong BS, Chen SG, Colucci M, Xie Z, Li R, Pan T, et al. Aberrant metal binding by prion protein in human prion disease. J Neurochem, in press; with permission.)
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Microsequencing shows that PrPSc type 1 is cleaved by PK at (or around) residue 82 and that PrPSc type 2 is cleaved at (or around) residue 97 [6]. This dierence in size is likely caused by conformational dierences between these two prion strains, which results in the exposure of dierent PK cleavage sites. Both PrPSc type 1 and type 2 have been transmitted to transgenic mice and are considered to represent human prion strains. The dierences in the size of the PK-resistant fragments along with dierences in glycosylation may account for some of the heterogeneity seen in the clinical presentation of the human prion diseases. The type of PrPSc also correlates with the 129 genotype [6,10]. Approximately 95% of the subjects with PrPSc type 1 are homozygous for methionine at 129 (M/M), whereas 86% of those with the type 2 are either homozygous for valine (V/V) or heterozygous (M/V) (Table 5). Parchi and colleagues analyzed the physiochemical properties of PrPSc in conjunction with the 129 genotype. They subdivided 300 cases of the most common sporadic diseases into six phenotypic variants, ve distinct subtypes of CJD, and the sporadic form of FFI. This analysis provides a classication of disease variants based on biochemical analysis rather than on histopathologic and clinical evaluations. Some of the clinical and pathologic features of these six phenotypic variants are summarized in Table 6.
Oxidative stress, metals, and prion diseases It is clear that PrPC and PrPSc are important in the pathogenesis of prion diseases. Nevertheless, the biochemical pathways that lead to neurodegeneration remain unknown. It has been speculated that metallochemical alterations, which result in oxidative stress, play a critical role in the pathogenesis of neurodegenerative diseases, such as Alzheimers disease and Parkinsons disease, as well as in experimental prion diseases [41]. Oxidative stress is an abnormal physiologic condition caused by overproduction of reactive oxygen species (ROS) [41]. Hydrogen peroxide (H2O2) is the most common ROS. ROS is generated during normal metabolic processes such as the reduction of oxygen to water by the mitochondrial
Table 5 Preferential association of type 1 diseases with methionine/methionine homozygous and Type 2 diseases with valine/valine homozygous 129 genotype Type 1 Type 2 M/M 94.9% 14.0% M/V 3.7% 31.4% V/V 1.4% 54.6%
Abbreviations: M, methionine; V, valine. Data from Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeer W, Windl O, et al. Classication of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:22433; with permission.
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Table 6 Some of the clinical features at presentation and immunohistochemical staining patterns of the ve subgroups of sporadic Creutzfeldt-Jakob disease and sporadic fatal familial insomnia cases based on 129 genotype and type of scrapie prion protein Subtypes of sporadic human prion diseases MM1/MV Number of cases Age of onset (years) Duration (months) Cognitive loss Myoclonus Aphasia Insomnia PrPSc staining pattern in immunostaining Synaptic Cerebellar kuru plaques Plaque-like deposits 186 65.5/62.1 3.9 75/50% 18/12% 23/25% 8/0% VV1 3 39.9 6.5 100% 0% 33% 0% MM2-C 6 64.3 17.1 100% 0% 33% 0% MM2-sFI 6 52.3 15.6 67% 0% 0% 17% MV2 23 59.4 15.7 74% 0% 11% 15% VV2 43 61.3 15.3 27% 0% 0% 9%
100% 0% 0%
100% 0% 0%
0% 0% 0%
33.3% 0% 0%
100% 100% 100%
100% 0% 100%
Abbreviations: M, methionine; V, valine; PrPSc, scrapie prion protein. The MM, MV, VV represent 129 genotype. MM1 and MV1 cases have similar phenotypes; thus, they were grouped together. The numbers (1 or 2) are the PrPSc types as determined by immunoblots. MM2-C represents a subgroup with cortical involvement, and MM2-T represents sporadic fatal familial insomnia with prominent thalamus involvement. Data from Parchi P, Giese A, Capellari S, Brown P, Schulz-Schaeer W, Windl O, et al. Classication of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol 1999;46:22433; with permission.
electron transport chain. Because of their highly reactive nature, ROS are potentially quite toxic to cells. They can readily combine with other molecules, such as proteins, lipids, and nucleic acids. Attack by ROS can result in breakage of proteins and nucleic acids. ROS can also chemically modify proteins and lipids, which results in the loss of their normal functions. In normal conditions, two families of molecules tightly regulate the levels of ROS: the pro-oxidants and the antioxidants. Overproduction of ROS may be attributed to either an increase in pro-oxidant activity or a decrease in antioxidant availability. One of the most important antioxidants is superoxidedismutase (SOD). This family of enzymes converts damaging superoxide anion free radicals to H2O. Both recombinant PrP and brain-derived PrP have been reported to have SOD-like activity when they carry bound copper (Cu) [42]. In contrast, this SOD-like activity is lost when Cu is replaced with manganese (Mn) [43]. Protein oxidation and lipid peroxidation are two of the best-characterized markers of oxidative stress. Recently, we investigated whether these markers are detectable in sporadic human prion diseases. We found that the levels of protein oxidation and lipid peroxidation were greatly increased in the brain of all sCJD cases [44]. More interestingly, we observed a striking elevation of Mn accompanied by a signicant reduction of Cu bound to PrP in all
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sCJD patients. These metal imbalances varied according to the PrP 129 genotype and PrPSc type [44]. Cu and Mn changes were pronounced in sCJD subjects homozygous for methionine at codon 129 and carrying PrPSc type 1 (sCJD M/M1). Furthermore, correlating with the increases in the markers of oxidative stress, the PrP-associated SOD-like activity was reduced by approximately 85% in each of the sCJD variants. The loss of antioxidant function associated with increased oxidative stress suggests a change in the metal-ion occupancy of PrP. This change might play a pivotal role in the pathogenesis of prion diseases. Because the metal change is dierent in the sCJD variants, it may also contribute to the diversity of PrPSc and disease phenotype in sCJD [44]. Whether alteration in metal binding is the cause of the diseases or the consequence of the diseases remains to be determined. Recent studies in an animal model suggest that alterations in metal binding can be observed in experimentally infected mice at a presymptomatic stage (Wong et al, manuscript submitted). Diagnosis and surveillance of human prion diseases Currently, the diagnosis of human prion diseases is based on a set of established clinical, immunohistochemical, and biochemical criteria [2,10]. Advances in molecular biologic techniques have allowed rapid screening of individuals with pathogenic mutations. This screening can be carried out with non-CNS tissues (eg, peripheral blood). In contrast, the diagnosis is much more cumbersome for the most common sporadic human prion diseases. PrPSc detection by histochemistry or Western blot analysis is nonquantitative, time-consuming, and technically demanding. It also relies exclusively on the availability of brain tissues. No diagnostic test based on PrPSc detection in peripheral tissues (eg, blood) is available for human or animal prion diseases. This is because the infectious agent, PrPSc, is not present in the peripheral tissues or the level of PrPSc in peripheral tissues may be much too low for currently available assays [9,31]. Since the discovery of vCJD in 1996, the need for a rapid, eective, and relatively early diagnostic test for the detection of human and animal prion diseases is of obvious importance. Human prion diseases should be diagnosed as early as possible so as to avoid the potential transmission of infectious prions through the donation of blood, other tissues, and organs. The British experience indicates that unchecked animal prion diseases may be transmitted to human beings. As a result, it is just as important to develop tests that can detect PrPSc in animals before the animals reach the food chain. Recently, a diagnostic test for the presence of a family of proteins known as 14-3-3 proteins was introduced [45]. The sensitivity and specicity of this test was reported to be greater than 90%. Because the 14-3-3 proteins are essentially markers of brain parenchymal damage, they are also present in a variety of conditions other than prion diseases. For example, they are present in conditions that aect the CNS both focally (eg, neoplasm, infarct)
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and with widespread distribution (eg, Alzheimers disease). Furthermore, it is currently unclear whether the 14-3-3 protein test is positive in all ve variants of sCJD and in sporadic FFI or only in typical CJD [46]. In addition to diagnosis, monitoring disease incidence is important in public health. After the discovery of vCJD in the United Kingdom, many European counties have established surveillance centers to monitor the appearance and spread of vCJD, and other prion diseases. In 1997, we established a National Prion Diseases Pathology Surveillance Center in the United States. The major purposes of this center are to monitor the incidence of prion diseases in the United States, to identify any potential case of human prion disease that might have been transmitted from animals; and to collect and provide human tissues for research on the pathogenesis of prion diseases. Since then, we have received and diagnosed more than 326 cases of human prion diseases (Table 7). So far, we have not uncovered any vCJD case in the United States. Future challenges Like all other human diseases, the challenge for human prion diseases is in the diagnosis, cure, and eventual prevention of the diseases. Of these three challenges, the development of a more reliable and rapid diagnostic test is the easiest task. Since the appearance of vCJD, signicant progress has been made in the diagnosis of prion diseases. Conversely, like all other neurodegenerative diseases, nding a cure for prion diseases is likely to be dicult. This is because most patients with sCJD do not have obvious clinical signs until they are close to the terminal stage of the diseases. Many attempts have been made to identify compounds that might interfere with the PrPC-toPrPSc conversion in in vitro and in vivo experimental models. Only time can tell whether any of these approaches reaches clinical application. To nd a cure and prevent human prion diseases, we must focus on a better understanding of the molecular mechanisms that are responsible for the diseases. Human prion diseases belong to a group of heterogeneous diseases. Identication of the infectious agent is only the rst step in a long and arduous process. We must endeavor to unravel the mechanisms by which this
Table 7 Cases of human prion diseases received and diagnosed by the National Prion Diseases Surveillance Center at Case Western Reserve University Human prior diseases Year 1997 1998 1999 2000 2001 (3/1) Sporadic 54 45 65 97 31 Familiar 4 5 9 12 1 Iatrogenic 0 1 0 2 0 Total 58 51 74 111 32
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small protein causes diseases. The control and containment of prion diseases is likely to remain a major challenge for scientists, clinicians, and public health ocials in the days ahead. Acknowledgment Dr. Sy dedicates this manuscript to Pearl Ling. References
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[20] Zahn R, Liu A, Luhrs T, Riek R, von Schroetter C, Lopez Garcia F, et al. NMR solution structure of the human prion protein. Proc Natl Acad Sci USA 2000;97:14550. [21] Bueler H, Fischer M, Lang Y, Bluethmann H, Lipp HP, DeArmond SJ, et al. Normal development and behaviour of mice lacking the neuronal cell-surface PrP protein. Nature 1992;356:57782. [22] Wong BS, Pan T, Liu T, Li R, Petersen RB, Jones IM, et al. Prion disease: a loss of antioxidant function? Biochem Biophys Res Commun 2000;275:24952. [23] Pan KM, Baldwin M, Nguyen J, Gasset M, Serban A, Groth D, et al. Conversion of alphahelices into beta-sheets: features in the formation of the scrapie prion protein. Proc Natl Acad Sci USA 1993;90:109626. [24] Caughey B, Race RE, Ernst D, Buchmeier MJ, Chesebro B. Prion protein biosynthesis in scrapie-infected and -uninfected neuroblastoma cells. J Virol 1989;63:17581. [25] Gorodinsky A, Harris DA. Glycolipid-anchored proteins in neuroblastoma cells form detergent-resistant complexes without caveolin. J Cell Biol 1995;129:61927. [26] Herrmann LM, Caughey B. The importance of the disulde bond in prion protein conversion. Neuroreport 1998;9:245761. [27] Lehmann S, Harris DA. Blockade of glycosylation promotes acquisition of scrapie-like properties by the prion protein in cultured cells. J Biol Chem 1997;272:2147987. [28] Kaneko K, Zulianello L, Scott M, Cooper CM, Wallace AC, James TL, et al. Evidence for protein X binding to a discontinuous epitope on the cellular prion protein during scrapie prion propagation. Proc Natl Acad Sci USA 1997;94:1006974. [29] Kocisko DA, Come JH, Priola SA, Chesebro B, Raymond GJ, Lansbury PT, et al. Cellfree formation of protease-resistant prion protein. Nature 1994;370:4714. [30] Saborio GP, Soto C, Kascsak RJ, Levy E, Kascsak R, Harris DA, et al. Cell-lysate conversion of prion protein into its protease-resistant isoform suggests the participation of a cellular chaperone. Biochem Biophys Res Commun 1999;258:4705. [31] Wong BS, Green AJ, Li RL, Xie Z, Pan T, Liu T, et al. Absence of protease resistant prion protein in the cerebrospinal uid of Creutzfeldt-Jakob disease. J Pathol 2001;194:914. [32] Lasmezas CI, Deslys JP, Robain O, Jaegly A, Beringue V, Peyrin JM, et al. Transmission of the BSE agent to mice in the absence of detectable abnormal prion protein. Science 1997;275:4025. [33] Goldfarb LG, Brown P, McCombie WR, Goldgaber D, Swergold GD, Wills PR, et al. Transmissible familial Creutzfeldt-Jakob disease associated with ve, seven, and eight extra octapeptide coding repeats in the PRNP gene. Proc Natl Acad Sci USA 1991;88:1092630. [34] Flechsig E, Shmerling D, Hegyi I, Raeber AJ, Fischer M, Cozzio A, et al. Prion protein devoid of the octapeptide repeat region restores susceptibility to scrapie in PrP knockout mice. Neuron 2000;27:399408. [35] Hsiao K, Baker HF, Crow TJ, Poulter M, Owen F, Terwilliger JD, et al. Linkage of a prion protein missense variant to Gerstmann-Straussler syndrome. Nature 1989;338:3425. [36] Manson JC, Jamieson E, Baybutt H, Tuzi NL, Barron R, McConnell I, et al. A single amino acid alteration (101L) introduced into murine PrP dramatically alters incubation time of transmissible spongiform encephalopathy. EMBO J 1999;18:685564. [37] Bruce ME, Will RG, Ironside JW, McConnell I, Drummond D, Suttie A, et al. Transmissions to mice indicate that new variant CJD is caused by the BSE agent [see comments]. Nature 1997;389:498501. [38] Ironside JW, Hilton DA, Ghani A, Johnston NJ, Conyers L, McCardle LM, et al. Retrospective study of prion-protein accumulation in tonsil and appendix tissues. Lancet 2000; 355:16934. [39] Belay ED, Gambetti P, Schonberger LB, Parchi P, Lyon DR, Capellari S, McQuiston JH, Bradley K, Dowdle G, Crutcher JM, Nichols CR. Creutzfeldt-Jakob disease in unusually young patients venison who consumed. Arch Neurol 2001;58:167378. [40] Ministry of Agriculture, Fisheries, and Food. BSE in Great Britain. A progress report. London: Department for Environment, Food, and Rural Aairs Publications; 1998.
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[41] Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. 3rd edition. Oxford: Oxford University Press; 1999. [42] Brown DR, Wong BS, Haz F, Clive C, Haswell S, Jones IM. Normal prion protein has an activity like that of superoxide dismutase. Biochem J 1999;344:15. [43] Brown DR, Haz F, Glassmith LL, Wong BS, Jones IM, Clive C, et al. Consequences of manganese replacement of copper for prion protein function and proteinase resistance. EMBO J 2000;19:11806. [44] Wong BS, Chen SG, Colucci M, Xie Z, Li R, Pan T, et al. Aberrant metal binding by prion protein in human prion disease. J Neurochem 2001;78:140008. [45] Zerr I, Pocchiari M, Collins S, Brandel JP, de Pedro Cuesta J, Knight RS, et al. Analysis of EEG and CSF 143-3 proteins as aids to the diagnosis of Creutzfeldt-Jakob disease. Neurology 2000;55:8115. [46] Green AJ, Knight RS, Macleod MA, Lowman A, Will RG. Misleading results with the 143-3 assay for the diagnosis of Creutzfeldt-Jakob disease. Neurology 2001;56:9867. [47] Li R, Lio T, Wong BS, Pan T, Morillas M, Swietnicki W, ORourke K, Gambetti P, Surewicz WK, Sy M-S. Identication of an epitope in the C terminus of normal prion protein whose expression is modulated by binding events in the N terminus. J Mol Biol 2000;301:56773.
Med Clin N Am 86 (2002) 573590
Dementia epidemiology
Walter A. Kukull, PhDa,*, James D. Bowen, MDb
a
Department of Epidemiology, University of Washington, Box 357236, Seattle, WA 98195-7286, USA b Department of Neurology, University of Washington School of Medicine, Box 356465, Seattle, WA 98195-7286, USA
Dementia has become one of the leading public health concerns facing our society. The past few decades have seen remarkable success in treating some acute illnesses and in reducing the incidence of others, such as stroke. Epidemiology has played a central role in identifying the risk factors and potential causes of these acute illnesses, whereas clinical medicine has provided new and more eective treatments. This has allowed us to develop a wide array of interventions, such as antibiotics, safer working conditions, and improved sanitation. Our success in preventing and controlling the acute diseases that strike between childhood and early middle age has led to greater longevity and the aging of our population. In the developed world, chronic diseases are the leading causes of morbidity and mortality. Of these chronic illnesses, dementia is one of the most common, extracting an enormous social, emotional, and economic burden on society. At least 6% to 10% of persons in the United States aged 65 years or older may suer from some form of dementia [1]. Approximately 2.32 million persons in the United States were estimated to be living with Alzheimers disease (AD) in 1997 [2]. The enormous burden that dementia inicts on individuals, families, and society underlies the increased emphasis medical science has placed on the study of these diseases. As with other scientic elds, there is great interest in studying causes and risk factors for dementia with all the tools that epidemiology can bring to bear. The epidemiologic study of dementia has some unique challenges, however. Case detection and identication (or diagnosis) are critical to the epidemiologic study of dementia. In other words, how are new dementia cases found, and once found, how accurately are they diagnosed? The diagnosis of dementia is dicult because specic antemortem biologic markers for
* Corresponding author. E-mail address: kukull@u.washington.edu (W.A. Kukull). 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 1 0 - X
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W.A. Kukull, J.D. Bowen / Med Clin N Am 86 (2002) 573590
most dementias, and specically for AD, do not exist. Instead, the diagnosis must be made on the basis of clinical evidence. There can be considerable variation in making the diagnosis of dementia based on a clinical examination, potentially leading to diagnostic heterogeneity and misclassication of those patients with dementia. Fortunately, some of this heterogeneity has been reduced by the recent introduction of clinical criteria for the diagnosis of various types of dementia. Standardization of clinical criteria can limit the amount of misclassication; however, in practice, standardization is difcult to achieve. Case detection is a further problem for most epidemiologic studies. Cases identied using death certicates alone are simply not comparable to those identied by direct patient examination; there are too many extraneous factors aecting whether dementia might or might not be entered as a cause of death. The method of identifying and including cases, if associated with exposure history, could cause serious selection bias and lead to spurious conclusions. Can all identied cases from a particular study base be enrolled in a study? Usually, this does not happen, because many persons (or their families) decline to participate in research studies. Frailty, age, ethnicity, gender, education, and a host of other factors also inuence participation. If any of these participation factors is systematically related to exposure status, an uncontrolled bias may result. Case identication methods are also critical to cohort studies (and intervention trials). Failure to start with a cohort that is free of the disease of interest can potentially bias results. Lack of sensitivity or specicity in screening or diagnosing disease during follow-up leads to incorrect estimates of incidence and to distorted risk factor relations. Exposure measurement (valid determination of risk factor information) is critical for analytic risk factor studies. For dementia, determining when, relative to disease onset, an exposure may have been able to inuence disease is complicated by the often insidious and indeterminate onset of disease. Long past exposure histories are dicult to construct and validate, especially in diseases that aect memory. Self-reported histories and those obtained from proxies are often the basis for risk factor inference but may be awed by distorted recollection or recall bias. Actual records, for example, of medication history or occupational exposures are seldom available. Biologic markers of exposure (except for genotype) are dicult to obtain; and some may be aected by the disease itself. For example, low serum cholesterol levels in existing/prevalent cases may be a function of the impact of disease on diet or may be inuenced by physical wasting. Potential markers obtained from analysis of peripheral blood may not correspond to marker exposure levels in neuronal tissue. Biopsy of the aected tissue is not available in most dementia diagnoses, and autopsy, which is the gold standard for the diagnosis of many dementias, may reect cumulative disease processes, leaving the picture additionally confusing. As one leaves major research institutions or attempts to begin epidemiologic research studies in less developed countries, the problems grow in mag-
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nitude. Dierences in available facilities and local practices are likely the easiest to overcome. Addressing political concerns and suspicions to gain the cooperation necessary to begin a study may take additional time and preparation. Case detection, case identication, and risk factor exposure measurement remain critical to valid research in these settings, but the diculty in obtaining acceptable levels of each is increased substantially. Clinical overview Dementia can sometimes occur suddenly as the result of a stroke. More often, it presents with a slowly progressive loss of cognitive function as with AD. Cognitive loss may begin with mild memory problems, language diculties, or problems with activities of daily living that many might ascribe to aging but progress to more serious socially and functionally debilitating cognitive impairment. Memory may not always be the rst domain aected. The usually insidious nature of most dementia makes it dicult to determine the point of disease onset. Moreover, it is especially dicult to determine whether dementia is present in people with only some mild indications of cognitive impairment and whether that mild impairment is benign and nonprogressive or a prodrome of the progressive disease. Valid early identication of true disease would be most helpful in linking exposures and risk factors to the disease. Behavioral changes may be prominent, including agitation, wandering, personality change, and depression. In late stages, patients may be completely dependent on others. Various denitions of dementia have been used in past research studies, but that of the Diagnostic and Statistical Manual: Edition IV (DSM-IV) is the most commonly used now [3]. The DSM-IV criteria for dementia require memory impairment and one or more additional cognitive disturbances. These include aphasia (language disturbance), apraxia (impaired ability to carry out motor activities despite intact motor function), agnosia (failure to recognize or identify objects despite intact sensory function), and disturbances in executive functioning (ie, planning, organizing, sequencing, abstracting). The cognitive decits must be severe enough to cause signicant impairment in social or occupational functioning and represent a signicant decline from a previous level of functioning. Dementia must be dierentiated from delirium (eg, caused by illness, medications, or intoxicants). The causes of dementia are listed in Table 1. There is some controversy concerning whether memory loss should be the cardinal feature of dementia (ie, necessary for the diagnosis) or whether loss in a combination of other cognitive domains, without memory loss, should be considered sucient for diagnosis. Leaders in the study of vascular dementia have raised interest and debate concerning this question. Beyond the umbrella category of dementia, there are clinical and sometimes histopathologic criteria for dierentiation of dementia subtypes. To date, diagnostic criteria have been developed for mild cognitive impairment, AD, vascular dementia, dementia with Lewy bodies,
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Table 1 Causes of dementia Idiopathic Alzheimers disease Frontal temporal dementia Focal/central nervous system pathologic ndings Multi-infarct dementia Binswangers disease Multiple sclerosis Mass lesions Tumors, multiple sites Tumors, single site Gliomatosis cerebri Abscess Subdural malformation Hydrocephalus Infections AIDS (HIV) Chronic meningitis Encephalitis Progressive multifocal leukoencephalopathy Subacute sclerosing panencephalitis Syphilis Lyme disease Prion disease (kuru, Creutzfeldt-Jacob) Toxins Drugs Alcohol Heavy metals Industrial toxins Domoic acid Inherited disease Huntingtons disease Gerstmann-Straussler syndrome Porphyria Propionic aciduria Adult-onset lysosomal storage diseases Hexosaminidase Arylsulfatase (metachromatic leukodystrophy, or MLD) Kuf disease Adrenoleukodystrophy Others Myotonic muscular dystrophy Downs syndrome Hereditary ataxias Hereditary spastic paraplegias Cerebrotendinous xanthomatosis Systemic disease Cardiac Pulmonary Renal Renal failure (continued on next page)
W.A. Kukull, J.D. Bowen / Med Clin N Am 86 (2002) 573590 Table 1 (continued ) Dialysis dementia Hepatic Hepatic failure Hepatocerebral degeneration Wilsons disease Endocrine Hyper/hypothyroid Hyper/hypoparathyroid Hyper/hypoadrenalism Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) Rheumatologic Vasculitis (including systemic lupus erythematosus, or SLE) Giant cell arteritis Sarcoid Amyloid Neoplastic Metastasis Carcinomatous meningitis Paraneoplastic (limbic encephalitis) Associated movement disorder Huntingtons disease Parkinsonian diseases Parkinsons disease Progressive supranuclear palsy Postencephalitic dementia Posttraumatic (dementia pugilistica) Diuse Lewy body disease Myoclonus Creutzfeldt-Jakob disease Alzheimers disease Metabolic derangement Other movement disorder Hereditary ataxias Hereditary spastic paraplegia Kuru Wilsons disease Seizures Kuf disease Deciency Vitamin B12 deciency Thiamine Niacin (Pellagra)
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frontotemporal dementia, and HIV dementia. Unfortunately, for the researcher seeking a common standardized denition, there is often more than one diagnostic criteria set for each condition; often, too, they do not agree. Although AD is the most common form of dementia, many other disorders must be considered, including drug-induced conditions, alcoholism, stroke, Parkinsons disease, Huntingtons disease, subdural hematoma, brain tumors, hydrocephalus, vitamin B12 deciency, hypothyroidism, neurosyphilis,
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and HIV infection. Two commonly used criteria for the diagnosis of AD have been proposed [3,4]. Vascular dementia is dicult to dierentiate from AD because of the common occurrence of cerebrovascular disease and stroke with AD in the elderly. The more sophisticated the search for stroke, the more likely it is that some strokes are found. The clinical identication of stroke is surpassed by CT, which is surpassed by MRI. The false-positive identication of stroke also increases, however. Many dierent criteria have been developed to diagnose vascular dementia [3,5,6]. Much of the pioneering work in the denition and recognition of vascular dementia can be attributed to Hachinski and his colleagues [715]. Recently, two additional types of dementia, dementia with Lewy bodies [16] and frontotemporal dementia [17], have been separated from AD based on their clinical presentations and pathologic characteristics. Dementia with Lewy bodies presents with cognitive losses. In addition, uctuating cognitive performance, visual hallucinations, and parkinsonism are suggestive of this disease. Memory impairment may not necessarily be prominent in the early stages of the disease. Decits in attention, frontal subcortical skills, and visuospatial ability predominate. In frontotemporal dementia, changes in behavior dominate the early course of the disease These include loss of personal awareness, loss of social graces, disinhibition, overactivity, restlessness, impulsivity, distractibility, hyperorality, withdrawal from social contact, apathy or inertia, and stereotyped or perseverative behaviors. Speech output changes occur, including progressive reduction of speech, stereotypy of speech, perseveration, and echolalia. Physical signs include early or prominent primitive or frontal reexes, early incontinence, late akinesia, rigidity, and tremor. Decits in social comportment, behavior, judgment, or language are out of proportion to the memory decit. The memory loss is variable and often seems to be caused by lack of concern or eort. Frontal lobe impairments are notable, including abstraction, planning, and self-regulation of behavior. There are several pathologic ndings that may lead to frontotemporal dementia, including some with dominantly inherited mutations related to the protein tau. Current cases versus risk of dementia and Alzheimers disease The prevalence of dementia is the proportion of persons in a population suering from dementia at a particular time. It represents a cross-sectional picture of the populationthe burden of that disease on society. Prevalence is useful in determining the needs for resources and societal burden from a disease. The prevalence of dementia is aected by dierences in length of survival, eectiveness of treatment, emigration, and institutionalization as well as by the occurrence of new disease cases. The incidence of dementia (ie, risk or rate) is calculated as the new cases per population at risk per time period. Often, incidence is presented as a cumulative gure (eg, 15 new
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cases per 1000 persons older than 65 years of age in 1999) or as a density or instantaneous rate (eg, 12 new cases per 1000 person-years). Incidence is less useful in determining societal burden, and prevalence is not useful in determining disease risk, but kept in their own arena, they are useful descriptors of disease occurrence, and they are linked by disease duration. Evans et al [18] reported the results of a community study in East Boston. The prevalence estimates for dementia and AD were based on a complex community sampling scheme [19]. Because of the diagnostic criteria and screening procedures, the results of this study have been somewhat controversial, but they are widely accepted as an observed but high estimate of the potential dementia prevalence in East Boston. Prevalence proportion rose from 3% among those 65 to 74 years of age to 47% in those older than 85 years of age. More than 80% of the observed dementia cases were classied as AD. Evans later applied the observed rates to census data, projecting that 10.3 million persons would have AD in the year 2050. Recently, a meta-analysis of prevalence studies worldwide was conducted [20], which concluded that the prevalence proportions and incidence rates observed across studies were geographically consistent, except for variations caused by methodologic differences. Prevalence proportions rose from 0.3% to 1.0% in 60- to 64-yearolds to 43% to 68% in persons aged 95 years or older. As a summary gure, prevalence is often reported as 6% to 10% among persons aged 65 years or older in North America [1]. Brookmeyer et al [2] have estimated that if disease age-specic incidence curves could be shifted generally to delay onset by 2 years, that would result in 2 million fewer cases in the future. The dementia prevalence proportion in the population is a function of disease incidence and disease duration (or survival). Jorm and Jolley [21] gathered data from 23 studies and produced a meta-analysis of dementia incidence. Incidence was estimated for Europe, the United States, and East Asia; dementia, AD, and vascular dementia incidence rates were computed. Incidence rates for the United States and Europe were quite similar: moderate dementia incidence rose from 3.6 per 1000 person-years (in persons aged 6569 years) to 37.7 per 1000 person-years (in persons aged 8589 years) in Europe and from 2.4 to 27.5 per 1000 person-years for the same age groups in the United States. Mild AD incidence was also computed, ranging from 2.5 per 1000 person-years (in persons aged 6569 years) to 46.1 per 1000 person-years for Europe compared with 6.1 to 74.5 per 1000 person-years for the United States and 0.7 to 39.7 per 1000 person-years for East Asia. Rocca et al [22] reanalyzed dementia and AD incidence data for 1975 through 1984 based on charted data from the Rochester Epidemiology Project at the Mayo Clinic. The results showed dementia incidence overall as 2.2 per 1000 person-years in 65- to 69-year-olds rising to 40.8 per 1000 person-years in those aged 90 years or more. Similarly, for AD, rates rose from 1.2 to 33.9 per 1000 person-years. These investigators noted that annual incidence seemed to stay rather stable during the 1975 to 1984 time interval. After disaggregating the data for the oldest people, Rocca et al [22]
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also reported that rates seemed to continue to rise with age after the age of 84 years. They also noted that rates were similar for men and women. The combined analysis of four large ongoing European cohort studies of dementia and AD was recently reported by Launer et al [23]. Cohorts enrolled in Denmark, France, the Netherlands, and the United Kingdom totalled more than 16,000 members aged 65 years or older at enrollment. After a mean follow-up of 2.2 years (comprising approximately 28,600 person-years), the overall incidence of dementia was 14.6 per 1000 personyears. Approximately two thirds of these cases were attributed to AD. Incidence of dementia was 2.5 per 1000 person-years in 65- to 69-year olds and rose to 85.6 per 1000 person-years in those aged 90 years and older. Similarly, AD rose from 1.2 per 1000 person-years to 63.5 per 1000 personyears across the same age groups. The report by Launer et al [23] is one of the rst using data from the large cohort studies that are now underway in Europe and the United States. As more cohort studies begin to report incidence, consistent estimates are likely to emerge. Most of the dierence between dementia and AD incidence rates reported here likely represents the next most common form of dementia, vascular dementia. We cannot be sure of this at present, however. Despite the compilation of several competing diagnostic criteria for vascular dementia [5,6], this syndrome remains an area of controversy and uncertainty [2429]. Application of the diagnostic criteria has been shown to be dicult and unreliable in practice, even by experienced research investigators [30]. Many of the reliability and validity problems experienced by investigators in classifying a case as vascular or AD may stem from the mutual exclusion of the two conditions imposed principally by the DSM-IV diagnostic criteria. There is a growing realization that a vascular component can contribute to the dementia seen in AD [26,3136]. Late-stage dementia and AD hold little hope for treatment or the identication of consistent risk factors; as a result, interest has continued to shift toward early and valid identication of disease. Early forms of pre-AD or predementia are dicult to distinguish from the relatively benign cognitive decline associated with aging. Nevertheless, when mild cognitive decline can be identied, it seems that perhaps 50% of such cases may progress to become dementia [3741]. Distinguishing between normal persons, those with mild cognitive impairment, and those with incipient dementia/AD may provide important clues about risk factors and critical periods of exposure before disease onset. Reliable and valid distinctions may also help to determine whether mild cognitive impairment is a treatable and reversible phenomenon. Exposures associated with the onset of Alzheimers disease Studying dementia and its relevant exposures presents many methodologic and logistic challenges. Careful, consistent, and valid case identication and detection (discussed previously) must always be addressed by researchers.
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Comparison groups must also be carefully dened and enrolled to avoid spurious associations as a result of bias. In the absence of a biologic marker identifying all cases of AD, there is considerable diculty in ascertaining all cases and in ensuring that everyone identied as having AD truly does as well as in ensuring that all who clinically do not show symptoms truly do not have the disease. If a case series includes substantial misclassication of disease, the ability to recognize risk factors is reduced. In other words, the observed relative risk estimate tends to be biased toward the null (assuming the misclassication is nondierential). Exposure to risk factors for AD could possibly occur many years before the recognition of clinical disease or rather close to recognition. The relevant time window may vary for each exposure; some exposures could cause a disease change immediately after a single exposure, whereas others may take years of sustained exposure, either by themselves or in combination with one or more other factors, to cause disease changes. The later in the clinical course a patient is identied as having dementia, the more remote the risk factor exposure must be, and the more diculty there is in recognizing it. Complicating the situation is the lack of veriable records for most exposures coupled with the patients and patient proxys diculty in recalling a specic exposure or the details surrounding it. The use of caregivers as proxies is an imperfect solution to the patients loss of recall, but it is sometimes the best we have to work with. Most early analytic observational studies of AD were based on a casecontrol design. In this design, cases of disease were identied, and their exposure histories were compared with those of persons without the disease. The design itself is well accepted and valid as a method of study. It is subject to bias if not judiciously applied, however. In the case of AD (and dementia), problems with case identication and detection, case selection for study, and exposure measurement may have caused at least some results to be biased or spurious. Now, as cohort studies of AD and dementia are beginning to emerge, ndings that were viewed as consistent in case-control studies are being questioned or refuted. One example of a potential bias concerning a potential protective eect for AD associated with cigarette smoking was addressed in a recent article [42]. The argument for that potential bias is described as an example that could apply to risk factors other than smoking. A meta-analysis of studies of smoking and AD showed a consistent decreased risk associated with smoking [43]. Most of these studies were of the case-control design. When case-control studies rely on crosssectional samples to obtain cases, they are more likely to encounter those patients with the longest survival after diagnosis [4446]. Also, when decreased postdiagnosis survival among patients is associated with the exposure of interest (eg, smoking), a potential spurious excess of exposure among controls may be observed. Wang et al [47] conducted a cross-sectional and longitudinal study to observe the relation between smoking and AD. They found that although mortality between smokers and nonsmoking control subjects was rather similar, AD case smokers had a threefold
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increase in risk of death compared with AD nonsmokers. As a result of mortality, smoking would be less common in a cross-sectional sample of AD patients than among controls. Cohort studies where this selection bias is minimized now report either no association or a potential increased risk of AD associated with smoking [23,4749]. Head trauma has also been shown to be a relatively consistent risk factor for AD, primarily based on case-control studies [50,51]. Here, selective recall or recall bias may be more important than the eect of survival, even though risk of death or continued cognitive impairment immediately resulting from the injury is substantial [52]. Several recent longitudinal studies now show a negligible risk of AD associated with head injury [23,53,54], although others still nd some potentially increased risk [55,56]. Higher educational level has been proposed as inuencing a decreased risk of AD, but the relation between education and AD may be quite complex [1,5765]. Educational level inuences a subjects likelihood of participating in epidemiologic studies. Educational level inuences the diagnostic process, at least in the early stages of disease, because of the individuals ability to respond correctly in testing situations. Education may inuence health care use and may result in greater income or a higher occupational level. The idea that higher education confers greater cognitive reserve to be accessed when disease strikes is tantalizing, although biologically unsubstantiated. Recently, an important idea was raised concerning the importance of early life development in increasing susceptibility to AD [42]. The biologic plausibility of this association has been reviewed [66]. Several protective factors for AD have been raised in the past 10 years. These factors include anti-inammatory medications [1,6773], estrogen replacement therapy [7488], and antioxidants such as vitamin C and vitamin E [89]. Although the initial associations seemed relatively consistent across studies, designs dier, and conclusions are still tentative. Randomized trials to test the observed associations are either proposed or underway. In the case of estrogen as a potential treatment for AD, results have shown no indication that estrogen replacement therapy is an eective treatment for AD [78,81]. This result does not address estrogen as a preventive measure, however. AD is likely to be heterogeneous both diagnostically and etiologically. What results in the AD phenotype may be the sum or product of aging, environmental factors, genetic constitution, and sociodemographic experiences. Aside from the observable eect of aging dramatically increasing the risk of dementia and AD, success in nding environmental risk factors has been limited and potentially related to design and selection factors. Genetics and Alzheimers disease Great progress has been made in the genetics of AD. Most of the strict genetic causes of disease have been limited to familial AD, however. Familial AD behaves similar to an autosomal dominant genetic pattern and predom-
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inantly tends to aect persons younger than 60 years of age. Familial AD, so dened, seems to account for less than 5% of all AD, but important clues may be learned from the study of familial disease, which may apply to the more common form (often called sporadic, but it may also have undiscovered genetic causes). Several current reviews of AD genetics are available [9099]. The largest proportion of familial AD is attributed to mutations in the presenilin 1 gene (chromosome 14), and the next largest known contribution is from mutations in a homologous gene on chromosome 1, presenilin 2. A small proportion of cases are caused by specic mutations in the amyloid precursor protein gene (chromosome 21). It is abnormal cleavage of the amyloid precursor protein that results in the formation of amyloid-b protein(142). Amyloid-b protein aggregates in the brain, forming the characteristic plaques of AD. Recently, important work has been published concerning the identication of enzymes that cleave the precursor protein abnormally, forming the amyloid-b 142 protein. This work may ultimately help to identify sites for drug intervention not only for familial AD but for nonfamilial AD [93,100105]. Perhaps one quarter to one half of the genes for familial AD have yet to be identied [9598]. Arguably, the strongest and most consistent risk factor for nonfamilial AD (other than age) is apolipoprotein E (APOE) genotype. The association was rst described from Allen Roses laboratory [106111]. ApoE naturally occurs as three dierent alleles (e2, e3, and e4), which pair to form one of six genotypes for each individual. Genotypes containing the e4 allele are associated with an increased risk of AD; homozygous e4 greatly increases the risk (>8-fold). Since the initial description of increased risk associated with the e4 allele, many investigators have observed the association. Discussion of ApoE genotype is now included in most risk factor studies of AD either as a focus or as a potential confounder/eect modier of an association. Farrer et al [112] provided a meta-analysis of the age and gender eects, and Mayeux et al [113] later described caveats for the potential value of ApoE genotype in AD diagnosis. Despite the huge volume of studies that include ApoE genotyping, relatively little is known concerning how the e2, e3, and e4 alleles actually work to inuence the risk of AD. Evidence for the eects of other genes on AD has also been presented. a2Macroglobulin was rst shown as a potential risk factor by Blacker et al [117], but a number of other investigators failed to replicate the association [114116,118]. Other genetic associations have been studied but with limited impact to date [96,119129]. Progress continues, and there is considerable hope for the discovery of important genes that may provide indications for prevention or therapy. Summary Determining the incidence and prevalence of dementia is an inexact science. Dementia is dicult to dene and detect in the population. Even
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with the diculties of determining prevalence and incidence, it is clear that dementia causes a substantial burden on our society. Problems with diagnostic inaccuracy and insidious disease onset inuence our ability to observe risk factor associations; factors related to survival may be mistaken for risk/ protective factors. Current studies suggest that factors inuencing brain development or cognitive reserve may delay the onset of AD, perhaps through a protective mechanism or a delay in diagnosis caused by improved performance on cognitive tests. The recent identication of genes that cause dementia suggests that these genes or their biochemical pathways may be involved in the pathogenesis of nonfamilial cases. The contribution of genes that cause disease in and of themselves may be smaller than that of genes that act to metabolize or potentiate environmental exposures. The interaction between gene and environment should be increasingly well studied in the future. Epidemiology must take advantage of these molecular advances. The tasks of public health and epidemiology should still involve prevention, the nonrandom occurrence of disease, and its environmental context in addition to heredity. The tools to address these tasks should continue to be rened.
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Med Clin N Am 86 (2002) 591614
Genetics of dementia
Debby W. Tsuang, MD, MSca,b,c,*, Thomas D. Bird, MDb,c,d
Departments of Psychiatry and Behavioral Sciences and Epidemiology, University of Washington, Seattle, WA, USA b Alzheimers Disease Research Center, University of Washington, Seattle, WA, USA c Veterans Aairs Puget Sound Health Care System, Mental Illness Research, Clinical, and Education Center, 116MIRECC, 1660 South Columbian Way, Seattle, WA 98108, USA d Departments of Neurology, Medical Genetics, and Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA
a
This article reviews seven of the most prominent examples of dementing disorders for which genes have been identied. These disorders comprise the most common causes of dementia in the elderly; however, this list is not exhaustive. Interested readers should refer to the texts by Pulst [1] and Terry et al [2] for detailed descriptions regarding specic disorders. Alzheimers disease Clinical features Alzheimers disease (AD) is the most common cause of dementia [2]. It is a slowly progressive disease that initially presents with short-term memory loss. Additional symptoms include executive dysfunction, confusion, aphasia, gait, and behavioral disturbances. The typical age of onset is older than 65 years. The average duration of illness ranges from 4 to 20 years. More women than men are aected even after adjustment for the greater longevity of women. Pathologic features Pathologically, AD is characterized by diuse cerebral atrophy associated with b-amyloid (Ab) neuritic plaques, neurobrillary tangles, and amyloid
* Corresponding author. Veterans Aairs Puget Sound Health Care System, Mental Illness Research, Clinical, and Education Center, 116MIRECC, 1660 South Columbian Way, Seattle, WA 98108, USA. E-mail address: dwt1@u.washington.edu (D.W. Tsuang). 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 3 - 2
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D.W. Tsuang, T.D. Bird / Med Clin N Am 86 (2002) 591614
angiopathy as rst described by Alois Alzheimer in 1911 [3]. Senile plaques are complex structures consisting primarily of a core of abnormal aggregates of a small protein molecule known as Ab. Neurobrillary tangles are dense bundles of helically wound abnormal bers composed of a modied form of a normally occurring neuronal protein, the microtubule-associated protein tau. The presence of either senile plaques or neurobrillary tangles is not pathognomic of AD [4]. They are both known to occur in other neurodegenerative disorders as well as in normal aging. A higher density of these lesions in specic brain regions along with the presence of a clinical history of dementia consistent with AD conrms the diagnosis of AD. Epidemiology The risk for AD increases with advancing age. Approximately 10% of the white population over the age of 70 years have dementia, and more than half of these patients have AD [5]. In addition, approximately 20% to 40% of individuals older than 85 years have clinically signicant dementia. The next most important risk factor for AD is family history. Epidemiologic studies show that individuals who have an aected rst-degree relative with AD have an approximately fourfold greater risk of developing AD and a total lifetime risk of 23% to 48% [6], although more recent European studies do not report such high estimates [7]. To date, reports on monozygotic and dizygotic twin pairs have suggested higher concordance rates in monozygotic twins than in dizygotic twins [8]. Although the sample sizes are small, they suggest that genetic components play an important role. The lack of complete concordance in monozygotic twins suggests that environmental components are also important in the etiology of AD. The risk for AD is even higher if there are individuals in more than one generation with the disease, especially when the disease is of early onset (age <65 years). In some of these rare families, AD occurs as a single-gene autosomal dominant trait. Further proof for a genetic basis in AD is that all persons with trisomy 21 (Down syndrome) who survive beyond the age of 40 years invariably demonstrate the neuropathologic features of AD [9]. These observations led to the nding of mutations in the amyloid precursor protein (APP) gene on chromosome 21, the rst documented genetic cause of AD [10]. Although there are fewer than 20 families worldwide with APP mutations, the discovery of these mutations conrmed that genetic factors are important in AD. Familial Alzheimers disease Although there is no universally accepted denition of familial AD (FAD), a working denition is three or more aected rst-degree relatives (with at least one individuals diagnosis conrmed at autopsy). The clinical features of FAD are typically indistinguishable from nonfamilial (or sporadic) AD [11]. Disease duration is usually 6 to 10 years but can range from
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2 to 20 or more years. Familial AD is typically divided into early-onset (<65 years old) and late-onset (>65 years old) types. Thus far, three causative genes have been found in early-onset families. Although these genes account for less than 2% of all cases of AD, the discovery of these genetic mutations has been critical in designing studies to investigate the underlying pathophysiology in AD. A fourth gene, the apolipoprotein E (APOE) e4 is a major genetic risk factor for both early- and late-onset AD. Other important genetic and environmental risk factors remain to be discovered. Amyloid precursor protein The APP gene maps to the long arm of chromosome 21. It encodes for a precursor protein that is proteolytically cleaved to form Ab protein. Ab is a 39 to 43 amino-acid peptide that is the major component of the neuritic plaque, one of the neuropathological hallmarks of AD. Two proteolytic pathways for APP processing have been shown to occur normally (Fig. 1). The rst is cleavage within the Ab sequence by a protease referred to as a-secretase [12]. Ab is destroyed by this cleavage, meaning that this pathway does not contribute to Ab formation. The second cleavage is on either side of the Ab sequence. Enzymes called b- and c-secretase cleave APP to form the N (amino) and C (carboxy) termini of Ab peptide, respectively. b-secretase cleaves APP rst, followed by c-secretase cleavage, which can result in Ab peptides of dierent lengths [13]. Two b-secretases have been identied and are referred to as BACE 1 and BACE 2 [14]. c-secretase cleavages occur within the predicted transmembrane domain of APP, resulting in the Ab40 and Ab42 species. The predominant species, Ab40, is formed by cleavage after the fortieth amino acid of Ab. Conversely, Ab42 only accounts for 10% of the totally secreted Ab. It is hypothesized that Ab42 is the pathogenic
Fig. 1. Schematic representation of the amyloid b (Ab) peptide portion of the amyloid precursor protein (APP) demonstrating mutation sites associated with familial Alzheimers disease (positions 670-671 and 717) and hereditary cerebral hemorrhagic amyloidosis of the Dutch type (positions 692 and 693). The three normally occurring sites for processing this portion of the APP are also indicated by the a-, b-, and c-secretases. Note that cleavage by the a-secretase interrupts the Ab peptide, whereas cleavage by only the b- and c-secretases allows the Ab peptide to remain intact. (From Levy-Lahad E, Bird TD. Genetic factors in Alzheimers disease. Ann Neurol 1996;40:82940; with permission.)
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species in FAD, because plasma exhibits a selective increase in Ab42 and because Ab42 is the major constituent of amyloid plaque deposits in the brain [13,15]. b- and c-secretases are potential therapeutic targets, because inhibition of their activity would decrease Ab production. There is evidence that presenilin-1 has c-secretase activity and may be the major c-secretase [16]. In 1990, a mutation in the APP gene was rst discovered in the rare condition called cerebral hemorrhagic amyloidosis of the Dutch type [17]. Because cerebral amyloidosis is also a hallmark of AD, this led to the search for APP mutations in FAD. In 1991, it was discovered that a valine-to-isoleucine substitution existed at codon 717 (Val717Ile) in two families [10]. Subsequently, more than 20 dierent families have been identied with diseasecausing APP mutations. APP mutations are a rare cause of early-onset FAD (which is itself uncommon). They account for probably less than 10% of early-onset FAD and certainly less than 1% of all AD. Clinically, APP mutations result in autosomal dominant early-onset AD, which is typically fully penetrant by the time an aected individual reaches his/her early sixties. In the Val717Ile mutation, age of onset ranges from 41 to 64 years (mean 50 50 years). There is no evidence that APP mutations are responsible for lateonset FAD. There is no commercially available test for APP mutations. Presenilin 1/chromosome 14 gene In 1992, genetic linkage of FAD to a chromosome 14 locus was established and conrmed [18]. The gene, presenilin 1 (PS-1), was subsequently discovered in 1995 [19]. This gene is predicted to encode a 467amino acid protein with 7 to 10 hydrophobic transmembrane domains (Fig. 2). More than 70 different mutations in PS-1 have been identied worldwide [20]. Most of the mutations are missense mutations (ie, a single base-pair change that results in a single amino acid substitution). However, very few of these mutations result in a truncated normal protein, however, suggesting that the mutations likely cause a change or gain in protein function rather than a loss of function. The function of PS-1 remains unknown, but it may have c-secretaselike activity [16,21]. Of the three genes known to cause FAD, PS-1 mutations are associated with the earliest age of onset and cause the most rapidly progressive disease. Disease onset ranges from 35 to 55 years of age. Penetrance is nearly complete by the age of 65 years. Disease duration is usually short (5.86.8 years) [6]. PS-1 mutations are more common than APP mutations, representing approximately 30% to 60% of early-onset FAD and less than 5% of all AD [6]. A commercial test is available for PS-1 mutations. It is critical that genetic counseling take place before genetic testing in asymptomatic individuals, however [22]. The clinical picture associated with PS-1 mutations is typically characterized by severe dementia associated with language disturbance and myoclo-
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Fig. 2. Schematic representation of one possible form of the transmembrane proteins encoded by the presenilin-1 (PS-1) gene on chromosome 14 and presenilin-2 (PS-2) gene on chromosome 1. This diagram shows eight transmembrane domains, but other congurations remain possible. Several known mutations are indicated, including PS-1 (lled circles) and PS-2 (open circles). Not all mutations are shown. The arrow at the top left of the gure points to the Volga German PS-2 N141I mutation, the rst PS-2 mutation discovered. The arrow at the bottom of the gure points to a PS-1 mutation (an exon 9 deletion) that is often associated with early spasticity.
nus, which appear relatively early in the course of the disease [23,24]. One mutation in the PS-1 gene (an exon 9 deletion) is often associated with early spasticity (see arrow in Fig. 2) [25]. Presenilin 2/chromosome 1 gene The third AD gene was discovered shortly after the discovery of the PS-1 gene. It was found in FAD kindreds with Volga German (VG) ancestry [26]. These families are ethnic Germans who migrated to Russia but remained separated from the native Russian population. Many of these families subsequently immigrated to the United States, and eight of these families were found to have FAD presumably on the basis of a genetic founder eect (ie, a single common aected ancestor). The presenilin 2 (PS-2) gene was cloned through its homology with the PS-1 gene [27]. It was also called STM-2 (seven-transmembrane domains), although the exact number of transmembrane domains remains unknown. PS-2 is predicted to encode a 448amino acid protein that is 67% identical to PS-1 (see Fig. 2). The highest degree of conservation is within the hydrophobic/transmembrane domains, suggesting that these regions are important in the normal functioning of the protein. Furthermore, the genomic similarity between PS-1 and PS-2 suggests that they arose by duplication. To date, only four or ve mutations in PS-2 have been discovered, making this the least common known genetic cause of AD [20]. A single mutation (N141I) occurs in all the reported early-onset VG
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pedigrees, which is consistent with the founder eect hypothesis. All PS-2 mutations are also missense mutations. Clinical features associated with PS-2 mutations have been reported primarily in the VG families. The mean age of onset in these families is 54.9 8.5 years, and mean disease duration is 7.6 3.2 years. Within the VG families, there is high variability in age of onset, ranging from 40 to 75 years [26]. Ths PS-2 mutation is highly penetrant (>95%). The dementia in PS-2 AD is clinically and neuropathologically indistinguishable from that of sporadic AD. Apolipoprotein E The APOE gene was initially identied as a genetic risk factor in AD by genetic linkage analysis of late-onset FAD pedigrees [28]. Because APOE was known to be present in amyloid plaques and neurobrillary tangles, these observations made APOE a plausible candidate gene. A strong allelic association between APOE e4 and AD was established in 1993 [29,30] and was rapidly conrmed in autopsy-proven sporadic and familial lateonset AD cases. AD risk associated with APOE is dose dependent [29,31]. The presence of the e4 allele seems to modify the age of onset of AD [32]. Compared with the most common APOE genotype (e3/e3), odds ratios range from 2.8 to 4.4 for AD subjects with one e4 allele compared with normal controls; the odds ratio increases from 7.0 to 19.3 for subjects with two e4 alleles [33,34]. These risk estimates are not as strongly observed in blacks or Hispanics (reviewed by Farrer et al [33]), although Hispanics with an e4 allele and blacks who are e4 homozygous remain at increased risk for developing AD [35]. Studies suggest a dierent e4 allele eect in men than in women. In men, only e4/e4 homozygotes have a younger age of onset; whereas one e4 allele is sucient to reduce the age of onset in women [36]. The APOE e4 risk seems to be more pronounced in women [32]. This study reported that women with the e4/e4 genotype (approximately 1% of the general population) have a 40% risk of developing AD by the age of 73 years. Not all studies support these ndings, however. In addition, several studies suggest a reduced frequency of the APOE e2 allele in AD patients [37,38]. Apolipoprotein E genetic testing in Alzheimers disease APOE genotyping is not recommended in asymptomatic persons without dementia, because the presence or absence of e4 is not highly predictive of future AD. Individuals with an e4 allele may not develop AD, whereas those without an e4 allele sometimes develop AD. Some have advocated APOE testing as an adjunct in the diagnostic evaluation of demented persons [39]. A community-based study suggests that such testing only adds a small amount of certainty to diagnostic accuracy [40].
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Late-onset Alzheimers disease More than 50 genes have been implicated in late-onset AD [41]. Linkage studies suggest that chromosome 12 contains such candidate genes, including the a-2 macroglobulin gene [42] and low-density lipoprotein receptors [43]. Neither has been clearly established as an AD gene, however [44,45]. Other studies requiring further evaluation have suggested the involvement of genes on chromosome 10 [46,47]. Numerous association studies have implicated other potential genetic factors in AD, but most have not been conrmed or replicated. These factors include interleukin-6, human leukocyte antigen, a1-antichymotrypsin, and angiotensin converting enzyme [41]. Dementia with Lewy bodies Dementia with Lewy bodies (DLB) [48] encompasses any case that exhibits clinical dementia and has Lewy bodies (LBs) on autopsy, thereby including (1) diuse LB disease, (2) LB variant of AD, as well as (3) dementia associated with classic Parkinsons disease (PD). As anticipated, there is substantial clinical overlap between DLB and AD as well as PD. Clinically, DLB is characterized by progressive and uctuating cognitive impairment, parkinsonism (either de novo or neuroleptically induced), and psychosis with prominent visual hallucinations. Over half of the patients with autopsyproven DLB have hallucinations or systematized delusions during the course of their illness [49]. Behavioral disturbances (ie, systematized delusions or hallucinations) that require neuroleptic treatment, which can worsen parkinsonian signs and symptoms, present therapeutic challenges for clinicians. Neuropathologically, DLB is characterized by the presence of LBs, which is also the hallmark of PD. Twenty to fty percent of cases with neocortical LBs also have substantial AD pathologic ndings, namely, Ab deposition [49]. The boundaries of DLB are still far from being clearly dened because of its shared clinical and neuropathologic features with PD and AD. Although most cases with DLB are considered sporadic, there are several reports in which LB disease seems to be familial [50,51]. To date, no genes have been identied that cause DLB, and additional genetic and neuropathologic studies are necessary to further investigate the role of genetic factors in DLB. Two genes have been shown to cause rare genetic types of PD: a-synuclein and parkin. Families with a-synuclein mutations have LB pathologic ndings and may develop dementia [52,53]. Patients with parkin mutations do not necessarily have dementia or LB pathologic ndings [54]. Vascular dementia Clinical features Binswanger (1894) and Alzheimer (1911) described behavioral disorders related to arteriosclerosis. Initially, these conditions were categorized as
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subcortical arteritis; later, they were classied as Binswangers disease. With newer neuroimaging techniques, small vessel ischemic disease is now commonly observed in geriatric patients. The contribution of small vessel atherosclerotic disease to clinical dementia remains controversial. Vascular dementia typically does not have a distinct genetic risk factor, although multiple cerebrovascular risk factors are heritable (eg, hyperlipidemia, hypertension). The genetics of vascular dementia is likely multifactorial. As a result, assessing the genetic contributions of each of the risk factors is extremely complicated. For the purposes of this article, we focus on a rare cerebrovascular disease associated with dementia for which a gene has been discovered. An autosomal dominant syndrome of hereditary multi-infarct dementia has been described with subsequent gene identication [55]. This disorder is called cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Although this is a rare form of vascular dementia, it is the rst genetic form of geriatric dementia and depression to be identied. As a result, this disorder should be considered in the dierential diagnosis of geriatric patients presenting with these symptoms. Clinically, patients with CADASIL can have dementia (80%), depression (30%50%), and migraine with an aura (30%) during the course of their disease. The typical age of onset is in the 50s or 60s; the typical age at death is 64.5 years. Cognitive impairment in CADASIL is best characterized as frontal lobe disturbance, including inattention, perseveration, apathy, and pseudobulbar aect. On T2-weighted MRI, patients with CADASIL have areas of high signal in the periventricular and deep white matter as well as in the basal ganglia. These abnormalities may be observed while patients are in their 20s, asymptomatic, and are initially similar to patients with multiple sclerosis. Hyperintensities increase over the next two decades of life until conuent areas of high signal in the subcortical white matter are observed. Transient ischemic attacks begin to occur when patients are in their 40s and 50s, with some cases showing extensive lacunar infarcts. The patients are not hypertensive. Pathologically, there is a narrowing of small arteries throughout the brain caused by smooth muscle layer hypertrophy, with electron microscopy showing osmophilic densities in the arteriolar media. The diagnosis of CADASIL can sometimes be conrmed by skin biopsies showing the arteriolar pathologic changes. False-negative skin biopsies have been reported, however. Notch3 Linkage analysis mapped the CADASIL gene to the short arm of chromosome 19. Mutations in the Notch3 gene were rst reported in 1996. Subsequent studies reported that these mutations may be present in individuals without a positive family history [56]. The frequency of Notch3 mutations in sporadic and familial cases with vascular dementia remains unclear but seems to be rare. In addition, mutations in the APP and cystatin-b genes are rare causes of cerebral amyloid angiopathy and hemorrhagic strokes.
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Regardless of their prevalence, the discovery of these mutations provides an opportunity to explore the genetics of cerebrovascular disease. The interaction of the multitude of risk factors related to stroke remains unclear. Each of these risk factors is inuenced by diverse pathogenetic mechanisms. In the future, additional knowledge regarding the genetic and environmental risk factors related to conditions such as atherosclerosis, diabetes mellitus, and hypertension should result in prevention of and intervention in dementia associated with cerebrovascular disease in the future. Huntingtons disease Clinical features The clinical triad in HD includes chorea, cognitive impairment, and behavioral disturbances. Chorea is the main motor sign in HD. These involuntary movements are present only during waking hours. Typically, they cannot be voluntarily suppressed and can increase with stress. Some patients may develop bradykinesia, rigidity, and dystonia. Aspiration secondary to dysphagia is the most common cause of mortality and morbidity. A typical pattern of cognitive decline includes slowness of thought and impaired ability to integrate new knowledge, particularly new motor skills, and a lack of awareness of ones own disability. Visuospatial memory is particularly aected, whereas verbal memory remains preserved until late in the course of the disease. Patients may be able to remember facts, stories, and words but have difculty copying designs on the Mini-Mental State Examination. Orientation to time and place remains intact until late in the illness. Changes in mood and personality are common, ranging from irritability to prolonged periods of depression as well as psychosis [57]. Suicide is more common in patients with HD than in the general population. Psychiatric symptoms may precede motor signs and symptoms by many years and do not necessarily relate to the severity of chorea or dementia. Other symptoms commonly observed include apathy, aggressive behavior, sexual disinhibition, and alcohol abuse. The diagnosis of HD is indicated by the presence of a positive family history of an autosomal dominant degenerative disorder consistent with HD; presence of progressive motor disability, including voluntary and involuntary movements; cognitive decline; and behavioral disturbances. Caudate atrophy on CT or MRI provides additional support for the diagnosis. Finally, DNA analysis conrms the diagnosis. The mean age of onset in HD is approximately 40 years [58], although the age of onset ranges from 2 to 80 years. The duration of HD is typically 15 years, with the age of death ranging from 51 to 63 years. Pathologic features The primary pathologic feature in HD is neuronal loss in the corpus striatum, occurring rst in the caudate and later in the globus pallidus. Caudate
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atrophy is evident on MRI, with characteristic concavity of the ventrolateral aspect of the lateral ventricles. A neuropathologic grading system rates the macroscopic and microscopic appearance of the striatum [59]. The neuronal loss seems to be selective, with the medium spiny neurons being preferentially lost. Neurons containing gamma-aminobutyric acid and enkephalin are the most severely aected, and the most consistent neurochemical ndings suggest low levels of these two neurotransmitters. The discovery of intranuclear inclusions in HD brains that contain the protein encoded by the HD gene (huntingtin) [60] has resulted in new avenues of animal research. Whether these inclusions interfere with nuclear function or whether they are markers for neurodegeneration remains unknown. Epidemiology Many epidemiologic studies have been performed worldwide. There is general agreement that the prevalence of HD in Western European countries is between 3 and 10 cases per 100,000 persons. The rates are lower in Japan, China, and Finland as well as in African black populations. George Huntington, who rst described the syndrome in 1872 [61], noted clear familial aggregation in HD. Genetics HD is inherited as an autosomal dominant trait. In 1983, HD became the rst genetic disorder to be linked by restriction fragment length polymorphism markers to a locus on chromosome 4. [62] Ten years later, an international research consortium reported the successful cloning and sequencing of the HD gene [63]. A novel gene containing a trinucleotide repeat (CAG) that is repeated beyond the normal range is associated with HD. This highly polymorphic CAG repeat is located in the 5 region of the HD gene (Fig. 3). Individuals with symptomatic HD have more than 36 CAG repeats in the HD gene. Individuals with the greatest number of repeats (>60) are more likely to have juvenile-onset illness. Most adult-onset HD cases have 38 to 50 CAG repeats. A signicant correlation between the number of CAG repeats and age of onset of HD has been demonstrated [6467]. The association was the greatest in patients with higher CAG repeats (>60), who tended to have a lower age of onset. But the number of CAG repeats is not useful in predicting the age of onset or type of symptoms at presentation in individual patients, however. HD is the rst of numerous neurodegenerative disorders associated with a trinucleotide repeat expansion. Several other neuropsychiatric disorders (eg, fragile X mental retardation, hereditary ataxias) that exhibit anticipation are also trinucleotide repeat disorders [68,69]. Genetic testing issues in HD are complex and require careful thought and counseling [70,71]. Interestingly, the discovery of dynamic repeat mutations helps to account for the long-observed clinical phenomenon of anticipation. Anticipation is
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Fig. 3. The Huntingtons disease (HD) gene on chromosome 4. Genetic markers are indicated at the top of the gure. D4S10 was the initial marker linked to HD. The bold lines indicate the HD gene, which was called Interesting Transcript-15. This novel gene contains highly polymorphic trinucleotide repeats, (CAG)n, at the 5 end of the HD gene. Individuals with symptomatic HD have more than 36 CAG repeats at this locus. (Courtesy of Elisabeth Almqvist, PhD, Stockholm, Sweden).
the observation that a disease becomes more severe and appears earlier with each successive generation. As in other trinucleotide repeat disorders, this is a result of the unstable expansion of the CAG trinucleotide repeats when the disorder is passed from parent to ospring. In addition, paternal HD alleles are more likely to undergo signicant expansion than maternal alleles, resulting in the observation that those individuals with larger repeat sizes are more likely to have aected fathers. Frontotemporal dementia Clinical features Initially, Pick described a clinical syndrome with dementia, progressive aphasia, and frontal cortical atrophy [72]. Neuronal cytoplasmic inclusions (Pick bodies) were observed later in neuropathologic studies of some cases. Because most patients with dementia and prominent frontal lobe dysfunction do not have Pick bodies, confusion has reigned in the nosology of frontotemporal dementia (FTD). Terminology has included Picks disease, Pick complex, non-AD dementia, disinhibition-dementia-parkinsonism-amyotrophy complex, and frontal lobe degeneration with spinal motor degeneration. In the 1970s, clinical and pathologic studies helped to solidify consensus diagnostic criteria for FTD [7375]. Specically, the discovery of genetic mutations in some FTD families with taupathies (eg, FTD, parkinsonismlinked to chromosome 17 [FTDP-17]) has resulted in new diagnostic categories (see below). Typically, the clinical presentation of FTD includes personality or behavioral change (often disinhibition) with a relatively intact memory. Later in the course of disease, there may be marked confusion, mutism, and parkinsonian features. There are at least three subtypes of FTD, including progressive
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aphasia, semantic dementia, and frontal lobe degeneration [76]. Patients with progressive aphasia have progressively nonuent speech with agraphia, alexia, and acalculia with preservation of word meaning. Patients with semantic dementia have predominantly temporal lobe abnormalities with progressive loss of word meaning but a preserved ability to read and write regular words. Patients with frontal lobar degeneration have a marked loss of personal and social awareness with hyperorality, distractibility, and task impersistence. In general, patients with inferior-frontal lobe involvement tend to be more disinhibited, whereas patients with involvement of dorsolateral-frontal regions tend to be abulic. Pathologic features Pathologically, there is frontal or temporal lobar atrophy. Many cases have only gliosis and neuronal loss without distinctive features. Other cases have cytoplasmic inclusions that may be typical Pick bodies or other varieties of tau-positive material, sometimes resembling neurobrillary tangles. Classic Picks disease with Pick bodies is considered a subtype of FTD. Some cases also have anterior horn cell loss in the spinal cord. Epidemiology Incidence and prevalence estimates of FTD are not well established, partly due to the clinical heterogeneity of the disorder. The only available sample estimating disease incidence is based on clinician referrals. In this study [77], the prevalence rises from 1.2 to 28 cases per 1 million persons from the third decade to the sixth decade. But because this was not a populationbased study, this is probably an underestimate. Among all patients with dementia, FTD is thought to comprise approximately 10% of cases (and probably more in younger age groups). FTD is the most common syndrome with prominent frontal lobe degeneration. It is commonly misdiagnosed as AD, and less commonly as DLB or AD with vascular disease. Most FTD cases are misdiagnosed as AD. In the Consortium to Establish a Registry for Alzheimers Disease neuropathologic studies, FTD-like pathologic ndings were observed in 3% to 9% of patients with a clinical diagnosis of AD [78]. The frequency of FTD in autopsy case series with dementia varies from 0% to 15% [79]. Genetics Familial aggregation was the rst feature of FTD suggesting that there may be an underlying genetic cause. Several groups reported a positive family history in 10% to 60% of cases [77,80]. Segregation analyses have suggested that rst-degree relatives of FTD patients are 3.5 times more likely to develop dementia than rst-degree relatives of normal controls. It has also been suggested that age of onset in relatives of FTD patients is, on average,
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11 years younger than in other dementia patients [77]. There are clearly a few large families with multiple aected individuals in which FTD seems to segregate in a highly penetrant and autosomal dominant fashion. The success of gene identication (see below) in families with atypical dementia not only conrmed the genetic basis of FTD but established it as a distinct clinical and pathologic entity. Frontotemporal dementia and parkinsonism-linked to chromosome 17 The rst systematic linkage study of FTD families mapped the causative gene to chromosome 17 [81]. Subsequently, many other families with FTDlike features also showed linkage to the same region. Interestingly, several other clinically distinct syndromes also mapped to 17q21-22, including parkinsonism [82] and schizophreniform features [83]. At the consensus meeting on chromosome 17-linked dementia in 1996, these syndromes were classied as FTD and FTDP-17 [84]. Even though many clinical dierences exist, pathologic similarities between the various syndromes include tau protein aggregates in the absence of amyloid plaques. Some of these aggregates have similar morphology to the neurobrillary tangles (NFTs) seen in AD. Because tau is a major component of NFTs and the tau gene is located in the critical region, it has been considered an important candidate gene for FTDP-17. After some failed attempts to identify mutations in this gene, the rst tau mutation was identied in a family with familial presenile dementia with psychosis [85] and was conrmed in additional studies [86,87]. This mutation (V337M) is located in exon 12 of the tau gene (Fig. 4). Since then, more than 20 tau mutations have been identied in FTDP-17 families [88,89]. Other families not linked to chromosome 17 have been identied, however, and linkage to chromosome 3 has been reported in one such family [90]. The causative gene in this family is yet to be identied. Tau gene The modied product of the tau gene is a major component of NFTs seen in AD. The tau gene is large, with 100,000 base pairs of DNA and 15 exons. It also exhibits complex splicing (see Fig. 4). There are commonly six alternatively spliced isoforms of the tau gene involving exons 2, 3, and 10. All but one of the currently identied mutations aect microtubule binding domains. Most of these mutations are missense, appearing in the coding regions as well as in the noncoding regions (introns). Some mutations are believed to cause disease by producing functional changes that interfere with the normal binding of microtubules, whereas other mutations appear to change the ratio of tau isoforms in the brain (3 and 4 repeat tau). The discovery of tau mutations in families with FTDP-17 has conrmed the fact that genetics plays a role in a subgroup of FTD cases. More work needs to be done to determine the range of tau mutations in FTD and related disorders.
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Fig. 4. The tau gene on chromosome 17 has a complex genomic structure with more than 15 exons spread over 100,000 base pairs of genomic DNA (top of gure). It undergoes complex dierential splicing. Exons 2, 3, and 10 are alternatively spliced, making up six commonly alternatively spliced isoforms of the tau gene. The large bold arrow points to the rst tau mutation (V337M) associated with frontotemporal dementia, which was discovered in exon 12. (Courtesy of Parvoneh Poorkaj, PhD, Seattle, WA).
Tau mutations have not been found in AD or sporadic cases of FTD. In conditions with tau aggregate pathologic ndings, such as Guamanianamyotrophic lateral sclerosis-parkinsonism-dementia complex and progressive supranuclear palsy, there are genetic association data that suggest that tau may play a role in the disease process [9193]. Explanations for these various clinical, pathologic, and molecular ndings are necessary to better understand the role of tau and the frontal lobes in behavior and cognition. Understanding the in vivo processing of the tau gene is likely to be important in the eventual development of therapeutic treatments. But most FTD cases are sporadic and are not associated with mutations in the tau gene [94,95]. If FTD is familial and aected individuals have tau-related neuropathologic ndings, the frequency of tau mutations increases to as high as 30% to 40%. Prion disease Although prion diseases are relatively uncommon, they exemplify both transmissible and heritable forms of dementia. What we now know as prion diseases were rst described in the 1800s, with reports of scrapie in sheep. Scrapie was shown to be experimentally transmissible in 1936 [96]. Human prion diseases were recognized in the 1920s by Creutzfeldt and Jakob and
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were called spongiform encephalopathies [97,98]. In the 1960s, kuru (a deadly neurodegenerative disorder transmitted through ritualistic cannibalism) was recognized to be similarly transmissible. In the 1990s, the occurrence of bovine spongiform encephalopathy (mad cow disease) further increased the recognition of these disorders. The prevalence of CreutzfeldtJakob disease (CJD) is approximately 1 case per 1 million persons. Prions are small proteinaceous particles that resist inactivation by conventional proteinases. The normal cellular prion protein (PrPC) is a membrane protein primarily expressed in astrocytes [99101]. The mechanisms by which PrPC converts to the scrapie isoform (PrPSc) remain unclear, but the protein structure undergoes a three-dimensional conguration change. Six human diseases associated with prions have been described, including kuru, CJD, Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), atypical prion disease, and new variant CJD (Fig. 5). The identication of the prion protein (PRNP) gene that encodes the prion protein (PrP) [102] has rapidly transformed neurobiologic and genetics research in this area. Although some families have mutations in the PRNP gene that are transmitted in an autosomal dominant fashion and other cases are caused by known exposure to contaminated tissue, most sporadic cases have no known cause. Interestingly, some prion diseases (eg, CJD, new variant CJD) can be both vertically (heritable) and horizontally
Fig. 5. The human prion diseases include Creutzfeldt-Jakob disease, kuru, GerstmannStraussler-Scheinker disease, and fatal familial insomnia. The animal prion diseases include scrapie, transmissible mink encephalopathy, and bovine spongiform encephalopathy. Because these diseases all share the property of transmissibility and the characteristic pathologic nding of spongiform changes, they are often collectively referred to as transmissible spongiform encephalopathies.
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(infectious) transmitted. In this section, we review the genetics of CJD, GSS, and FFI. Current nosology may be replaced in the future by specic DNA mutations, such as familial prion disease with a P102L mutation and predominant ataxia. Creutzfeldt-Jakob disease Sporadic CJD most often aects patients in their 50s and 60s. The typical clinical presentation includes rapid progressive cognitive decline (<2 years to death) accompanied by a variety of neurologic signs (most commonly rigidity, ataxia, and myoclonus) and characteristic synchronous spikes on the electroencephalogram in an afebrile individual. The classic symptoms occur in less than 60% of cases, however. Other clinical features may include psychotic symptoms resembling schizophrenia as well as extrapyramidal and cerebellar dysfunction or akinetic mutism. The diagnosis of CJD should be entertained in individuals with rapidly progressive neuropsychiatric disorders. Clinical diagnostic criteria have been established by a large CJD surveillance group in Europe [103], although denitive diagnosis can only be made on neuropathologic or biochemical examination of the brain. The neuropathologic hallmarks of CJD include spongiform degeneration, neuronal loss, and astrocytic gliosis. PrPSc-positive kuru plaques and other PrP-containing amyloid plaques are pathognomic of prion disease. They are almost exclusively found in familial CJD cases with PRNP mutations. A cerebrospinal uid test for the 14-3-3 protein has been found to be diagnostically useful. Prion protein mutations The human PRNP gene is located on the short arm of chromosome 20. This gene is highly conserved throughout many species, suggesting that its function is critical. The cellular function of PrPC remains unknown, however. In families with inherited prion diseases, more than 15 types of mutations have been described [104]. There are no systematic studies that provide frequency estimates of known mutations in dierent patient samples. The most common PRNP mutation associated with familial prion disease is the E200K (glutamic acid [GAG] to lysine [AAG]) mutation. This mutation has been found in more than 50 families worldwide. Up to 50% of familial cases have this mutation. The largest known cluster is a group of Libyan Jews living in Israel, who have an incidence of CJD 100-fold greater than the population worldwide [105]. Another missense mutation (D178N) in the PRNP gene has been reported in a number of dierent families. Surprisingly, the phenotype depends heavily on the genotype present at an entirely dierent codon (codon position 129). In families with the D178N mutation and valine at position 129, the presentation is that of fairly typical CJD with memory loss,
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ataxia, and myoclonus. The age of onset is in the 50s and 60s, with the disease duration ranging from 9 months to 4 years. The electroencephalogram shows generalized slowing rather than periodic triphasic waves. Neuropathologic ndings include diuse spongiform degeneration in the cerebral cortex and basal ganglia with relative sparing of the thalamus. Alternatively, in families with the same D178N mutation but with methionine at position 129, the phenotype is that of FFI. These patients often present with insomnia and dysautonomia. They may later show signs of ataxia, dysarthria, myoclonus, and pyramidal tract dysfunction. In the later stages, patients exhibit complete insomnia, dementia, rigidity, dystonia, and mutism. The duration of illness is short (mean 13 months). Neuropathologically, FFI is characterized by neuronal loss and astrocytic gliosis preferentially aecting the thalamus. At least 21 families with FFID178N mutations have been reported [106]. It is unclear why the codon 129 genotype dramatically inuences the phenotype associated with the D178N mutation, but it presumably aects the three-dimensional structure of PrP. Another phenotype, the GSS syndrome, is caused by several dierent mutations in the PRNP gene [107]. Clinical symptoms include early ataxia, dementia, dysphagia, dysarthria, and hyporeexia. Patients with GSS are more likely to exhibit ataxia than patients with CJD. Conversely, patients with CJD are more likely to have dementia and myoclonus. Clinical symptoms often overlap, however, and do not always breed true within families. As such, family members with the same PRNP mutation may have either phenotype. GSS is always considered to be solely genetic and often has a longer disease duration than CJD. Neuropathologically, GSS is distinct from CJD in that GSS is characterized by the presence of large multicentric PrPcontaining amyloid plaques with variable spongiform changes. The most common mutation associated with GSS is the P102L mutation. More than 30 aected families in the Northern Hemisphere have been described to date [108]. This was the rst mutation to be formally linked to a human prion disease and is the causative mutation originally described by Gerstmann, Straussler, and Scheinker [109]. The clinical and neuropathologic characteristics of these families are indistinguishable from those of sporadic CJD. Interestingly, when infected brain tissue from CJD E200K patients was injected into primates, the disease was transmitted in most trials, but transmission has not been demonstrated in other families with dierent mutations [110]. This nding is similar to the results observed in experiments using brain tissue from sporadic CJD cases.
Mitochondrial disorders Mitochondrial disorders are clinically diverse and are dened by structural or functional abnormalities in the mitochondria or mitochondrial DNA
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(mtDNA). Because mtDNA has a poorly developed repair system, mutations are rarely repaired. Although infrequent, an increasing number of mtDNA mutations have been described in several neurologic disorders. The characteristics of inherited mitochondrial disorders include maternal inheritance, heteroplasmy, mitotic segregation, and the threshold eect. Because mtDNA is almost exclusively maternally inherited, all mtDNA mutations are passed on by mothers. Because of the clinical heterogeneity associated with mitochondrial disorders, analysis of large families is often necessary to establish the pattern of maternal inheritance. Heteroplasmy refers to the mixture of both mutant and wild-type molecules within mitochondria. In normal cells, all mtDNA molecules are identical. As heteroplasmic cells undergo cell division, the proportions of mutant and normal mtDNA allocated to daughter cells shift. As a result, some clinical symptoms may improve as a child ages. Mitotic segregation explains the markedly dierent levels of mutant mtDNA in members of the same family as well as among dierent tissues in a single individual. The threshold eect is the observation that a certain level of mutant mtDNA must be achieved before a cell expresses a defect. Variability in onset and severity of clinical manifestations results from a changing balance between the energy supply and oxidative demands of dierent organ systems. Mitochondrial disorders have been implicated in prevalent neurodegenerative disorders (eg, AD, PD) as well as in aging itself, but the evidence is controversial. Aging is associated with an increase in mtDNA mutations. These are not specically germline mutations but accumulating mutations that may increase over time in any organ, including the brain. The precise eects of these mutations are not known. These mutations are not genetically transmitted to the next generation but may cause dysfunction of the organs in which they occur. It has been hypothesized that several dierent mutations may ultimately contribute to functional impairment. There is evidence that mtDNA mutations may be involved in neurodegenerative conditions such as AD. In AD, it is postulated that mtDNA mutations may lower the oxidative eciency of critical neuronal populations early in life [111]. An increase in oxidative damage to mtDNA in AD brains has been reported. In addition, younger AD patients (<75 years old) are more likely to have an increased level of common mtDNA mutations than age-matched controls. Nevertheless, the data need to be conrmed. It remains unclear whether these observations are the consequences of the disease or whether they contribute to the pathophysiology. Screening for mtDNA mutations is not recommended for any neurodegenerative conditions until these frequency of these mutations is better established [112]. Summary Many neurodegenerative diseases are exceedingly complex disorders (Fig. 6). In the past decade, we have made tremendous advances in our under-
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Fig. 6. This diagram demonstrates the concept that the Alzheimers disease (AD) phenotype (as well as the other neurodegenerative conditions) is phenotypically heterogeneous. On the left are the four known genetic factors associated with AD. There are likely other early-onset as well as late-onset genes yet to be discovered. On the right are four potential nongenetic causes of AD that presently remain speculative. In summary, the bottom arrow shows that most cases of AD in the general population may be the result of a complex interplay between environment, genetic predisposition, and aging.
standing of the genetic basis of these disorders. One common characteristic of these disorders is the existence of rare families in which a given disease is inherited as a Mendelian trait. In this article, we have reviewed the genetics of several common neurodegenerative disorders that are associated with cognitive disturbances and for which causative genes have been identied. Further genetic analysis should clarify the roles of known genes in the pathogenesis of common sporadic forms of these various diseases. Investigation of the normal and aberrant functions of these genes should provide insight into the underlying mechanisms of these disorders. Such research should facilitate new strategies for therapeutic interventions. Although molecular genetics has helped to clarify the etiology of these disorders, clinicians have played a critical role in the careful identication and classication of many families who were involved in the eventual mapping and cloning of causative mutations. The role of the clinician should not be underestimated. Future clinical and molecular genetics ndings hold many clinical implications. It is likely that new diagnostic and therapeutic strategies for dementing disorders are just on the horizon.
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Acknowledgements The authors thank Lillian DiGiacomo, BA, and Charisma Eugenio, BS, for their editorial assistance and Molly Wamble, BA, for her technical assistance. References
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Med Clin N Am 86 (2002) 615627
The role of tau in Alzheimers disease

John Q. Trojanowski, MD, PhD*, Virginia M.-Y. Lee, PhD
Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Maloney Building, 3rd Floor, HUP, Philadelphia, PA, 19104, USA
Growing evidence over the past decade has led to the realization that many sporadic and familial neurodegenerative diseases are characterized by distinct hallmark brain lesions formed by lamentous deposits of abnormal brain proteins, and a group of heterogeneous disorders characterized neuropathologically by prominent intracellular accumulations of abnormal tau laments may share common disease mechanisms (for recent reviews, see [13]). Despite their diverse phenotypic manifestations, these disorders are collectively known as neurodegenerative tauopathies (Table 1), and the absence of other disease-specic neuropathological abnormalities in several tauopathies provided circumstantial evidence implicating tau abnormalities in the onset/progression of neurodegeneration [13]. However, this was controversial until 1998 when multiple tau gene mutations were discovered in families with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) and provided unequivocal evidence that tau abnormalities alone are sucient to cause neurodegenerative disease [48]. This opened up new avenues for investigating the role of tau abnormalities in mechanisms of brain dysfunction and degeneration in Alzheimers disease (AD) and related neurodegenerative disorders [13]. Indeed, these dramatic discoveries re-focused attention on the role of tau pathologies in mechanisms of brain degeneration in AD, and here we review recent insights into these aspects of the pathobiology of AD. Normal tau biology and functions Tau proteins are low Mr microtuble associated proteins (MAPs) that are expressed predominantly in axons of central nervous system (CNS)
* Corresponding author. E-mail address: trojanow@mail.med.upenn.edu (J.Q. Trojanowski). 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 2 - 0
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J.Q. Trojanowski, V.M.-Y. Lee / Med Clin N Am 86 (2002) 615627
Table 1 Neurodegenerative disease with tau pathology Alzheimers disease Amyotrophic lateral sclerosis/parkinsonism-dementia complex* Argyrophilic grain dementia* Corticobasal degeneration* Dementia pugilistica* Diuse neurobrillary tangles with calcication* Downs syndrome Frontotemporal dementia with parkinsonism linked to chromosome 17* Multiple system atrophy Myotonic dystrophy Neurodegeneration with brain iron accumulation type 1 (formerly Hallevorden-Spatz disease) Niemann-Pick disease, type C Picks disease* Post-encephalitic parkinsonism Prion diseases Progressive subcortical gliosis* Progressive supranuclear palsy* Subacute sclerosing panencephalitis Tangle only dementia*
* Diseases in which tau pathologies are the most predominant neurodegenerative brain lesions.
neurons, and they also are found in axons of peripheral nervous system (PNS) neurons, but they are barely detectable in CNS astrocytes and oligodendrocytes [9,1014]. Human tau is encoded by a single gene consisting of 16 exons on chromosome 17q21, and the CNS isoforms are generated by alternative mRNA splicing of 11 exons [1517]. In the adult human brain, alternative splicing of exons (E) 2 (E2), 3 (E3) and 10 (E10) generates six tau isoforms ranging from 352 to 441 amino acids in length which dier by the presence of either three (3R-tau) or four (4R-tau) carboxy-terminal tandem repeat sequences of 31 or 32 amino acids that are encoded by E9, E10, E11 and E12 [15,18,19]. Additionally, the three 3R-tau and 4R-tau isoforms differ due to alternative splicing of E2 and E3 that results in tau isoforms without (0N) or with either 29 (1N) or 58 (2N) amino acid inserts of unknown functions. In the adult human brain, the ratio of 3R-tau to 4R-tau isoforms is 1, but the 1N, 0N and 2N tau isoforms comprise about 54%, 37% and 9% of total tau, respectively [20,21]. Further, tau is developmentally regulated leading to expression of only the shortest tau isoform (3R/0N) in fetal brain, but all six isoforms are expressed in the adult human brain. In the PNS, inclusion of E4a in the amino-terminal half results in the expression of the largest tau isoform [12,22,23]. Several functions of tau have been extensively characterized (for review [13]). For example, tau binds to and stabilizes microtubules (MTs), in addition to promoting MT polymerization through MT binding domains in the carboxy-terminal half of tau that are composed of highly conserved
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18-amino acid long binding elements separated by less conserved 13-14 amino acid long inter-repeat sequences [13,11,2427]. The binding of tau to MTs is a complex process mediated by several MT binding sites distributed throughout the MT binding repeats and the inter-repeat sequences as well as sequences anking the repeats [13,20,24,26,2830]. The 4R-tau isoforms are more ecient at promoting MT assembly and have a greater MT binding anity than 3R-tau isoforms, but the inter-repeat sequence between the 1st and 2nd MT binding domains has >2 times the binding anity of any of the MT binding repeats, and this region is unique to 4R-tau, which may account for the higher MT binding anity of 4R-tau versus the 3R-tau isoforms. Tau phosphorylation is developmentally regulated and fetal tau is more highly phosphorylated in the embryonic compared to the adult CNS, while the degree of phosphorylation of the six adult tau isoforms decreases with age [13,3135]. The tau phosphorylation sites are clustered in regions anking the MT binding repeats, and 79 potential serine (Ser) and threonine (Thr) phosphate acceptor residues are present in the longest tau isoform, while phosphorylation at 30 of these sites has been reported in normal tau, the increasing phosphorylation of tau negatively regulates MT binding [13, 31,36,37]. Although the relative importance of individual sites for regulating the binding of tau to MTs is unclear, phosphorylation of Ser-262 has been reported to play a dominant role in reducing the binding of tau to MTs [38], but a similar role has been ascribed to phosphorylation of Ser-396 [31], while other studies suggest that neither of these sites dominantly regulate binding of tau to MTs [39]. However, both sites are phosphorylated in fetal tau and they are hyperphosphorylated in all six adult human brain tau isoforms that form paired helical laments (PHFs) in AD neurobrillary tangles (NFTs). Further, it has been suggested that a sequence of residues aminoterminal to the MT binding domains (224KKVAVVR230) promotes MT binding in combination with the repeat regions, and it is likely that phosphorylation at multiple phosphate acceptor sites regulates the binding of tau to MTs. Although the kinases and protein phosphatases that regulate tau phosphorylation are the focus of intense investigation, and a large number of Ser/Thr protein kinases have been suggested to play a role in regulating tau functions in vivo, this aspect of tau biology remains controversial (reviewed in [13]). The major candidate tau kinases include mitogen-activated protein kinase [36,40,41], glycogen synthase kinase 3b (GSK-3b) [4245], cyclindependent kinase 2 (cdk2) [46], cyclin-dependent kinase 5 (cdk5) [46,47] , cAMP-dependent protein kinase [48], Ca2/calmodulin-dependent protein kinase II [49], MT-anity regulating kinase [50], and stress-activated protein kinases [5153]. However, recent data suggest that GSK-3b and cdk5 plausibly regulate the in vivo phosphorylation of tau. For example, GSK3b is a Ser/ Thr kinase that is abundant in brain and associates with MTs, and cell culture studies indicate that GSK3b induces hyperphosphorylation of tau followed by dimished MT binding [45,5457]. In cultured neuronal cells, GSK3b
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mediated tau phosphorylation is inhibited by insulin and IGF-1 via a phosphatidylinositol 3-kinase and protein kinase B dependent pathway, and inhibition of GSK-3b by lithium salts or ATP inhibitors reduces tau phosphorylation and aects MT stability [43,44,5861]. On the other hand, cdk5 is a Ser/Thr protein kinase highly enriched in neurons that colocalizes with the cytoskeleton and contributes to the phosphorylation of tau, and it is activated by regulatory subunits such as p35 [46,47,54,62,63]. Moreover, cdk5 complexes with tau and anchors cdk5 to MTs while cdk5-mediated tau phosphorylation stimulates further phosphorylation of tau by GSK3b [64 66]. However, the relative contributions of individual kinases to tau phosphorylation in vivo remain to be elucidated. Protein phosphatases also have been the focus of research on tau since they counterbalance the eects of tau kinases, and studies have implicated protein phosphatse (PP) 1 (PP1), 2A (PP2A), 2B (PP2B) and 2C (PP2C) in regulating tau phosphorylation, although their role in vivo is unclear (reviewed in [13]). Both PP2A and PP2B are present in human brain tissue and they dephosphorylate tau in a site-specic manner. For example, both enzymes dephosphorylate Ser396, but PP2A also dephosphorylates tau at additional sites, and PP2A shows the major activity in brain on tau phosphorylated by a number of kinases [41,6769]. PP1 and PP2A bind to tau, possibly mediating an association with MTs, and PP2A also binds directly to MTs [7072]. Finally, although inhibition of PP1 and PP2A by okadaic acid in cultured human neurons was followed by increased tau phosphorylation, decreased tau binding to MTs, selective destruction of stable MTs and rapid axonal degeneration of axons [73], the specic role of individual phosphatases in the in vivo regulation of tau phosphorylation remains to be determined. Pathological tau in AD In contrast to tauopathies, wherein lamentous neuronal and/or glial tau inclusions are the only dening neuropathological features in aected brain regions, tau-rich NFTs and neuropil threads co-occur with deposits of Ab brils in the extracellular space as diuse and senile plaques as well as in blood vessel walls of AD brains (reviewed in [13]). The neurobrillary tau lesions in AD brains were rst shown to be stained with anti-tau antibodies more than 15 years ago [74,75], but more than 20 years earlier [76] electron microscopical (EM) studies had revealed that the major structural components of NFTs were PHFs and to a lesser extent straight laments (SFs). Subsequent EM studies demonstrated that PHFs contain two strands of brils twisted around one another with a periodicity of 80 nm and a width varying from 8 to 20 nm, while SFs do not demonstrate a similar helical periodicity [77]. However, after the appearance of a number of conicting reports on the composition of these laments in the early 1980s, the building block subunits of both PHFs and SFs were shown to be abnormally phosphorylated tau proteins [16,68,7883]. For example, biochemical analysis of
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PHFs puried from AD brains revealed three major bands of approximately 68-, 64- and 60-kDa, in addtion to a minor 72-kDa band, but after enzymatic dephosphorylation, six protein bands corresponding to the six adult human brain tau isoforms were evident. Indeed, the relative abundance of each of the six tau isoforms in AD PHFs (PHFtau) was indistinguishable from the six soluble tau isoforms in the normal adult human brain [3,21,84,85]. Moreover, most phosphorylated residues in PHFtau also were found in tau isolated from biopsies of normal human brain [69], but relative to normal, soluble adult brain tau isoforms, PHFtau was more extensively phosphorylated (ie, hyperphosphorylated) at these sites [8588]. Numerous kinases and protein phosphatases were implicated in the aberrant phosphorylation tau in the AD brain (for detailed reviews see [13]), but cdk5 abnormally activated by p25, a truncated form of p35, may play a mechanistic role in the conversion of normal tau into PHFtau in AD [8992]. While the role of tau phosphorylation in AD brain degeneration remains uncertain, it is possible that hyperphosphorylation of tau disengages tau from MTs, thereby increasing the pool of unbound tau which then may aggregate into insoluble lamentous inclusions, although there is no consenus on this at this time [13,9395]. Nonetheless, since increasing the ability of pathological tau to intereact with MTs may be benecial, the organic osmolytes trimethylamine N-oxide (TMAO), betaine or related compounds could have therepeutic potential in AD and related tauopathies because they appear to increase tau mediated MT assembly and restore the ability of phosphorylated tau to promote this assembly [96,97]. Nonetheless, while tau hyperphosphorylation is likely an early step in the generation of PHFtau from normal soluble tau [98], it is unclear if it directly mediates tau brillogenesis in vivo. Indeed, a number of early studies of tau brillogenesis showed that PHF-like laments can be assembled in vitro from bacterially expressed non-phosphorylated 3R-tau fragments, although PHFs from AD brain consist of full-length tau [99101]. In subsequent studies, sulphated glycosaminoglycans (GAGs) were shown to stimulate phosphorylation of tau by a number of protein kinases and induce brillization of full length tau [102104], while a short amino acid sequence (VQIVYK) in the third MT-binding repeat was suggested to be essential for heparin-induced lament assembly [105]. Further, tau brillization may occur in a nucleationdependent manner [106]. Moreover, RNA [107,108] and arachidonic acid [109] also were shown to induce brillization of full-length recombinant tau, and the detetion of GAGs and RNA co-localized with PHFtau in NFTs suggests that these in vitro ndings may be relevant to tau brillization in the AD brain [103,110112]. Implications of other neurodegenerative tauopathies for AD Despite controversies about the role of tau pathology in AD, indirect evidence of a causative role for tau protein abnormalities in brain degeneration
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comes from studies of pure tauopathies wherein there is abundant lamentous tau pathology and brain degeneration in the absence of extracellular amyloid deposits or other brain lesions (Table 1), and this is exemplied by sporadic tauopathies such as progressive supranuclear palsy and corticobasal degeneration (for which specic tau haplotypes appear to be genetic risk factors), and Picks disease (reviewed in [13]). However, more compelling evidence for this notion came from studies of a group of syndromes known as FTDP-17 that are autosomal-dominantly inherited neurodegenerative diseases with diverse, but overlapping, clinical and neuropathological features, and these disorders are characterized neuropathologically by prominent lamentous tau inclusions in neurons and/or glial cells (for recent reviews, see [13]). For example, in 1998, several groups identied pathogenic mutations in the tau gene that segregated with FTDP-17 [48], and within three years more than 20 distinct pathogenic mutations in the tau gene have been identied in a large number of new FTDP-17 families. As reviewed elsewhere [13], these include 11 missense mutations in coding regions of the tau gene involving E9 (K257T, I260V, G272V), E10 (N279K, P301L, P301S, S305N), E12 (V337M, E342V) and E13 (G389R, R406W), three silent mutations in E10 (L284L, N296N, S305S) and a deletion mutation (DK280), while ve substitutions in six dierent positions of the intron following E10 have been identied (at positions 3, 12, 13, 14, 16) and other mutations have been reported in recent meetings. Further, studies of FTDP-17 brains from several laboratories add increasing support to the hypothesis that FTDP-17 mutations lead to tau dysfunction and neurodegenerative disease by one or more distinct mechanisms including losses of tau functions and gains of toxic properties, while experimental conrmation of this notion is emerging from studies of a number of transgenic mouse and other model systems of tauopathies (see [17,21,113] for further details, reviews of other studies, and additional citations). Summary Despite earlier uncertainties about the role of tau patholgy in AD, the discovery of multiple mutations in the tau gene that lead to the abnormal aggregation of tau and the onset/progression of FTDP-17 demonstrates that tau dysfunction is sucient to produce neurodegenerative disease. The mutations lead to specic cellular alterations, including altered expression, function and biochemistry of tau. The nding that specic tau gene mutations lead to diverse FTDP-17 phenotypes raises the possibility that the clinical and pathological expression of hereditary and related sporadic tauopathies may be inuenced by tau gene polymorphisms, other genetic factors and epigenetic events. However, the precise mechanisms whereby tau assembles into laments and causes neurodegeneration in the human brain remain to be elucidated, but further investigation into the mechanisms of tau dysfunction, as well as the identication of potential disease-modifying
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factors, will provide additional insight into novel strategies for the treatment and prevention of AD and related disorders. Moreover, development of additional animal models of tauopathies that more closely recapitulate human diseases will facilitate this undertaking, and this is likely to have implications for other neurodegenerative disorders since the aggregation of tau in AD and and related tauopathies is an example of abnormal proteinprotein interactions resulting in the intracellular accumulation of lamentous proteins that is a common feature of many fatal CNS diseases characterized by relentlessly progressive brain degeneration [13]. Thus, the brillization and aggregation of proteins in the brain is a common theme in a diverse group of neurodegenerative disorders and insight into the pathogenesis of any one of these disorders may have implications for understanding the mechanisms that underlie all these diseases as well as for the discovery of better strategies to treat them [13]. Acknowledgements V.M.-Y.L. is the John H. Ware 3rd Chair of Alzheimers disease research at the University of Pennsylvania. Work done in the laboratories of the authors is supported by grants from the National Institute of Aging of the National Institutes of Health and the Alzheimers Association. We also thank our many collaborators and past as well as current members of the Center for Neurodegenerative Disease Research (CNDR) for contributions to the research from CNDR summarized here. Finally, the support of the families of our patients have made this research possible.
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[110] Ginsberg SD, Galvin JE, Chiu TS, et al. RNA sequestration to pathological lesions of neurodegenerative diseases. Acta Neuropathol (Berl) 1998;96(5):48794. [111] Snow AD, Mar H, Nochlin D, et al. Early accumulation of heparan sulfate in neurons and in the beta- amyloid protein-containing lesions of Alzheimers disease and Downs syndrome. Am J Pathol 1990;137(5):125370. [112] Verbeek MM, Otte-Holler I, van den Heuvel LP, et al. Agrin is a major heparan sulfate proteoglycan accumulating in Alzheimers disease brain. Am J Pathol 1999;155(6):211525. [113] Gamblin TC, King ME, Dawson H, et al. In vitro polymerization of tau protein monitored by laser light scattering: method and application to the study of FTDP-17 mutants. Biochem 2000;39(20):613644.
Med Clin N Am 86 (2002) 629639
The role of beta-amyloid in Alzheimers disease

Sukanto Sinha, PhD*
Elan Biopharmaceuticals, 800 Gateway Boulevard, South San Francisco, CA 94080, USA
Alzheimers disease pathology Alzheimers disease (AD) is characterized, upon postmortem analyses of the brain, by the presence of two major pathologic lesions, the senile or neuritic plaque, and neurobrillary tangles, both identied by Alois Alzheimer in 1906. Neuritic plaques are composed of extracellular brillar deposits of the beta-amyloid peptide, Ab, and are often associated with dystrophic neurites, activated microglial cells, and activated astrocytes. They are found widely in the limbic and association areas of the temporal cortex, as well as in the hippocampus, a structure that is aected dramatically in the disease [1]. Neurobrillary tangles, or NFTs, which have been shown to be composed of the abnormally phosphorylated microtubule-associated protein tau [2], are found extensively in all of the brain areas aected in AD. They occur as intraneuronal, cytoplasmic inclusions, ultrastructurally shown to occur as interwound paired-helical laments (PHF), remarkably resistant to solubilization even in strong chaotropic agents. Although both of these prominent pathologic lesions often occur simultaneously in the majority of AD cases, NFTs are sometimes found in diseases other than AD, especially some of the taupathies without coincidental beta-amyloid plaques. But all cases of clinical AD that have been analyzed for neuropathology have been shown to have Ab deposits, although the nature and extent of these varies widely in both sporadic and familial forms of the disease. Amyloid precursor protein (APP) and its metabolism Remarkable progress in understanding the underlying pathology of this disease has been made over the last fourteen years, dating approximately
* E-mail address: sukanto.sinha@elan.com (S. Sinha). 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 2 2 - 6
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S. Sinha / Med Clin N Am 86 (2002) 629639
from the time that the protein precursors to the Ab peptides, collectively called APP, were cloned [3] and subsequently expressed in cell culture. Studies of the metabolism of the APP from various laboratories have conclusively established that following maturation of the protein in the secretory pathway, proteolytic cleavages take place in the extracellular or luminal domain of the protein, which leads to the release (secretion) of the bulk of the N-terminal ectodomain of the protein as sAPP [4], which is detected not only in the culture medium of cells expressing APP, but also in physiologic uids such as plasma and cerebrospinal uid (CSF). It turns out that most of the sAPP generation takes place as a consequence of cleavage of the membrane-bound protein approximately 12 amino acids N-terminal to the membrane interface [5]. This a-secretase cleavage also leads to the loss of the intact Ab peptide region, the site of endoproteolysis being 16 aa C-terminal to the start of the Ab peptide sequence. The early identication of this pathway, and its recognition as the major, ubiquitous pathway of mature APP processing, led to the dogma that this represents normal APP metabolism, and that alternate, pathologically triggered pathways must be responsible for the aberrant generation of the Ab peptides, which are then subsequently deposited as insoluble amyloid during the disease process. The recognition that the Ab peptides are actually normal metabolites of APP came about as the consequence of the discovery that primary human neuronal cells release Ab peptides, Ab1-40, as well as Ab11-40, in their culture medium [6], and that tissue culture cell lines, such as HEK293 that are transfected with APP also release Ab peptides into their culture medium as well. Shortly thereafter, it was shown that a subset of sAPP is generated by an alternate b-secretase activity that cleaves the full-length membranebound APP immediately N-terminal to the Ab peptide sequence. This cleavage takes place between Met671-Asp672 (using the APP770 codon numbering), releasing a b-sAPP [7] that is C-terminally truncated compared with a-sAPP, and also generating a cell-associated 99 aa long C-terminal fragment (CTF) which starts with Asp672 (Ab1) (Fig. 1). This alternate secretory cleavage was found to be far more prevalent in primary neuronal cultures than in peripherally derived tissue culture cells; the b-sAPP made up as much as 4050% of total sAPP derived from culture medium of the neuronal cells, compared with 5% or less as found in culture medium from HEK293 cells transfected with APP. It therefore appeared that b-secretase cleavage of APP, enriched in neuronal cells, could initiate the normal production of Ab by the cellular turnover of the 99 aa b-CTF. Familial Alzheimer disease mutations and genetic risk factors Concurrent with the elucidation of these cellular pathways of APP metabolism that lead to the release of Ab peptides into the extracellular milieu came the identication of rare missense mutations in APP that lead
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Fig. 1. The a- and b-secretase cleavage pathways for APP.
to the familial inheritance of AD. These classied into two groups, one in which Val717 was found to be mutated into either Ile [8], Phe or Gly (London mutations, APP717), and a second pedigree [9] with a double mutation, changing the Lys670Met671 sequence of the b-secretase cleavage site to a Asn670Leu671 motif (Swedish mutation, APPNL). The identication of such disease-causing mutations that framed the Ab peptide region suggested that they somehow alter the metabolism of APP, leading to increased Ab production. This was demonstrated dramatically on transfection of the Swedish APP forms into HEK293 cells, which led to a ve to sixfold overproduction of the Ab peptides compared with Wt APP [10]. The increased Ab peptide release was accompanied by increased levels of b-sAPP as well, indicating that the Swedish double mutation at the b-secretase site leads to an increased cleavage of the full-length APP molecule at the altered sequence. The higher levels of the cell-associated b-CTF generated as a consequence of this gives rise to the higher levels of Ab peptide released. Although missense mutations in APP account for a very small number of total AD cases, epidemiologic data have long pointed to the strong contribution of genetic factors to the overall population risk for AD. For example, there is an increased age-dependent risk for AD among primary relatives of patients with AD [11], consistent with either incompletely penetrant singlegene defects, or with a more complex interaction among multiple hereditary and extrahereditary factors, such as possible environmental modiers. Approximately 10% of AD cases, however, appear to be transmitted in
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familial pedigrees in a classical Mendelian autosomal dominant manner, and the identication of the genes that account for the predominant numbers of such cases have provided key insights into the etiology of AD. With the exception of the small number of families that map to APP on chromosome 21, the majority of cases of familial Alzheimers disease (FAD) were found to map to chromosome 14, to a locus that was identied as a new gene, S182 [12]. The protein product of the S182 gene, named presenilin-1 (PS-1), was predicted to traverse the membrane multiple times (polytopic) and was shown to be widely expressed in all cells and tissues surveyed. A homologous gene, STML2, called presenilin-2 (PS-2), was concurrently mapped to chromosome 1, in a Volga-German family [13]. More than 80 separate missense mutations have been cataloged in PS-1, and 5 in PS-2, inheritance of any of which leads to fully penetrant AD at an early age (3565 age of onset). Distinct from these autosomally inherited single gene defects in PS or APP that lead to early onset AD, genetic linkage studies of other familial pedigrees led to the identication of the apolipoprotein E (apo E) locus on chromosome 19 as a potential AD susceptibility gene [14]. Apo E in humans is a polymorphic protein, with three commonly occurring variants, e2 (10%), e3 (75%) and e4 (15%), the numbers in parentheses indicating their approximate prevalence in a Caucasian population. Multiple studies have gone on to establish that the e4 allele is over-represented in patients with late-onset AD (40% in postmortem or clinically diagnosed AD). The inheritance of two e4 alleles correlates with an earlier age of onset in patients with AD than with a single allele [15], although it appears that the apo E polymorphism remains a risk factor and is not causative for AD. Current estimates suggest that the apoe4 allele may account for only 79% of all AD cases.
Ab42 and AD pathogenesis Although the analysis of Ab isoforms from primary cells, transfected cells, and CSF indicate that the predominant form of Ab is Ab1-40, it has turned out that a relatively minor form, Ab1-42, is the primary constituent of the amyloid burden in AD [16]. As demonstrated in vitro, the additional 2 amino-acid extension at the C-terminus renders this form much more prone to aggregation, consistent with its increased presence in insoluble amyloid plaques. The generation of antibodies specic to this form of the Ab peptide, and also to the shorter Ab40 peptide, made possible the development of sensitive and specic assays for both of these forms [17]. The utilization of such assays in the analysis of the eect of the various FAD mutations in PS-1, PS-2, and the London mutations in APP, has led to the emergence of a central hypothesis for the cause of AD. Immunohistochemical analyses of AD brain sections with such antibodies have revealed that the majority of diuse plaques, and most senile plaques,
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label strongly with antibodies specic to the 42 form of the peptide, although the mature, senile plaques label with antibodies to Ab40 as well [16]. At this level of analysis, the Ab42 appears to be a preponderant constituent of neuropil amyloid in AD, even though it makes up a relatively small proportion of normally secreted Ab peptides. Biochemical analyses of AD brain plaque composition have provided more quantitative conrmation of this as well. That said, it has been a dicult proposition to precisely nail down the exact composition of senile plaques in AD, and the heterogeneity of the Ab forms that have been identied from AD brain, using a variety of dierent methodologies, renders the biochemical problem quite formidable. The concurrent presence of cerebral amyloid angiopathy, vesselassociated amyloid, has also confounded the issue of what forms of the Ab peptides make up the senile plaque [17]. A roundabout approach to this problem has evolved as a consequence of careful analysis of Ab forms deposited in the various FAD families and the analysis of brains from individuals with Downs syndrome. Downs syndrome is accompanied, essentially without exception, with the progressive acquisition of AD-like pathology, and the availability of postmortem brain tissue from trisomy 21 individuals at various ages has enabled the reconstruction of the likely temporal progression of AD. Trisomy 21 theoretically leads to an extra copy of the APP gene, and the translation of this increased gene dosage at the protein level has been conrmed by analyzing for APP levels in the body uids of persons with Downs syndrome. The increased APP levels, not surprisingly, leads to increased levels of circulating Ab peptides [18]. The earliest amyloid deposits seen in very young individuals, approximately 12 years old, with DS have a diuse morphology, and although these diuse plaques label readily with Ab42 antibodies, they show no reactivity with either antibodies to Ab40, or with antibodies specic to the N-terminal region of the Ab peptide [19]. More Ab42 reactive plaques, accompanied by dystrophic neurites and activated microglial cells, show up in DS individuals who are 2030 years old, with neurobrillary tangles being evident by age 30. Plaques at this time label prominently with antibodies to the N-terminus of Ab, as well as with antibodies to Ab40.
Eect of FAD APP mutations on Ab42 As described earlier [8], the rst FAD mutation identied was the London mutation, which resulted in the substitution of an Ile for a Val at codon 717 of APP. Inheritance of this led to an autosomally dominant, early onset form of AD. Postmortem examination of brains from a Japanese family with this mutation showed dramatic and extensive presence of both diuse and neuritic amyloid plaques, which prominently labeled with antibodies specic to the Ab42 epitope. Other APP717 mutations have since been identied, leading to substitution of Phe and Gly for the naturally-occurring Val at
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that position. The observation that a single point mutation in APP can lead to AD provided the rst direct genetic evidence for Ab as a causative factor in AD. The pathologic observation of the preponderance of Ab42 plaques, in both sporadic as well as in this rst FAD disease, prompted the analysis of the mechanism by which APP717 leads to disease. Analysis of Ab species derived on transfection of the mutated APP717 form into 293 cells showed that a small yet signicant change in the composition of the Ab species secreted into the conditioned medium. Compared with cells transfected with Wt APP, an increased level of Ab42 peptides were secreted [20], relative to the Ab40 species, resulting in an 50% increase in the Ab42/Ab40 ratio. Analysis of plasma Ab from individuals with codon 717 mutations also showed an approximately twofold increase in Ab42 levels. The in vivo and in vitro data provided very strong evidence for the hypothesis that increased levels of Ab42 are produced from the mutated APP, and that this was sucient to cause early onset AD. The second FAD mutation identied was also in APP, the Swedish or APPNL, although the mechanism via which it causes AD was established chronologically earlier than that with the APP717 mutations. Transfection of APPNL into 293 cells led to a very large increase in the total amount of Ab secreted into the conditioned medium, accompanied by a large increase in the b-secretase-cleaved secreted APP, b-sAPP [10]. A twofold increase in total Ab was found in the plasma of individuals carrying the APPNL mutation, conrming the cellular results [21]. Thus, increased levels of total Ab (both Ab40 and Ab42) also cause early onset AD, providing a very strong basis for the hypothesis that Ab is causative for AD. Presenilins and AD Although the APP mutations provided strong evidence for the amyloidcentric view of AD, such mutations were very infrequent, and the locus on Chromosome 14 (APP is on Chromosome 21) seemed to account for the vast majority of FAD cases around the world. The identication of this gene, PS-1, opened up a new eld of investigation for AD researchers. PS-1 is widely expressed in various tissues and cells and exists in cells as a noncovalent yet stable complex [22], of a 30 kDa N-terminal fragment (NTF) and a 15 kda CTF. The NTF and CTF are derived by intracellular proteolytic cleavage of the intact PS-1 holoprotein [23], and the consequent stable complex appears to be the functionally relevant form of PS-1. PS-2 is processed in a similar manner as well. Most cells appear to have a saturable capacity for forming the stable NTF:CTF complex [24], and transfection of PS-1 in cell culture usually leads to only a relatively small (about twofold) increase in the levels of the cleaved forms detected; the PS-1 holoprotein, under these conditions, appears to be rapidly degraded, and not to be incorporated in a functionally relevant complex.
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The transfection of Wt PS-1 or PS-2 into cells has no detectable eect on Ab40 and 42 levels. Transfection of the disease-causing mutant forms invariably leads, however, to an elevation of Ab42, usually measured as an increase (50200%) of the Ab42/Ab42 ratio [25]. All other aspects of APP metabolism appear to remain virtually unchanged, including the cellular maturation, turnover, and the extracellular release of a- and b-sAPP. The disease-causing PS-1 and PS-2 mutants thus selectively increase cleavage at the Ab42 site, without aecting total levels of Ab (Ab40 + Ab42). Postmortem analysis of brains of PS-1 FAD individuals have demonstrated very high levels of Ab42-positive plaques [17], both of the diuse, noncompacted form, as well as the mature neuritic plaques, thus underscoring in vivo the likely pathogenetic mechanism deduced from the cellular observations. Knockout of the PS-1 gene in mice leads to severe developmental abnormalities and consequential fetal lethality, but primary cortical cultures generated from premorbid embryonic stages have been used to conclusively demonstrate that the absence of PS-1 leads to a 80% reduction of both Ab40 and Ab42 [26], without measurable eects on a- and b-secretory cleavages. An elevation of the steady state levels of the a- and b-CTF fragments is also observed, suggesting that the absence of PS-1 leads to a reduction in c-secretase cleavage of the CTFs generated by the action of a- and b-secretases. Thus, although the eect of the FAD mutations are restricted to an increased cleavage of APP at the Ab42 site, PS-1 appeared to have a much bigger role in c-secretase cleavage of APP-derived CTFs. A variety of experimental approaches have subsequently established that this is indeed the case. Mutation of either of two highly conserved aspartic acid residues in PS-1 and PS-2 leads to a dominant negative phenotype on Ab production on transfection of such forms into cells [27], accompanied by the stabilization of APP-derived a- and b-CTFs. Potent inhibitors of cellular Ab production have been shown to interact directly with PS-1 [28], and the consensus opinion in the eld is that the presenilins are essential biochemical components of c-secretase. The diculty of demonstrating increased levels of Ab production on overexpression of the presenilins has suggested the existence of as yet unidentied cellular factors [24] that may be necessary for the saturable formation of the high-molecular-weight presenilin complex. Nicastrin has recently been identied as another necessary component of this complex [29], although its biochemical role remains unelucidated.
Transgenic models for AD pathology The APP FAD mutations have also been utilized to obtain transgenic mice that overexpress in neuronal cells, at high levels, either APPNL (Tg2576) [30] or the Val Phe APP717 (PDAPP) [31]. Both of these lines of transgenic animals develop, in a age-dependent manner, diuse and
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compact amyloid plaques in the cortex and hippocampus, but not in other regions spared in AD such as the cerebellum. The pathologic changes observed in these transgenic mice lines also include microglial activation and astrogliosis, as well as neuritic changes in the vicinity of plaques that are remarkably similar to that observed in sporadic AD. Although it has been dicult to measure frank cell loss in these transgenic lines, other neurobrillary changes highly reminiscent of AD have been shown to occur in the PDAPP mouse with age [32]. In addition to demonstrating that the APP FAD mutations do result in the production of amyloid plaques, and ancillary pathologies seen in AD, these animal models have also proven to be useful in identifying pharmacologic agents that modulate the production or clearance of the Ab peptide. Immunization of the PDAPP transgenic mice with human Ab42 was shown to result in the clearance of existing plaques by microglial cells by an antibody mediated mechanism [33]. Peripheral administration of antibodies directed to the human Ab was also shown to result in a similar clearance [34], along with a reduction of the neuritic pathology and glial pathology. In a separate approach, an inhibitor of c-secretase, identied using cell culture models, was shown to inhibit the production of Ab in young PDAPP animals, in a dose- and time-dependent manner [35]. The ability to test potential drugs and therapeutic approaches directed toward the lowering of Ab peptide levels and the associated aggregated amyloid deposits has opened up the way in utilizing these animal models of AD pathology toward identifying and testing strategies for treating AD.
b-Secretase: initiation of Ab production Although the overwhelming majority of FAD cases manifest themselves via PS-1 mutations (increased Ab42), the APPNL FAD family suggested that b-secretase cleavage of APP is important for Ab generation. Studies of APP metabolism in cell culture established that b-secretase cleavage precedes that by c-secretase, and pharmacologic agents that disrupt b-secretase cleavage of APP selectively inhibit Ab production without inhibitory eect on a-secretase cleavage. b-secretase cleavage of APP, though observable in cultured cells, occurs at a much higher level in primary neuronal cultures, as evidenced by the higher proportion of b-sAPP relative to a-sAPP. This suggested that the enzymatic activity is enriched in the CNS. This indeed turned out to be the case, and b-secretase was independently identied by (1) biochemical purication from human brain [36], (2) expression cloning in HEK293 cells [37], and (3) homology based cloning and expression of novel human aspartic proteases [38]. The unique protein sequence identied by these dierent approaches turned out to encode a novel, membrane-bound aspartic protease, BACE. Knockout of BACE in mice is without any detectable developmental consequence, although these mice are totally decient in
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the ability to generate Ab, either from endogenous APP [39] or from concurrently expressed human transgenic APP forms [40]. Thus, cleavage of APP by BACE is absolutely required for the generation of the Ab peptide, and the lack of biologic redundancy in this process suggests that strategies directed toward inhibiting the activity of this enzyme in vivo should lead to salutary eects on the production, and subsequent aggregation, of Ab peptides.
Summary The current understanding of the role of amyloid in AD has been established by a remarkable congruence of multiple disciplines: neuropathology, biochemistry, molecular biology, and epidemiologic genetics. Although the precise etiology of AD still remains poorly understood, the identication of the key biochemical players in the Ab generation (APP, PS-1 and -2, and BACE), and the development of transgenic models exhibiting progressive disease pathology, provide a strong framework on which to build a better understanding of the molecular events that lead to progressive neurodegeneration in AD.
References
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[33] Schenk D, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999;400:1737. [34] Bard F, et al. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 2000;6:9169. [35] Dovey HF, et al. Functional gamma-secretase inhibitors reduce beta-amyloid peptide levels in brain. J Neurochem 2001;76:17381. [36] Sinha S, et al. Purication and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999;402:53740. [37] Vassar R, et al. Beta-secretase cleavage of Alzheimers amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999;286:73541. [38] Yan R, et al. Membrane-anchored aspartyl protease with Alzheimers disease betasecretase activity. Nature 1999;402:5337. [39] Cai H, Wang Y, McCarthy D, Wen H, Borchelt DR, Price DL, et al. BACE1 is the major beta-secretase for generation of Abeta peptides by neurons. Nat Neurosci 2001;4:2334. [40] Roberds SL, et al. BACE knockout mice are healthy despite lacking the primary betasecretase activity in brain: implications for Alzheimers disease therapeutics. Hum Mol Genet 2001;10:131724.
Med Clin N Am 86 (2002) 641656
Nonpharmacologic treatment of behavioral disturbance in dementia

Linda Teri, PhD*, Rebecca G. Logsdon, PhD, Susan M. McCurry, PhD
Department of Psychosocial and Community Health, University of Washington, 9709 3rd Avenue NE, Suite 507, Seattle, WA 98115, USA
Behavioral disturbances and dementia are inexorably linked. Problems such as depression, agitation/aggression, wandering, and sleep disturbances aect most if not all patients at some point in the disease course [13]. Highly associated with greater functional impairment in the patient and increased burden in the caregiver [46], such problems critically impede eective care and are often cited as the most dicult aspect of caregiving [7]. Consequently, they adversely aect quality of life for the patient as well as the caregiver. Despite this, health care providers routinely receive little training in the direct care management of behavioral problems in dementia. Practical suggestions abound in the literature, however, and although still relatively sparse, empiric data from clinical trials are accumulating to indicate that behavioral problems can be eectively managed with nonpharmacologic treatment. Furthermore, consensus conference documents have concluded that nonpharmacologic treatment is the most appropriate rst step to treating behavioral disturbances in patients with dementia [8]. This article provides an overview of the treatment of behavioral problems with nonpharmacologic means as well as guidelines for assessing and treating the most common behavioral problems seen in dementia, including depression, agitation/aggression, wandering, and sleep disturbance. We also discuss the role of the caregiver in nonpharmacologic treatment.
* Corresponding author. E-mail address: lteri@u.washington.edu (L. Teri). Preparation of this manuscript was supported in part by grants from the Alzheimers Association (PIO-99-1800) and the National Institutes of Health (AG10483, AG10845, MH01644). 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 6 - 8
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L. Teri et al / Med Clin N Am 86 (2002) 641656
Assessment The most common method for assessing behavioral disturbance in cognitively impaired older adults is a detailed clinical interview with the patient and an informant familiar with the patients day-to-day functioning, such as the patients family or caregiver. In the interview, the patient and informant are typically asked about the occurrence, frequency, and severity of typical problems, including wandering, anxiety, depression, agitation, aggression, sleep disturbances, paranoia, suspiciousness, and verbal or physical threats or abuse. To ensure that the full spectrum of problems is assessed in an ecient and thorough manner, a standardized inquiry list is a valuable tool. Such a list may be administered by a trained sta person (eg, a medical assistant) or provided to an informant to complete while the patient is being examined. This process is similar to the preliminary health screening forms used in many clinics. By asking the caregiver about the presence or absence of a variety of potential problems, the clinician can then focus on the ones that are of concern. In addition, the caregiver is given an opportunity to express concerns on paper and, later, to discuss these concerns privately with the clinician. A variety of mood and behavior assessment measures with good psychometric properties have been developed. Table 1 shows a representative sampling of instruments that have been used to measure depression, agitation, or general psychiatric disturbance in clinical controlled trials with dementia subjects. Some measures are based on paper-and-pencil informant report, whereas others require structured interviews with trained clinicians or direct behavioral observation. The instruments also vary in the data format they yield. Some (eg, the Cornell Scale for Depression in Dementia [15]) provide information on the severity of symptoms; others (eg, the Revised Memory and Behavior Problem Checklist [3]) rate behaviors on the frequency of their occurrence and provide information about caregiver reactions to symptoms when they do occur. For some measures (eg, the Neuropsychiatric Inventory [29]), summary subscale information is computed from a combination of frequency and severity ratings for individual behavioral symptoms. There are also a number of self-report instruments that have been shown to be valid when completed by surrogate informants, such as dementia caregivers [24]. As can be seen from Table 1, there is no single instrument that has gained universal use in clinical trials with dementia patients. The selection of appropriate measures varies according to the outcomes targeted by each study, and behaviors are often included as part of a comprehensive assessment with other cognitive, functional, and psychosocial measures. Both researchers and health care providers interested in using screening instruments should consider a number of factors, including the length of the measure, its reported sensitivity to change, and specic behaviors of concern for their clinical population. Providers caring for populations that include nonEnglish-speaking individuals from multicultural backgrounds or persons
L. Teri et al / Med Clin N Am 86 (2002) 641656 Table 1 Common mood and dementia screening instruments for dementia Informant report questionnaire X Interviewer administered Reliability/ validity data X [10]
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Title Agitation Agitated behavior in dementia scale (ABID) [9] Cohen-Manseld agitation inventory (CMAI) [12] Depression Cornell scale for depression in dementia (CSDD) [15] Dementia mood assessment scale (DMAS) [20] Geriatric depression scale (GDS) [23] Hamilton depression rating scale (HDRS) [25] General behavioral disturbance Behavioral pathology in Alzheimers disease (BEHAVE-AD) [27] CERAD behavior rating scale for dementia (CERAD-BRSD) [28] Neuropsychiatric inventory (NPI) [29] Revised memory and behavior problem checklist (RMBPC) [3]
Used in clinical controlled trials X [11]
X [10,13]
X [14]
X [16,17]
X [18,19]
X [17,21]
X [22]
X X
X [24] X [24]
X [19] X [19,26]
X [16]
X [14,18]
X [10,17]
X [26]
X X
X [17] X [10]
X [30] X [19,26]
CERAD: Consortium to Establish a Registry for Alzheimers Disease.
with limited education or reading skills particularly need to evaluate the validity of a given instrument for their situation. Readers interested in a comprehensive review of behavioral screening instruments used in dementia care and research are referred elsewhere [17,3135]. Once specic problems are identied, a thorough assessment of their possible causes is essential. The same behavioral disturbance may be triggered by a variety of dierent causes. In assessing behavioral disturbances, the clinician must consider possible medical triggers, cognitive- or dementia-related triggers, environmental triggers, and caregiver issues. Common causes of behavioral disturbance may include medical illness, injury, medication side eects, environmental changes, and interpersonal conicts. For example, restlessness may be triggered by an acute medical condition, such as a urinary tract
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infection, or by a change in medication. Restlessness may also result from changes in brain functioning caused by dementia, or it may be related to environmental triggers, such as lack of appropriate activity, too much noise or stimulation, or conicts with people with whom the patient comes into contact. Treatment Nonpharmacologic treatments are often recommended as the most appropriate initial strategy for managing behavioral disturbances in persons with dementia [7,36,37]. The risk of adverse side eects or interactions with other medications is nonexistent, and the increased involvement of caregivers often has a secondary benet of providing overburdened caregivers with an opportunity to receive support, information, and skills. Furthermore, environmental factors (eg, confusing or noisy surroundings) or interpersonal factors (eg, arguing with the patient) are frequently the primary triggers of behavior problems. Attention to these factors through nonpharmacologic approaches (caregiver education, support, and training in behavioral strategies for management) can be quite eective in alleviating or preventing behavioral problems in patients with dementia. Providing education, support, and advice to help families better understand and cope with the disease process has a long clinical history and often represents the core of any treatment whether it is nonpharmacologic or pharmacologic. Practitioners often advise families to use strategies to adapt the environment and modify their own behaviors so as to better care for patients. The amount and popularity of this kind of information have grown exponentially in recent years as is evident in the proliferation of books, training materials, informational handouts, videotapes and worldwide web technology. For example, The 36 Hour Day [38], long considered a staple of information to families, is in its second printing with over one-half million copies sold worldwide. A videotape training program entitled Managing and Understanding Behavior Problems in Alzheimers Disease and Related Disorders [39] has been used in Alzheimer Association support groups worldwide. It is also part of standard training in numerous long-term care facilities; has been translated into Japanese, Korean, and Italian; and has been used in three controlled trials thus far. Published reports of nonpharmacologic treatment span two decades. The earliest reports showed that caregivers were able to learn specic techniques and successfully reduce problematic behaviors [4043]. Later, case-controlled and randomized controlled trials investigated the eectiveness of nonpharmacologic treatment in reducing behavioral problems or delaying institutionalization in patients with dementia. Three investigations included behavior training as part of a larger psychoeducational and social support program and examined general behavioral outcomes and delayed patient institutionalization [4446]. One provided a focus on behavioral training to reduce patient depression [19], and another compared nonpharmacologic
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with pharmacologic approaches to reduce patient agitation [11,47]. Although certainly not conclusive, results thus far suggest that nonpharmacologic interventions can signicantly reduce general patient behavioral problems [46,47], decrease patient depression [19], delay institutionalization [45], and increase caregiver satisfaction [48]. (For more detailed reviews of nonpharmacologic treatments, the reader is referred to articles by Bourgeois et al [49] and Teri et al [50].) The Seattle Protocol A comprehensive behavioral training program for reducing behavioral problems in patients with dementia As mentioned earlier, a videotape training program entitled Managing and Understanding Behavior Problems in Alzheimers Disease and Related Disorders [39] teaches clinicians and caregivers to use a systematic behavioral approach to behavioral problems. The program consists of a series of 10 videotapes and a written trainers guide designed to provide background information about dementia and related disorders, teach caregivers skills to modify behavior problems that interfere with proper care, and identify and address the special needs of caregivers. Didactic information along with vignettes of specic problems and solutions guides caregivers through a systematic approach called the A-B-Cs of Behavior Change. In this approach, caregivers learn that A is the antecedent or triggering event that precedes the problem behavior, B is the behavior of concern, and C is the consequence of that behavior. Once the chain of behavior occurrence and response is understood, caregivers are provided with methods to change either the antecedents or the consequences so as to change the problem behavior. (For more information on this program, the reader is referred to the article by Teri [51].) Once the caregiver understands and can identify the A-B-Cs of a problem, a step-by-step problem-solving strategy is implemented involving six steps: Identify the problem. This is dening the B of the A-B-Cs. The caregiver needs to articulate exactly what the problem is in a specic and informative manner. For example, arguing all the time may seem clear to the caregiver, and the health provider may even think he or she understand what that means, but arguing can take many forms. What is the nature of the arguments? Do they really occur all the time, or are they more common at certain times of the day or with certain people? What specically is said? The more clearly a caregiver can dene a problem, the more likely it is that he or she can carry out an effective course of action. Gather information about the circumstances surrounding the problem. This is dening the A and C of the A-B-Cs. Identify what happens immediately before the problem occurs and what happens immediately
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after the problem begins. Many problems have more than one antecedent and consequence, and the more caregivers understand how the A-B-Cs t together, the more likely it is that they can successfully intervene. Set realistic goals and make plans to achieve those goals. For a plan to work, it must be creative but realistic and tailored to the individual patient and caregiver. For example, whereas a caregiver may want the patient to be happy, this goal is too broad and unstructured. Goals of increasing pleasant activity and not discussing upsetting topics are more realistic and more achievable. Start with small achievable goals, and proceed step by step. Encourage rewards for the patient and the caregiver for small successes. Changing behavior is hard work for everyone involved. It is important for caregivers to reward themselves and their patients for their accomplishments no matter how small. Continually evaluate and modify plans. It is important that caregivers be consistent in carrying out plans but exible in trying new approaches. Strategies need to change as caregivers discover some that do and do not work. One goal of the A-B-C approach is to help teach caregivers to develop strategies on their own so that once treatment is concluded, they can eectively deal with new problems that may develop over the course of the disease. In addition, specic suggestions can be helpful. In the Seattle Protocol, these suggestions are again framed in an A-B-C approach. We now provide some suggestions for management of several of the most common and troubling behavior problems, including depression, agitation/aggression, wandering, and sleep disturbances. For additional suggestions (although not framed within an A-B-C approach), the reader is referred to the books by Robinson et al [52], self-help books (eg, The 36 Hour Day [38] and Alzheimers Disease: A Guide for Families [53]), and materials available from the Alzheimers Association (www.alz.org; 1-800-272-3900).
Depression Depressive symptoms occur in 30% to 70% of individuals diagnosed with Alzheimers disease, the most common form of dementia in older adults [54 56]. Unhappiness, withdrawal, inactivity, fatigue, expressions of guilt and worthlessness, tearfulness, and loss of interest can all signify depression. Patients with dementia gradually lose the ability to engage in enjoyable hobbies or activities, and because of their cognitive impairment, they may be unable to identify replacement activities. Consequently, they may spend much of their time in activities that are not gratifying or meaningful, or they may disengage from activity altogether. Methods for modifying antecedents and altering consequences to depressive behaviors include:
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Increase and encourage enjoyable activities. Identifying activities that the person has enjoyed in the past and modifying them to be appropriate for the patients current level of functioning is a good way to begin. The Pleasant Events Schedule-AD [57,58], a 53-item inventory, was designed to help caregivers identify simple everyday pleasant activities that might be incorporated in the daily care of patients with dementia. Items include being outside, listening to music, having meals with family or friends, helping around the house, exercising, and going for a ride in the car. Redirect and refocus. Patients with depression and dementia are often incapable of ridding themselves of depressing thoughts. They need assistance in distracting themselves and thinking nondepressing thoughts. Memory books [59] with pictures of happier times, reminiscing of pleasant experiences, or having cheerful conversations can be quite helpful. Increase social activities. Initiating pleasant social activities that keep the patient alert and involved can signicantly improve a depressed mood. Plan outings with someone whose company the patient enjoys, particularly if the patient complains of feeling isolated or lonely. If the patient has had to stop driving, arrange transportation to activities the patient enjoys but is no longer able to attend without assistance. Eliminate sources of conict and frustration. Patients with depression often are asked to engage in activities they can no longer do. By ensuring that patients are not continually challenged and frustrated, sources of conict and frustration can be alleviated (and sometimes eliminated), resulting in a more contented patient. Depressed patients often have depressed caregivers [60]. If the patient lives with a caregiver, evaluate and discuss the caregivers own affective state. Improving caregiver mood is likely to have a positive outcome on patient behavioral problems. Agitation Agitated behaviors, such as irritability, restlessness, physical and verbal aggression, resisting needed assistance, pacing, and wandering, aect between 70% and 90% of patients with dementia at some point during the course of the disease [3,61]. As with depression, agitation may have a variety of causes, including physiologic, environmental, and interpersonal triggers. Furthermore, these causes often interact. For example, patients may have decreased tolerance for stimulation or decreased inhibition of inappropriate behaviors as a result of neurologic changes. They may experience agitation or catastrophic reactions in response to environmental triggers, such as overstimulation or activities they do not understand (eg, being bathed by a caregiver they do not know or remember). The key to nonpharmacologic intervention for episodes of agitation or aggression is to identify and avoid their triggers, thus reducing their frequency or impact.
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Methods for modifying antecedents and altering consequences to agitated or disruptive behaviors include: Intervene early. Recognition of problems and early intervention can help to prevent agitation and catastrophic reactions. Stay calm. Remain calm yourself as you strive to calm the patient. Use a reassuring and gentle voice. Use touch judiciously and gently. (Some patients do not nd touch reassuring; they may lash out.) Avoid arguing or trying to reason while the person is agitated. Arguing almost always causes the agitation to escalate. Prevent aggression. Approach an agitated person slowly from the front. Tell the person what you are going to do, and try not to startle him or her. Stand or sit at eye level rather than standing over the person. Redirect and refocus. Distract the patient with questions about the problem, and gradually turn his or her attention to something unrelated and pleasant. Change activities, go to another room, or leave the situa tion. Get help immediately if there is imminent danger. Wandering Cognitively impaired individuals who wander pose a danger to themselves and are of considerable concern to their care providers and family [62,63]. Most research on wandering has focused on nursing home or dementia clinicbased samples. In these samples, wandering occurs in up to 65% of patients at some point in the disease process and is related to severity of cognitive impairment [6365], rate of cognitive decline [66], and decreased length of survival [67,68]. In an investigation of disruptive wandering behavior in a population-based sample of 193 individuals with Alzheimers disease, 24% of subjects had wandered at least once, and 12% had wandered within the past week. Wandering occurred in subjects at all levels of cognitive impairment, but greater frequency of wandering was associated with signicantly more impairment in cognition, day-to-day functioning, and behavior. Caregiver distress increased signicantly with increased frequency of wandering [69]. There have been no published randomized controlled trials of interventions for wandering in dementia [70]. Research on strategies for preventing dangerous wandering has been conducted primarily in long-term care settings, and promising approaches include environmental modication [71,72], activity programming [73], electronic alarm systems [74], and reinforcement of nonwandering behaviors [75]. Methods for modifying antecedents and altering consequences of wandering include: Environmental modication. Visual cues and labels can be used to direct wanderers in a particular direction or away from potential dangers. For example, clear and unambiguous labels on bathrooms and bedrooms may
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direct residents to appropriate areas, whereas visual barriers, such as oor grids or stop signs, discourage wanderers from crossing into areas that are off limits. Removing objects or cues from the environment that suggest leaving, including coats or hats, and disguising exits by blending them in with surrounding walls may help to prevent individuals from banging on doors or repeatedly attempting to leave. Interesting displays or seating areas help by inviting individuals to stop pacing and enjoy them. Provide activities. Many individuals with dementia seem to wander because of boredom or loneliness. Programs that engage individuals in meaningful activities, exercise, and social interaction may decrease wandering and other problem behaviors. Install electronic alarm systems. Electronic alarms are in wide use in dementia residential care programs and range from a key code box and alarm that sounds when doors are opened to special radio transmitters that track the movements of individuals who wear them. These alarms do not prevent wandering but alert care providers so that dangerous consequences of wandering can be prevented. Have a safety plan. Keep a current photograph for reference in case the person should get lost. Have the person wear an identication bracelet with contact information and clearly marked with the statement memory impaired. Secure it so that it cannot be easily removed or slipped off. Clothing labels with this information may also be sewn into the persons clothing. The Alzheimers Associations Safe Return program is a resource for educational materials and identication labels for wanderers and their caregivers. Sleep disturbances Wandering at night, bedtime agitation, disturbed sleep, and night-day reversal are common problems for persons with dementia [76]. When present, such problems are quite stressful for family members. Caregivers who are awakened frequently during the night to reassure or assist the dementia patient eventually become exhausted. This exhaustion, and its associated impact on physical and emotional health, is one of the most common reasons why caregivers are forced to institutionalize their loved ones [77,78]. There is general agreement that hypnotic treatments for sleep problems should be used sparingly in the elderly so as to minimize falls, impaired memory, drug-related sleep disorders, or aggravation of a preexisting sleep apnea syndrome [79,80]. Cognitive-behavioral and psychoeducational strategies are readily available and known to be eective in normal older adults [81,82], but they have not been systematically studied in persons with dementia. There is evidence that environmental and behavioral factors, such as time spent in bed during the day, environmental noise and light, and nighttime incontinence care practices, are associated with sleep disturbances in institutionalized older adults [8386]. One recent study in 29 nursing
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home residents found that a combination of light physical exercise and other behavioral strategies (eg, keeping patients out of bed in the late afternoon and evening or providing quiet nighttime incontinence care) produced signicant improvements in measures of percentage of total sleep and duration of sleep episodes [87]. There is also a growing amount of literature suggesting that timed bright light exposure may be helpful in reducing the sleep disturbances found in Alzheimers disease patients [88,89]. Methods for modifying antecedents and altering consequences associated with sleep disturbances in persons with dementia include: Strive for consistent bedtime and rising times. Regular sleep time habits and routines help to reinforce time cues for demented individuals and may also promote circadian rhythmicity by maximizing cues to the brains time-keeping system [90]. Although there have been no clinical trials demonstrating the value of consistent sleep habits in dementia patients, sleep regularity is considered an important aspect of the treatment and prevention of sleep disturbances in all older adults [80]. Limit daytime napping. In the later stages of disease, many persons with dementia spend a signicant proportion of their daytime hours asleep [91,92]. Reductions in daytime napping, particularly in combination with an increase in physical activity, can increase the likelihood that the dementia patient has longer and more consolidated nighttime sleep. Restrict use of alcohol and caffeinated beverages (including chocolate products). When consumed close to bedtime, these can disrupt sleep and exacerbate the preexisting tendency of dementia patients to awaken more often and spend less time in deep (slow wave) sleep [93,94]. A light bedtime snack comprising foods that promote sleep, such as milk, bananas, or cheese, may reduce patient awakenings that are caused by nighttime hunger. Eliminate or reduce environmental nuisance factors that may interrupt sleep. Reductions in light levels and nighttime noise have been shown to be critical for the alleviation of sleep disturbances for nursing home residents [83]. In community home settings, potential environmental causes of disturbed patient sleep that should also be evaluated include the impact of household pets, live-in adult children or grandchildren, caregiver snoring, and outside trafc noise. Be aware that changes in daily routine, such as family get-togethers or holidays, may produce a worsening in nighttime sleep. Try to plan ahead, and build in some quiet catch-up time after any out-of-theordinary planned activity.
Role of the caregiver Practically speaking, teaching caregivers strategies to use with the patient on a daily basis is the focus of most nonpharmacologic treatments. Care-
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givers may include family members, unpaid caregivers, or paid caregivers who have a role in the patients day-to-day care. In planning management strategies, it is important to have a good understanding of the resources, skills, and energy of these individuals. A variety of factors have an impact on the caregivers ability to carry out recommended changes, and these factors must be addressed for successful nonpharmacologic treatment. For example, the degree of stress and burden the caregiver is currently experiencing inuences the caregivers willingness and ability to carry out a behavior change plan. Many caregivers are employed or have other family responsibilities in addition to caring for their relative with dementia. Some caregivers have physical or mental health problems of their own that interfere with their ability to follow through with treatment. The past and present relationship between patient and caregiver inuences the manner in which the patient and caregiver interact and, potentially, the occurrence and treatment of behavioral problems. Health care providers must spend time talking with the caregiver about their own concerns and well-being and address these problems when they are identied. Treatment must be tailored to meet the needs of both the patient and the caregiver to be most eective. Because dementia is a progressively worsening condition, exibility and creativity are needed to modify and adapt strategies as problems evolve. Finally, it is important to respect the dignity of the patient and the caregiver when developing treatment plans.
Conclusion Most if not all patients with dementia experience behavioral problems. Some forms of dementia seem particularly prone to behavioral disturbances. For example, individuals who have dementia with Lewy bodies may present with psychotic symptoms early in the course of dementia [95,96]. Persons with either frontotemporal or subcortical dementia often exhibit prominent impairment in executive functioning (eg, problem solving, judgment, planning) that aects patient care and safety; mood and personality changes are also common [97,98]. Whatever the cause, behavioral problems are prevalent, pervasive, and disruptive. They adversely aect patient and caregiver alike, often leading to patient institutionalization and caregiver burnout. It is important for health care providers to assess the occurrence and impact of these behaviors so as to best care for their patients with dementia. Measurement tools can augment the clinical interview to help the practitioner obtain a thorough assessment of behavioral problems. Once identied, these problems may be amenable to nonpharmacologic treatments designed to prevent or alleviate such problems. Although such strategies have been subjected to few rigorous controlled clinical trials, extensive clinical experience exists indicating their utility, and results thus far support the use of these strategies in patients with dementia. Caregivers, whether they
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are family members, long-term care sta, or health care professionals, are critical to the assessment and treatment of behavioral problems. Oftentimes, they are the sole providers of care for patients with dementia and must learn how to manage the variety of problems that are experienced, including depression, agitation, wandering, and sleep disturbance. We have provided an overview of the literature in this area as well as detailing one method using the A-B-C approach to patient care. We have also provided specic suggestions as to how to begin a treatment plan for common problems, such as depression, agitation/aggression, wandering, and sleep disturbance. As more and more patients become elderly and more and more elderly persons become demented, health care providers must become familiar with nonpharmacologic treatment of behavioral problems in dementia. Furthermore, they must be able to impart this knowledge to those caregivers providing essential daily care of patients with dementia. Acknowledgements The authors thank Elizabeth Buzzy Mounce for her help in preparation of this article. References
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Med Clin N Am 86 (2002) 657674
Pharmacologic treatments of dementia

Lauren T. Bonner, MD*, Elaine R. Peskind, MD
Department of Psychiatry and Behavioral Sciences, University of Washington School of Medicine, and Veterans Aairs Puget Sound Health Care System, Mental Illness Research, Education, and Clinical Center, 116 MIRECC, 1660 South Columbian Way, Seattle, WA 98108, USA
Alzheimers disease (AD) and other forms of dementia are estimated to aect millions worldwide. Because estimates of the incidence and prevalence of dementia are criteria dependent, the true number of people aected by dementia in the United States is unknown. Is it estimated that AD, the most common cause of dementia, accounts for nearly 70% of dementias [1]. There is still debate about the second and third most common forms of dementia. Recent neuropathologic studies have demonstrated that dementia with Lewy bodies (DLB) may be the second most common cause of dementia, accounting for 15% to 25% of dementia cases [2]. Other sources consider vascular/multiinfarct dementia (VaD) to be the second most common cause of dementia [3]. Because AD and other forms of dementia are diseases of the aged, prevalence rates should increase as our population continues to age. AD is estimated to aect 4 million Americans [4]. Currently, approximately 5% of Americans aged 65 years and older suer from AD, with an estimated 30% to 50% of Americans aged 85 years and older suering from the disorder [1]. By the year 2050, the number of Americans suering from AD is estimated to rise to 14 million [4]. AD is characterized by a gradual insidious onset of memory loss, global cognitive deterioration, and functional deterioration. Short-term memory is aected early in the course of the illness, reecting early involvement of the hippocampus and medial temporal lobes. Visuospatial decits and executive dysfunction also appear early in the illness. Gradually, as the disease process advances, all cognitive functions are impaired. The duration of the illness is 5 to 10 years, with pneumonia or sepsis as the usual cause of death. The
* Corresponding author. E-mail address: lauren.bonner@med.va.gov (L.T. Bonner). This work was supported by the Department of Veterans Aairs and NIA AG05136 and AG18644. 0025-7125/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved. PII: S 0 0 2 5 - 7 1 2 5 ( 0 2 ) 0 0 0 0 7 - X
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L.T. Bonner, E.R. Peskind / Med Clin N Am 86 (2002) 657674
typical ndings on neuropathologic examination include hippocampal and neocortical neuritic plaques, neurobrillary tangles, and neuronal loss. Although there is no cure for AD, two pharmacologic treatment options can provide symptomatic improvement in cognitive and functional deterioration: cholinesterase inhibitors and vitamin E. Cholinesterase inhibitors, which exert their eects by increasing the availability of intrasynaptic acetylcholine, have been demonstrated to be more eective than placebo in the treatment of the cognitive decits of AD [516]. The antioxidant vitamin E (a-tocopherol) slows functional deterioration in AD [17]. In this article, we review data supporting the use of cholinesterase inhibitors and vitamin E in the treatment of AD and related dementias and present recommendations for incorporating their use into clinical practice. Unless otherwise specied, when specic eect sizes are described, the ecacy data presented were derived from analysis of observed cases.
Minimizing excess disability Before consideration of pharmacologic management of the cognitive impairments of dementia, sources of excess disability and comorbidity should be eliminated or reduced, with special emphasis on the use of nonpharmacologic approaches to treatment. Comorbid medical and psychiatric conditions, such as depression, should be identied and optimally treated. Avoid polypharmacy; that is, use the fewest number and lowest eective doses of medications for comorbid medical and behavioral conditions. In addition, certain classes of drugs should be avoided if possible, particularly those with anticholinergic or sedating side eects. The list of drugs that may contribute to cognitive impairment is large. Common oenders include oxybutynin used for treatment of urinary incontinence, the anticholinergic tricyclic antidepressants amitriptyline and imipramine, and the benzodiazepine antianxiety and hypnotic drugs. Alcohol puts endangered neurons at even greater risk; in the patient with a dementing disorder, alcohol use should be minimized. Optimizing vision, hearing, and nutrition helps to maximize function and promote general health. Caregiver support is a crucial component of managing the dementia patient. AD is often described as causing more suering in caregivers than in the AD patients themselves, and depression in AD caregivers is common. The clinician should inquire about the presence of depressive symptoms in the AD caregiver and provide treatment or appropriate referral. Periodic respite for the caregiver is often benecial. Caregivers need to be provided with education, encouragement, and practical advice. This includes instructing caregivers in providing an appropriate environment for the demented patient and in the fundamentals of behavior management techniques. Provision of appropriate referrals for needed services is important as well. Caregivers should be encouraged to utilize the resources of their local Alzheimers Association chapter.
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Cholinergic systems and memory: cholinergic hypothesis of Alzheimers disease There have been clear demonstrations of presynaptic cholinergic decits in AD [1821]. In AD, there is well-documented loss of neurons in the nucleus basalis of Meynert [21,22], the basal forebrain nucleus that is the site of origin of the cholinergic neurons that project widely to many brain regions, use acetylcholine as their neurotransmitter, and are involved in memory and other cognitive functions. In addition to loss of cholinergic neurons, there is a marked decrease in the activity of choline acetyltransferase, the synthetic enzyme for acetylcholine, in target areas in the cortex and other brain regions as well as overall reductions in other markers of cholinergic activity [1820,2226]. These ndings provide a scientic rationale for the consideration of cholinergic strategies as a treatment for AD. Several strategies have been attempted to increase cholinergic transmission in the brain. These strategies are analogous to the dopaminergic enhancement strategies that have proven successful in ameliorating the motor disturbances of Parkinsons disease. These include choline and phosphatidylcholine precursor loading [2731], muscarinic and nicotinic cholinergic receptor agonists [32], and cholinesterase inhibitors [516,33]. The only drugs that have demonstrated ecacy and safety in large-scale, placebocontrolled, randomized trials in AD are the cholinesterase inhibitors. By inhibiting the degradative metabolism of acetylcholine released by presynaptic cholinergic neurons, cholinesterase inhibitors increase the amount of synaptic acetylcholine available for neurotransmission. Cholinesterase inhibitor use in Alzheimers disease Cholinesterase inhibitors for which data from large-scale placebo-controlled clinical trials support ecacy in the treatment of AD include the US Food and Drug Administration (FDA)approved drugs tacrine, donepezil, rivastigmine, and galantamine (Table 1). Multicenter trials were conducted in patients with mild to moderate disease, dened as having a Mini-Mental State Examination (MMSE) [34] score between 10 and 24. The criteria used to diagnose AD included the Diagnostic and Statistical Manual IIIRevised [35] and Diagnostic and Statistical Manual IV [36] of the American Psychiatric Association and the National Institute of Neurologic and Communicative Disorders and StrokeAlzheimer Disease and Related Disorders Association criteria [37]. The ecacy measures used in these trials were generally uniform and included the Alzheimers Disease Assessment ScaleCognitive Subscale (ADAS-Cog) [38] as a primary ecacy measure. The ADAS-Cog, scored from 0 to 70, with higher scores reecting increased severity of cognitive impairment, generally declines approximately 6 to 10 points per year in the mild to moderate stages of AD, with 8 points as the average decline over 1 year. Drug-placebo dierences of approximately 3 to 4 points on the
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Table 1 Cholinesterase inhibitor titration schedule Cholinesterase inhibitor Donepezil Rivastigmine Galantamine Starting dose 5 mg qhs 1.5 mg bid 4 mg bid Titration period/maximum dose increase per titration period 46 weeks/5 mg 46 weeks/1.5 mg bid 46 weeks/4 mg bid
Maximum dose 10 mg qhs 6 mg bid (total of 12 mg) 12 mg bid (total of 24 mg)
Abbreviations: qhs, at bedtime; bid, twice daily.
ADAS-Cog over 6 months have been accepted as indicating drug ecacy. This dierence represents approximately 6 months of cognitive and functional ability. Various measures of quality of life, activities of daily living, and noncognitive behavioral disturbances supported drug ecacy in various trials. It is becoming increasingly clear that, on average, cholinesterase inhibitors stabilize cognitive function and activities of living for at least 1 year in the AD patient with mild to moderate cognitive impairment [11,3942]. The most frequent adverse events experienced by subjects in cholinesterase inhibitor trials reect eects of increased cholinergic activity on the gastrointestinal system. Nausea is the most common adverse eect, followed by vomiting and diarrhea. These eects are dose dependent. Weight loss has also been demonstrated with some cholinesterase inhibitors. The only absolute contraindication to use of cholinesterase inhibitors is severe hypersensitivity to the specic drug or its derivatives. Caution is advised with use in patients who have a previous history of allergy or adverse reactions to prior cholinesterase inhibitors, severe liver disease, preexisting bradycardia, peptic ulcer disease, current alcoholism, asthma, or chronic obstructive pulmonary disease. Tacrine Tacrine, the rst generation cholinesterase inhibitor, was shown to have modest ecacy in improving cognition in several large-scale placebocontrolled trials in AD [7,8,10]. After 6 months of treatment, the drugplacebo dierences on the ADAS-Cog obtained from intent-to-treat analysis (ITT) were approximately four points, interpreted as delay of cognitive decline by approximately 6 months [7,8,10]. A retrospective analysis of the tacrine trial data suggests that tacrine doses of greater than 80 mg/d may delay time to nursing home placement and provides evidence for long-term cost-eective use of tacrine [42]. In this study, 102 patients on low-dose or no tacrine (80 mg or less/d) were compared with 198 patients on high-dose tacrine (>80 mg/d). Patients were followed for approximately 800 days. At the end of this period, 45% of patients in the low-dose or no-tacrine group had undergone nursing home placement as compared to approximately 21% of patients in the higher dose tacrine
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group. These ndings suggest that benets of cholinesterase inhibitors on stabilization of cognition, function, and behavior translate into caregivers being able to provide care at home longer. During the tacrine trials, a high incidence of reversible hepatotoxicity and gastrointestinal adverse eects resulted in poor study completion rates [7, 8,10]. In clinical practice, tacrine-induced reversible hepatotoxicity occurs in up to 50% of patients [43]. Because transaminase levels may reach up to 10 times the normal level, the FDA requires monitoring of transaminases during dose titration and maintenance therapy, recommending measuring alanine aminotransferase levels weekly for the rst 18 weeks, with monitoring every 3 months after a stable dose is reached. Weekly monitoring should be resumed for an additional 6 weeks if the dosage is adjusted up. Tacrine has been demonstrated to have clinically signicant drug-drug interactions with cimetidine and theophylline [44]. Because of the availability of other cholinesterase inhibitors that are not hepatotoxic, lack signicant drug-drug interactions, and have more convenient dosing regimens, the use of tacrine is limited to patients with an initial good response to this agent. Donepezil The piperidine derivative donepezil is a noncompetitive reversible acetylcholinesterase inhibitor with specicity for the brain [45]. Donepezil has been demonstrated to be modestly eective in stabilizing the cognitive function of AD patients in three large, randomized, placebo-controlled trials [5,12,13]. These trials all used ITT analyses. Donepezil is metabolized in the liver; its half-life is approximately 70 hours. Donepezil has no signicant eect on the metabolism of other drugs, including cimetidine, theophylline, warfarin, furosemide, and digoxin; donepezil metabolism is inhibited by ketoconazole and quinidine [44,46]. Donepezil at doses of 5 and 10 mg was compared with placebo in a 30-week treatment trial [13]. Four hundred seventy-three patients with AD were randomly assigned to three treatment groups: placebo or 5 or 10 mg of donepezil. Signicant and equivalent drug-versus-placebo group differences were found for both the 5- and 10-mg donepezil groups on the ADAS-Cog. The mean dierence between active treatment and placebo groups was approximately three points. There was no dierence between the 5- and 10-mg doses. Donepezil was well tolerated, with no signicant dierence in occurrence of adverse events between the 5-mg and placebo groups. An international study of 818 patients with the same study design demonstrated similar results [5]. There were signicant drug-versus-placebo dierences on the ADAS-Cog. The mean drug-versus-placebo dierences for the 5- and 10-mg donepezil groups were 1.5 and 2.9 points, respectively. A trial in 468 patients consisting of a 12-week treatment phase followed by a 3-week washout phase compared 5 and 10 mg of donepezil with placebo and
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demonstrated similar results [12]. In this trial, both treatment groups demonstrated improvement in ADAS-Cog scores when compared with placebo, with mean drug-versus-placebo dierences of 2.5 points for the 5-mg group and 3.1 points for the 10-mg treatment group, reecting a dierence equivalent to appropriately 6 months of cognitive deterioration. Because of its safety and ease of administration, donepezil is considered a second-generation cholinesterase inhibitor with several clear advantages compared with tacrine. Donepezil is not hepatotoxic, and liver transaminase monitoring is not necessary [5,12,13]. Donepezil is administered in a single bedtime dose; the recommended starting dose of donepezil is 5 mg at night, with or without food. If the drug is well tolerated, the dose may be increased to 10 mg after 4 to 6 weeks. Gastrointestinal side eects and occasional sleep disturbance are the most common adverse eects. Rivastigmine Like donepezil and tacrine, rivastigmine is a noncompetitive reversible inhibitor of acetylcholinesterase [47,48]. Pseudoirreversible enzyme inhibition has also been used to describe its mechanism of action, because the duration of inhibition of acetylcholinesterase induced by rivastigmine is longer than its half-life [49,50]. Rivastigmine has relatively more inhibitory activity for butyrylcholinesterase than acetylcholinesterase compared with other cholinesterase inhibitors [51]. The clinical relevance of this dierential property remains unclear. Compared with other cholinesterase inhibitors, rivastigmine may have increased selectivity for the hippocampus and neocortex, which are the areas of the brain preferentially aected by AD [47,51,52]. Rivastigmine is metabolized by the cholinesterases in brain, liver, and intestine and is renally excreted [50,51]. Rivastigmine has been shown to have no eect on the metabolism of other drugs, including warfarin, diazepam, uoxetine, and digoxin [50,51]. It has not been shown to aect hepatic enzymes or other laboratory parameters [6,14,50,51]. Clinical trials indicate that rivastigmine is modestly eective in the treatment of the cognitive impairments of mild to moderate AD [6,14]. Rivastigmine was compared with placebo in a 26-week international treatment trial [14]. Seven hundred twenty-ve patients with mild to moderate AD were randomly assigned to three treatment groups of 1 to 4 mg of rivastigmine, 6 to 12 mg of rivastigmine, or placebo. Dose increases occurred weekly, with a maximum dose increase of 1.5 mg/d allowed during the 12-week dose escalation phase. During weeks 8 through 12, no dose changes were permitted. There was a 13-week maintenance phase during which the dose could be adjusted with the goal of administering the highest tolerated dose. Mean drug-versus-placebo dierences on the ADAS-Cog were 0.17 for low-dose rivastigmine and 2.58 for high-dose rivastigmine. Only the high dose diered signicantly from placebo. In the United States, a 26-week, double-blind, placebo-controlled trial of 699 patients compared low-dose rivastigmine (14 mg), high-dose rivastigmine
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(612 mg), and placebo [6]. Patients in the 6- to 12-mg rivastigmine group demonstrated signicantly better cognitive function than patients treated with placebo. The mean drug-versus-placebo dierence in the ADAS-Cog between the 6- to 12-mg group and the placebo group was 4.94 points. In addition, patients receiving high-dose rivastigmine demonstrated better preservation of functional ability as measured by the Progressive Deterioration Scale [53] when compared with the placebo group. There was an additional 6-month extension phase of the US trial in which all patients who completed the double-blind phase were eligible for treatment with a exible maintenance dose of rivastigmine, ranging from a minimum of 1 mg administered twice daily to 6 mg administered twice daily [41]. Initially, all patients were treated with open-label rivastigmine at a rate of 1 mg administered twice daily for the rst week, with maximum allowed dose increases of 1 mg administered twice daily per week for a maximum allowed total dose of 6 mg administered twice daily. Decreases in dose were allowed per patient tolerability, with a minimum required dose of 1 mg administered twice daily. The change in ADAS-Cog score at week 52 was compared in four groups: the three original treatment groups given placebo, 1 to 4 mg of rivastigmine, or 6 to 12 mg of rivastigmine, and a fourth group consisting of a theoretic 52-week placebo group based on a modeling procedure of the projected decline if placebo had been continued for the full 52 weeks. Mean treatment dierences on the ADAS-Cog at week 52 for the original placebo group were 1.4 points versus the original 6- to 12-mg/d rivastigmine group, 0.3 points versus the original 1- to 4-mg/d rivastigmine group, and 4.3 points versus the theoretic 52-week placebo group. The theoretic 52-week placebo group versus the original 6- to 12-mg/d rivastigmine group mean dierence in ADAS-Cog scores was 5.7 points. These data suggest that rivastigmine may modify the course of AD and are consistent with data for other cholinesterase inhibitors [11,39,40,42]. The recommended starting dose of rivastigmine is 1.5 mg administered twice daily given with breakfast and dinner. Administration of rivastigmine at mealtime helps to minimize nausea. Although the rivastigmine package insert recommends titration increases at 2-week intervals, gastrointestinal adverse eects may be minimized by using a slower 4- to 6-week titration schedule. The dose should be increased to 3 mg administered twice daily, then to 4.5 mg administered twice daily, and nally to 6 mg administered twice daily at 4- to 6-week intervals as tolerated. As with all cholinesterase inhibitors, the dose should be titrated slowly upward to the maximum tolerated dose. If rivastigmine therapy is interrupted for more than a few days, it is recommended that treatment be restarted at 1.5 mg administered twice daily (the lowest starting dose) and then titrated up again every 4 to 6 weeks to the highest tolerated dose. Nausea, the most common side eect, can be minimized by adequate hydration. If necessary, an antiemetic may be used. As with other cholinesterase inhibitors, the incidence of gastrointestinal side eects is dose dependent. Rivastigmine is the only cholinesterase inhibitor with which weight loss is a clinically meaningful problem.
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Galantamine Galantamine hydrobromide, a derivative of the snowdrop plant, is the most recently approved cholinesterase inhibitor. Unlike tacrine, donepezil, and rivastigmine, it is a competitive and reversible acetylcholinesterase inhibitor. It has little eect on butyrylcholinesterase, being more selective for acetylcholinesterase [54]. Galantamine is unique among cholinesterase inhibitors in having a potential second mechanism of action as an allosteric modulator at the nicotinic cholinergic receptor [55,56]; this eect is separate from cholinesterase inhibition [55]. In vitro, galantamine acts as an allosterically potentiating ligand, increasing the likelihood of acetylcholine-induced channel opening and decreasing the rate of receptor desensitization [55]. This additional mechanism of action is a possible explanation for the nding that the amount of cholinesterase inhibition induced by galantamine and other cholinesterase inhibitors does not correlate well with their clinical potency [55]. The clinical relevance of this property is unknown, however. Galantamine is metabolized by the liver [44,57] and has no eects on the metabolism of other drugs. It is renally excreted. The half-life of galantamine is 7.5 hours. Absorption is not aected by food. The results of three published large-scale placebo-controlled trials indicate that galantamine is modestly eective in the treatment of the cognitive impairments of mild to moderate AD [11,15,16]. These trials also demonstrate that galantamine preserves the activities of daily living. All trials demonstrated that doses of 16, 24, and 32 mg were signicantly statistically superior to placebo. Galantamine at doses of 8, 16, and 24 mg administered in divided doses twice daily was compared with placebo in a 21-week treatment trial in 978 patients with AD [15]. Doses were started at 8 mg/d (4 mg twice-daily dosing) and were increased by 8 mg/d every 4 weeks. Signicant drug-versus-placebo group dierences were found for both the 16- and 24-mg galantamine groups on the ADAS-Cog. The mean dierences between the 16- and 24-mgversusplacebo groups were 3.3 and 3.6 points, respectively, on the ADAS-Cog, which is equivalent to approximately 6 months of cognitive function. There was not a statistically signicant dierence between the 16-mg versus 24-mg dose groups. Both doses were well tolerated. The number of discontinuations secondary to adverse events in the placebo and active treatment groups was similar (7% in the placebo group and 6%10% in the active treatment groups) and increased in a dose-dependent fashion. In addition, galantamine had similar benecial eects on global function and behavior. Galantamine at doses of 24 and 32 mg was compared with placebo in two 26-week treatment trialsone in the United States and the other international [11,16]. Both studies demonstrated that galantamine signicantly improved cognitive function relative to placebo. Mean dierences between the 24- and 32- mgversus-placebo groups on the ADAS-Cog were 3.9 and
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3.8 points in the US trial and 3.1 and 4.1 points in the international trial, a dierence equivalent to approximately 6 months of cognitive function. There was no statistically signicant dierence between the 24-mg versus 32-mg groups. In the US trial, there was an additional 6-month extension phase during which all patients who completed the double-blind phase were eligible for open-label treatment with 24 mg of galantamine [11]. Patients taking 24 mg of galantamine for 12 months demonstrated preservation in activities of daily living compared to patients who received placebo for six months followed by 24 mg open-label galantamine for six months. Activities of daily living were evaluated by using the Disability Assessment for Dementia [58]. Those patients who were randomized to placebo in the 26-week parallelgroup design who then went on to open-label active galantamine in the 6-month extension formed, in eect, a delayed-start design group. Interestingly, this group of patients cognitive function then stabilized but never reached the level of the patients who had received 12 months of continuous active drug. Thus, at the 12-month time point, there remained a statistically signicant dierence in the ADAS-Cog scores between patients on 12-month continuous galantamine versus 6 months of placebo followed by 6 months of galantamine (2 points on the ADAS-Cog). These data and similar data from other cholinesterase inhibitor studies suggest these agents may have disease-modifying eects that may slow disease progression in AD. All trials demonstrated that galantamine had no eect on liver transaminases or other laboratory parameters. As with other cholinesterase inhibitors, gastrointestinal adverse events were the most common side eects and increased with increasing dose. Mild weight loss was also common. The recommended starting dose of galantamine is 4 mg administered twice daily given with breakfast and dinner. Administration of galantamine at mealtime helps to minimize nausea associated with its use. The dose is increased by 4 mg administered twice daily every 4 to 6 weeks as the patient tolerates it. If galantamine therapy is interrupted for more than a few days, it is recommended that treatment be restarted at 4 mg administered twice daily, with the patient then titrated up every 4 to 6 weeks to the highest tolerated dose. Nausea, the most common adverse event, usually resolves within a week and can be further minimized by adequate hydration. If necessary, an antiemetic may be used. Cholinesterase inhibitor use in moderate to severe Alzheimers disease A small international trial [9] evaluated the use of donepezil in patients with moderate to severe AD. In this 24-week trial, 290 AD patients with MMSE scores between 5 and 18 were randomly assigned to two treatment groups: 5 to 10 mg of donepezil or placebo. The primary ecacy measure was the Clinicians Interview-Based Impression of Change with caregiver input [59], a seven-point scale ranging from markedly improved to markedly
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worse based on a semistructured interview performed with the patient and caregiver. Various secondary ecacy measures of cognition, global functioning, and behavior were also obtained. Last observation carried forward analysis revealed signicant dierences between the donepezil and placebo groups. Sixty-three percent of donepeziltreated patients received Clinicians Interview-Based Impression of Change with caregiver input ratings of improved or no change in comparison to 42% of placebo patients. There were signicant drug-versus-placebo dierences in all secondary ecacy measures as well. This study suggests that donepezil may stabilize or improve cognition and functional status in patients with moderate to severe AD. Larger studies are needed to conrm these results. Summary In summary, the cholinesterase inhibitors have provided the rst known eective treatments for the cognitive decits of AD. Symptomatic ecacy is modest and may include positive eects on memory, language, praxis, and problematic noncognitive behaviors, such as pacing, delusions, and uncooperativeness. It should be noted, however, that only approximately one third of patients have clinically meaningful improvement in cognitive function. It is much more common for patients to have stabilization of their cognitive, behavioral, and functional status. This is the message that should be conveyed to patients and their families: the goal of treatment is stabilization. Currently available data suggest that this period of stabilization at or near baseline function lasts at least a year [11,29,3942].
Vitamin E and antioxidants in Alzheimers disease Vitamin E Vitamin E (a-tocopherol) administration is a second pharmacologic approach to slowing progression in AD. Vitamin E has been demonstrated to protect cell membranes from oxidative damage and, in animal models, to reduce hippocampal neurodegeneration [60,61]. The production of neurotoxic free radicals during oxidative metabolism has been suggested as a potential mechanism of neurodegeneration in AD [62]. This neurobiologic consideration, plus the demonstration that the monamine oxidase inhibitor selegiline seems to slow disease progression in Parkinsons disease, another late-life neurodegenerative disorder, has stimulated investigation of drugs with antioxidant activity as therapeutic agents for AD. Several small placebo-controlled trials and a much larger Alzheimers Disease Cooperative Study clinical trial [17] provide evidence for the ecacy of antioxidant strategies in slowing disease progression in AD. The Alzheimers Disease Cooperative Study consisted of a four-arm parallel-group study in which 341 patients with moderate-stage AD were randomized to
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receive one of three active treatments or placebo for a 2-year period. The active treatments consisted of vitamin E at a dose of 1000 IU administered twice a day, selegiline (1-deprenyl) at a dose of 10 mg (given as 5 mg twice a day), or a combination of vitamin E and selegiline. Primary outcome measures were indices of functional decline: progression from moderate to severe dementia; loss of two of three basic activities of daily living, ie, feeding, grooming, and toileting; nursing home placement; or death. Vitamin E and selegiline both delayed progression to the outcome endpoints. The average delay for vitamin E was approximately 230 days compared with placebo. Because of its low cost and relative safety, vitamin E is now recommended in addition to a cholinesterase inhibitor for slowing progression in AD. Vitamin E is started at a dosage of 400 IU/d and is increased by 400 IU as tolerated each week until the maximum dose of 2000 IU in divided doses administered twice daily is reached. Because vitamin E inhibits platelet adhesion [63,64] and may alter vitamin Kdependent coagulation factors [65,66], its use is contraindicated in patients with vitamin K deciency, and cautious use is recommended in patients receiving anticoagulant therapy. Ginkgo biloba Ginkgo biloba is a traditional Chinese herbal medicine with reputed mood-elevating, cognitive-enhancing, and behavior-altering properties. Its theoretic properties include anti-inammatory and antioxidant eects [67,68]. Although its safety prole has not been fully characterized, ginkgo biloba is a modest anticoagulant [68]. EGB 761, a standardized extract of the Ginkgo biloba tree, was evaluated in a 52-week, double-blind, randomized, placebo-controlled trial to assess ecacy and safety in patients with AD and VaD [69]. Primary outcome measures included the ADAS-Cog and the Clinical Global Impression of Change. In addition, the nonvalidated Geriatric Evaluation by Relative Rating Instrument (GERRI) [70], a caregiver-rated measure of patient functioning, was used as an outcome measure. The GERRI is a 49-item inventory that includes a range of scores from 1 to 5 in which an increasing score indicates poorer patient functioning. An ITT analysis was used to compare data. When compared with placebo, EGB 761 at a dose of 40 mg three times a day demonstrated a small but statistically signicant dierence in the ADAS-Cog with a drug-versus-placebo dierence of 1.4 points. There was also a statistically signicant drug-versus-placebo group dierence in the GERRI of 0.14 points. There was no dierence demonstrated in the Clinical Global Impression of Change. The number of adverse events was similar in the placebo and active treatment groups. There was a high attrition rate during the 52-week trial; only 137 of the 309 subjects included in the ITT analysis completed the trial. The eects of EGB 761 on agitation and mood were assessed but not reported.
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The results of this study must be interpreted with caution. There are a number of methodologic aws that render interpretation of the data somewhat dicult. Until the results of this study are replicated and the safety prole of ginkgo biloba is further claried with regard to potential for causing signicant bleeding events, the use of ginkgo biloba in AD is not supported by the available data. In addition, the manufacture of ginkgo biloba and other herbal supplements is unregulated and lacks FDAmandated standards for potency and purity. Treatment of dementia with Lewy bodies DLB is characterized by a cluster of signs and symptoms distinct from AD, including dementia, hallucinations, early-stage parkinsonian motor features, and uctuating cognitive decits [2,71,72]. Neuropathologically, cortical neurons of DLB patients exhibit Lewy bodiesspherical intracytoplasmic inclusions [2]. Patients with DLB demonstrate a number of neuroanatomic and neurochemical decits, including a decreased numbers of neurons in the substantia nigra and abnormalities of the dopaminergic, cholinergic, serotonergic, and noradrenergic neurotransmitter systems [2,73]. DLB patients demonstrate more severe decits of choline acetyltransferase activity and more functional and upregulated postsynaptic muscarinic receptors when compared with AD patients [7274]. Because the cholinergic decit in DLB is thought to be greater than in AD, patients with DLB have been hypothesized to have a better response to cholinesterase inhibitors than patients with AD [2,73]. Although there are no FDA-approved treatments for DLB, case reports and open-label studies as well as one recent double-blind placebo-controlled clinical trial have suggested ecacy of cholinesterase inhibitors in the treatment of DLB [7577]. McKeith and colleagues [76] reported a 23-week European study of 3 mg (1.5 mg twice a day) to 12 mg (6 mg twice a day) of rivastigmine versus placebo in 120 patients diagnosed with mild to moderately severe probable DLB. DLB was dened by consensus guideline criteria. Mild to moderate disease was dened by an MMSE score of greater than 9. A 20-week titration and treatment phase was followed by a 3-week washout phase. The maximum length of the titration period was 8 weeks. The Neuropsychiatric Inventory (NPI) [78] and a computerized cognitive assessment system speed score (a sum of scores reecting various parameters, including picture recognition reaction times, spatial memory, and word recognition) were the primary ecacy measures [76]. MMSE scores and other global index measures were used as well as the NPI-4, a subscale cluster of the four items on the NPI identied as a DLB cluster: apathy, depression, delusions, and hallucinations. Fifty-six percent of patients reached the maximum daily dose of 12 mg, and 92% reached doses of 6 to 12 mg. Dierences between the rivastigmine and placebo groups on the NPI-4 and computerized cognitive assessment system
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speed score were statistically signicant. Sixty-three percent of patients in the rivastigmine group demonstrated at least a 30% reduction from baseline in NPI score as compared to 30% in the placebo group. The rivastigmine and placebo groups did not dier with respect to MMSE scores or global function. After the 3-week study medication washout period, dierences between the placebo- and rivastigmine-treated groups on the NPI were no longer signicant. In summary, cholinesterase inhibitors may also be eective in the treatment of DLB. One small placebo-controlled trial demonstrated that rivastigmine was eective in the treatment of behavioral decits of DLB [76]. Large-scale placebo-controlled trials are necessary to conrm these results, however. Treatment of vascular dementia There are currently no FDA-approved treatments for VaD. Because the cause of VaD is a consequence of cerebrovascular disease, treatment of VaD has focused on controlling the risk factors for cerebrovascular disease [79,80]. Prompt identication and treatment of hypertension, the major risk factor for stroke, are critical in the prevention of stroke and VaD [79,80]. In addition, management and modication of lifestyle factors are crucial, including the elimination of cigarette smoking, weight reduction, nutritional education, and treatment of hypercholesterolemia and hypertriglyceridemia [79,80]. Summary The management of dementia patients encompasses pharmacologic, behavioral, and psychosocial intervention strategies. Before pharmacologic intervention is instituted, it is important that sources of excess disability and comorbidity be eliminated or reduced. Identication of comorbid medical and psychiatric conditions, such as depression and delirium, should be identied and appropriately treated. Providing caregivers with education, support, and practical advice is a critical component of the management of the demented patient. The current standard of care for pharmacologic management of the cognitive and functional disabilities of AD consists of the combination of a cholinesterase inhibitor and high-dose vitamin E. This standard is based on the results of large-scale, double-blind, placebo-controlled trials. Cholinesterase inhibitors are the only FDA-approved pharmacologic treatments for AD. Cholinesterase inhibitors have been shown to be eective in the treatment of the cognitive, behavioral, and functional decits of AD. Large-scale placebo-controlled trials of tacrine, donepezil, rivastigmine, and galantamine have demonstrated moderate benets in patients with mild to moderate AD. Donepezil, rivastigmine, and galantamine are the rst-line choices in the treatment of AD because of their lack of hepatotoxicity, ease of administration, few signicant drug-drug interactions, and mild to moderate side eects.
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There are few contraindications to the use of cholinesterase inhibitors. Known hypersensitivity to a specic drug or its derivatives is the only true contraindication. Cautious administration of cholinesterase inhibitors is advised in patients who have a previous history of allergy or adverse reactions to prior cholinesterase inhibitors, severe liver disease, preexisting bradycardia, peptic ulcer disease, current alcoholism, asthma, or chronic obstructive pulmonary disease. Nausea, vomiting, diarrhea, and anorexia are the most common side effects of cholinesterase inhibitors. These gastrointestinal side eects can be minimized by gradual dose increases, administration with food, adequate hydration, and judicious use of an antiemetic. Vitamin E has been demonstrated to slow the progression of AD in several small and one large placebo-controlled trials. Because of its low cost and safety, it is recommended in addition to a cholinesterase inhibitor for the treatment of AD. There are no FDA-approved treatments for DLB and VaD. One small placebo-controlled trial demonstrated that rivastigmine may be eective in the treatment of DLB. More large-scale placebo-controlled trials are needed to conrm the results of this study. Treatment of VaD focuses on the control, identication, and management of cerebrovascular disease and vascular risk factors. Although there are no peer-reviewed reports on the ecacy of cholinesterase inhibitors for VaD or mixed AD/VaD, early reports suggest that these agents may also be eective for mixed AD/VaD. The indications for the use of cholinesterase inhibitor drugs are eventually likely to broaden to include DLB, mixed AD/VaD, and AD in its more advanced stages. References
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Med Clin N Am 86 (2002) xixiii

James D. Bowen, MD Guest Editor

Preface / Med Clin N Am 86 (2002) xixiii

Preface / Med Clin N Am 86 (2002) xixiii

Med Clin N Am 86 (2002) 455476

The diagnosis and dierential diagnosis of dementia

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy.

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

G.W. Ross, J.D. Bowen / Med Clin N Am 86 (2002) 455476

Med Clin N Am 86 (2002) 477499

Vascular dementia revisited: Diagnosis, pathogenesis, treatment, and prevention

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

G.C. Roman / Med Clin N Am 86 (2002) 477499

Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

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A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518

A. Kertesz, D.G. Munoz / Med Clin N Am 86 (2002) 501518