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Are frontotemporal lobar degeneration, progressive supranuclear palsy and corticobasal degeneration distinct diseases?
Sharon Sha, Craig Hou, Indre V Viskontas and Bruce L Miller* S U M M A RY
New findings relating to the clinical, genetic and molecular bases of neurodegenerative disorders have led to a shift away from traditional nomenclatures of clinical syndromes. Historically, frontotemporal lobar degeneration (FTLD), corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) were classified on the basis of distinct clinical and pathological features. In recent years, however, advances in molecular and genetic research have led clinicians to suggest that the similar etiologies of the three disorders warrant their amalgamation into a single disorder with three subtypes. In this Review, we consider the utility and validity of combining FTLD, CBD and PSP. The earliest reports of these disorders demonstrate their distinctiveness, whereas recent findings challenge traditional nomenclatures by showing etiological overlap. For example, tau inclusions have been confirmed in patients with CBD and those with PSP, and in some patients with FTLD, implying that all three disorders are tauopathies. Furthermore, most patients with progressive nonfluent aphasia, a subtype of FTLD, show PSP or CBD post-mortem. Even tau-related cases of FTLD, CBD and PSP are distinguishable on the basis of other criteria, however, and many FTLD cases do not show tau pathology. We argue, therefore, that FTLD, CBD and PSP should be considered as pathologically similar but distinct syndromes. New research criteria for CBD and PSP should note that progressive nonfluent aphasia is often a precursor of these conditions.
KEYWORDS dementia, genetic, movement disorders, neuronal inclusions, tau protein

INTRODUCTION

REVIEW CRITERIA PubMed was searched using Entrez for articles published up to 1 August 2006. Search terms used were corticobasal degeneration, corticobasal syndrome, frontotemporal dementia, frontotemporal lobar degeneration, progressive nonfluent aphasia, semantic dementia, speech apraxia, progressive supranuclear palsy, tau and ubiquitin. The abstracts of retrieved citations were reviewed and prioritized by relevant content. Full articles were obtained and references were checked for additional material when appropriate.

S Sha is an intern in internal medicine at California Pacific Medical Center, C Hou is a neurology physician at Kaiser Permanente Hospital, IV Viskontas is a postdoctoral fellow at the Memory and Aging Center at the University of California, San Francisco (UCSF), and BL Miller is Professor of Neurology, holds the AW & Mary Margaret Clausen Distinguished Chair, and is clinical director of the Memory and Aging Center at UCSF, San Francisco, CA, USA.
Correspondence
*UCSF Memory and Aging Center, 350 Parnassus Avenue, Suite 706, San Francisco, CA 941431207, USA bmiller@memory.ucsf.edu
Received 29 August 2006 Accepted 6 October 2006
www.nature.com/clinicalpractice doi:10.1038/ncpneuro0357

Knowledge about the clinical, pathological and genetic bases for neurodegenerative disorders is rapidly expanding. As modern molecular and genetic techniques are exploited, distinctions between disorders once considered separate diseases are beginning to blur. Recent genetic and pathological findings suggest that there are common molecular mechanisms for corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), two atypical parkinsonian syndromes that were initially considered unrelated. Also, it is now apparent that some patients who meet the clinical criteria for frontotemporal lobar degeneration (FTLD) show CBD or PSP at autopsy. Growing awareness of the similarities between CBD, FTLD and PSP has led their classification as distinct disorders to be challenged.1,2 In particular, some authors argue that FTLD with tau mutations, CBD and PSP should all be considered as subtypes of Picks disease.1,3 Fundamental differences between these three syndromes still exist, however, and these differences justify their continued separation. Early descriptions of CBD, PSP and FTLD are reviewed here to provide insights into how these diseases became classified as separate entities. This review is followed by a discussion regarding the similarities and differences between CBD, PSP and FTLD (Tables 1 and 2). Implications for clinical diagnosis and treatment are considered with regard to combining or splitting these disorders. Finally, an argument for continued separation of CBD, PSP and FTLD is made.
CORTICOBASAL DEGENERATION

The clinical features of CBD were first described in case reports by Rebeiz, Kolodny and Richardson.4 In 1967, the term corticodentatonigral degeneration with neuronal achromasia was introduced to describe three individuals who presented with progressive awkwardness and slowness of voluntary limb movement. This motor abnormality began in an asymmetric fashion before it became generalized.

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Table 1 Overview of the features of corticobasal degeneration, progressive supranuclear palsy, and the three subtypes of frontotemporal lobar degeneration (frontotemporal dementia, progressive nonfluent aphasia and semantic dementia).
Disease Corticobasal degeneration Cognitive and behavioral features Nonfluent aphasia, frontal executive deficits, oral and limb apraxia, apathy, depression Nonfluent aphasia, frontal executive deficits, apathy Movement Asymmetric parkinsonism, ocular apraxia, myoclonus, alien limb, dystonia Axial rigidity, falls, impaired vertical gaze, dysphagia in the early stages Anatomy Mesial frontal, frontal opercular, sometimes parietal, basal ganglia Dorsal midbrain and widespread brainstem, sometimes frontal insular Frontal insular, anterior temporal, sometimes parietal Frontal insular, basal ganglia Pathology Tau 4R, astrocytic plaques, achromatic neurons Tau 4R, neurofibril tangles, globose neurons Genetics H1 tau haplotype, tau mutations (rare)

Progressive supranuclear palsy

H1 tau haplotype, tau mutations (rare)

Frontotemporal dementia

Disinhibition, apathy, emotional blunting, overeating, frontal executive deficits Speech deficits, nonfluent aphasia, oral apraxia, agrammatic, frontal executive deficits Lack of knowledge for words, faces, emotion

Amytrophic lateral sclerosis develops in 15% of cases, CBD or PSP features can be observed Evolves into CBD or PSP (commonly)

Tau or ubiquitin inclusions

Tau (rare) or progranulin mutations Unknown

Progressive nonfluent aphasia Semantic dementia

Tau, CBD or PSP

Spared until late in the disease course

Anterior temporal, orbital frontal

Usually ubiquitin

Uncommon

Abbreviations: 4R, four-microtubule repeat; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy.

Involuntary motor activity was prominent and, in one case, the affected left arm resisted purposeful action of the right arm. Despite the severity of motor deficits, it was reported that mental faculties were relatively spared until the end. Post-mortem examination showed asymmetric frontal and parietal lobe atrophy, cortical neuron loss, swelling of the remaining cell bodies, and absence of the Nissl substance (achromasia). The substantia nigra showed severe cell loss.4 In the early studies, movement abnormalities were noted, whereas more recently the frontal executive, speech or behavioral disorders often seen in CBD have been emphasized. In 1989, Gibb, Luthert and Marsden5 shortened the disease name to corticobasal degeneration and described three main clinical features: abnormality of motor function, constructional difficulty, and impaired eye movement. Motor symptoms included akinesiarigidity, myoclonus, dystonia, and alien limb. In the cognitive domain, the authors described problems with the copying of simple designs and shapes, which suggested parietal dysfunction. Horizontal and vertical saccades were absent in two cases. Ideomotor apraxia, which is characterized by impairments in demonstrating an objects use in the absence of the object itself,

was common. Patients showed the conventional improvement in gesturing when the object itself was made available to them, or when they imitated the examiner, indicating that the apraxia is not caused simply by motor difficulties.68 Neuropathology showed frontoparietal atrophy and swollen ballooned achromatic neurons that resembled Pick cells.5 Changes in movement can be the presenting feature of CBD, but cognitive changes are remarkably common. In 10 of 13 autopsyproven CBD cases, memory loss, word finding difficulty and global cognitive dysfunction were presenting symptoms.9 Early reports of CBD noted parietal deficits, but impairments in frontal function are probably more typical,10 with impaired set shifting, verbal fluency and memory retrieval, apathy, depression, and repetitive behaviors being commonly observed.1012 If frontal lobe degeneration begins in the dominant hemisphere, CBD can present as progressive nonfluent aphasia (PNFA).12,13 Finally, in a recent study of patients with PNFA, 70% showed CBD or PSP at autopsy, suggesting particularly close links between PNFA, CBD and PSP.3 The tau protein is central to the neuropathology of CBD; the neuronal inclusions, intracellular coiled bodies and astrocytic plaques associated with this condition all stain

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Table 2 Myths and facts about corticobasal degeneration, progressive supranuclear palsy, frontotemporal dementia, progressive nonfluent aphasia and semantic dementia.
Disease Corticobasal degeneration Potential myths 1. Primarily presents as a movement disorder and cognition is relatively spared until later in the illness 2. Always asymmetric 3. Parietal lobes are affected more than the frontal lobes 1. Primarily presents as a movement disorder, the dementia is mild, and the cortex is largely spared 2. Not asymmetric, if so suspect CBD 3. Easily separated from CBD 1. Only affects movement later in the disease course, and is cortically predominant 2. FTD is a tauopathy A cortical disorder that is clinically and pathologically unrelated to CBD or PSP Temporally predominant degeneration is associated with Pick bodies The facts 1. Usually begins with executive, language or speech deficits 2. Often symmetrical 3. When parietal involvement is greater than frontal involvement, suspect Alzheimers disease 1. Often begins as a frontal or PNFA syndrome and frontal lobes can be involved 2. Often asymmetric 3. CBD and PSP are difficult to predict at autopsy 1. Many cases begin as a basal ganglia or motor neuron syndrome 2. Half of cases are ubiquitin-positive but tau-negative Most PNFA cases develop PSP or CBD features and neuropathology Most semantic dementia cases are ubiquitin-positive but tau-negative

Progressive supranuclear palsy

Frontotemporal dementia Progressive nonfluent aphasia Semantic dementia

Abbreviations: 4R, four-microtubule repeat; CBD, corticobasal degeneration; PSP, progressive supranuclear palsy.

for tau.14 Similarly, mutations in the gene on chromosome 17 that codes for the tau protein can cause CBD. Blurring the distinction between CBD and frontotemporal dementia (FTD) is the discovery that identical tau mutations within a family resulted clinically in CBD in the son and FTD in the father.15 With sporadic and genetic forms of CBD, the fourmicrotubule repeat (4R) isoform of tau is the main pathological inclusion. Also, the A0 tau allele is over-represented in patients with CBD compared with controls, further linking CBD to tau at the molecular level.16 Over time, CBD has, therefore, evolved from an idiopathic asymmetric basal ganglia disorder with parietal involvement to a frontalparietalbasal ganglia disorder in which frontal executive, behavioral or speech deficits are often the first symptoms to emerge. Tau provides the link between the pathology and genetics of CBD.
PROGRESSIVE SUPRANUCLEAR PALSY

The clinical features of the nine cases of PSP first described by Steele et al. in 196417 included axial rigidity, supranuclear palsy, pseudobulbar palsy and dysarthria. The axial rigidity manifested as dystonic rigidity of the neck and upper body. Impaired vertical gazeparticularly with regard to looking downward on command was an early sign, whereas horizontal eye movements were affected only later in the course

of the disease. Dementia was mild, but changes in personality and behavior were presenting symptoms in three patients. Neuropathological findings included neurofibrillary tangles, granulovacuolar degeneration, neuronal loss, and gliosis.17 Since these first cases, descriptions of the abnormalities in eye movements associated with PSP have been refined.18,19 Square-wave jerks during fixation are common, and in addition to impaired vertical eye movements saccades are now known to be hypometric with decreased velocity in the horizontal direction.18,19 Prominent motor symptoms present early in the disease and include bradykinesia, axial rigidity, falls and myoclonus.2023 As with CBD, despite early emphasis on the parkinsonian features of the condition, PSP often begins as a cognitive disorder affecting executive function or language, or as a neuropsychiatric disorder with apathy or other behavioral symptoms.2426 Albert et al.27 originally described the dementia of PSP as a subcortical dementia, hypothesizing that degeneration of the midbrain led to dysfunction of circuits projecting to the cortex. Cognitive slowing is common, but deficits extend beyond slowed processing speed.28,29 Patients with PSP perform poorly on tasks of verbal fluency, sequencing, set shifting and abstract thought.21 As with CBD, PNFA can be a prodrome of PSP.

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In common with CBD, the key pathological feature of PSP is the presence of abnormally phosphorylated tau in neurons and glia. Diagnosis is determined by neurofibrillary tangles or neuropil threads in the basal ganglia and brainstem.30 Mutations in the intron region near exon 10 on the tau gene can lead to a familial PSP-like syndrome.31 Similarly, as in CBD, genetic studies show that the A0 tau allele is over-represented in cases with PSP compared with normal controls.16,32 The nearly identical percentage of PSP and CBD patients with the H1 tau haplotype further links the two disorders.33 The amyloid deposits or neuritic plaques that characterize Alzheimers disease (AD) are not present in pure PSP, but AD and PSP can be seen together.32,34 The majority of PSP and CBD cases, however, can be pathologically differentiated from AD. In AD, tau accumulation has been shown to result from amyloid- (A)-induced neuronal damage.35 Tau mutations do not cause AD; rather, inherited forms of AD result from mutations in the amyloid precursor protein (APP) or presenilin 1 and 2, which lead to an increase in A42-amyloid deposition. The form of tau found in PSP is morphologically, ultrastructurally and biochemically distinct from that found in AD: in PSP, tau exists as mainly straight tubules, which are slightly thinner than the paired helical fragments found in AD.36 Also, in PSP tau deposits are found in both glial cells and neurons, whereas they are found only in neurons in AD. The PSP and CBD forms of tau are more similar to each other than to the tau in AD; in both PSP and CBD 4R tau is the predominant isoform, there is glial pathology, and the tau filaments are mainly straight. CBD and PSP are differentiable in that in CBD there are ballooned neurons that are weakly immunoreactive to tau, and tau-positive astrocytic plaques.
FRONTOTEMPORAL LOBAR DEGENERATION

FTLD was first described by Arnold Pick in 1892,37 and language and behavioral changes were emphasized in the disorders early history. Picks first patients had focal left anterior temporal atrophy, although he also described a frontally predominant patient. Later, Alzheimer showed that these focal atrophy patients had argyrophilic inclusions that he called Pick bodies.37,38 Onari and Spatz coined the term Picks disease for patients with a frontal or temporal degenerative disorder, ballooned

neurons, and Pick bodies.39 It was not until 1994, however, that the Lund and Manchester groups published formal research criteria and introduced the term frontotemporal dementia (FTD).40 These groups noted that Pick bodies were absent in most cases of FTD. In 1998, a consensus conference proposed the term FTLD, dividing the syndrome into FTD, PNFA and semantic dementia (SD) subtypes, implying that the pathology was similar in all three.37 The core features of FTD were defined as insidious onset, slow progression, a decline in social conduct, impaired regulation of personal conduct, emotional blunting, and loss of insight.41 Impulsivity, inflexibility, disinhibition, repetitive behaviors, apathy, hyperorality, carbohydrate craving and poor hygiene are common symptoms. The core features of FTD are behavioral, but the cognitive profile is notable for executive deficits with relatively spared memory, language and visuospatial functions. Like CBD and PSP, verbal fluency, set shifting (as measured by the Trails B task), attention, abstraction, inhibition of an over-learned response (as measured by the Stroop test), and planning are impaired. Although FTD was initially characterized as cortically based, many patients with FTD show movement syndromes similar to those associated with CBD or PSP, along with behavioral deficits. Furthermore, there is a strong link with motor neuron disease; 15% of patients with FTD develop amyotrophic lateral sclerosis (ALS). Conversely, many patients with ALS develop frontal executive disorders. Unlike CBD and PSP, FTD pathology is molecularly heterogeneous. Atrophy of the frontal or anterior temporal lobes is universal, and cortical and basal ganglia neuron loss and gliosis are evident microscopically.42,43 Approximately half of FTD cases are associated with insoluble tau aggregates within neurons and glia; these aggregates usually consist predominantly of 4R or three-microtubule repeat (3R) isoforms. 4R tau is over-represented in CBD, PSP and some FTD cases, whereas 3R tau is associated with classical Picks disease. In FTD, this tau pathology has been seen both with tau mutations44,45 and in sporadic cases. Patients in whom FTD has been diagnosed sometimes show CBD or PSP pathology. Many FTD cases show tau-negative but ubiquitin-positive inclusions. Patients with these inclusions are classified as having FTD with motor neuron disease (FTDMND). Some, but not all, patients with FTDMND pathology develop ALS.

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More recently, mutations in the progranulin gene on chromosome 17 have been associated with this FTD-ubiquitin pathology.46 There are other families in whom FTD and ALS co-occur and show linkage to chromosome 9,47 and the H1 haplotype of the tau gene on chromosome 17q21 is also associated with FTLD.48 Unlike PSP and CBD, however, many FTD patients with the H1 haplotype do not show tau-positive inclusions via immunohistochemistry. It seems likely, therefore, that the mechanism for degeneration is distinct between the disorders. Furthermore, the A0 tau allele that associates with CBD and PSP does not associate with FTD.16,49 Language impairment is the primary manifestation of the two other subtypes of FTLD PNFA and SD. With PNFA, the syndrome begins with speech apraxia, decreased fluency and agrammatism.50 Anatomically, PNFA is associated with asymmetric, left-greater-than-right, frontal, opercular, insular degeneration. Like CBD and PSP, cognitive deficits often involve frontal executive function, while memory is relatively spared. Typically, behavior is spared until later in the illness. The most likely pathological outcome in PNFA is CBD or PSP.3 SD is a temporally predominant subtype of FTLD. Patients with SD most commonly show asymmetric neural degeneration, with left temporal lobe atrophy more severe than right, and the disorder begins with deficits in knowledge about facts, objects, words and names. Prosody and syntax of speech are intact, allowing fluent verbal language, but patients will often have empty speech. This pattern is also apparent in written language. Neuropathologically, most SD cases show ubiquitin-positive inclusions, and only rarely does the temporal variant overlap pathologically with PSP or CBD.
OVERLAP AND DISTINCTIVE FEATURES

The similarities and differences between CBD, PSP and FTLD are summarized in Figure 1. As described above, CBD, PSP and the three FTLD subtypes FTD, PNFA and SD, all represent clinically defined syndromes that are linked to specific neuropathological patterns. CBD and PSP were originally defined as atypical parkinsonian syndromes and were associated with relative sparing of cortical functions, whereas FTD, PNFA and SD were considered to be cortically based syndromes in which movement was relatively spared. Since the generation of these original definitions, the characterization of the

clinical syndromes for CBD, PSP, FTD, PNFA and SD has expanded and become more precise. There is little overlap between the temporally predominant SD syndrome and CBD or PSP. Specifically, CBD and PSP tend to spare the temporal lobes, whereas SD involves basal ganglia only late in the disease, and SD is usually associated with ubiquitin, not tau, inclusions. The remainder of this discussion, therefore, focuses on the similarities and differences between CBD, PSP, FTD and PNFA. PSP, CBD, PNFA and some cases of FTD are strongly linked from both clinical and pathological perspectives. The rigid definition of CBD and PSP as movement disorders has disappeared and there is increasing evidence for early involvement of frontal regions in both. Also, it is now evident that CBD and PSP are not purely movement disorders, but are clinical syndromes that encompass motor, cognitive, behavioral and language deficits that might overlap clinically with FTD and PNFA.7 Conversely, although PNFAand sometimes FTDbegin as cortical syndromes, they can rapidly evolve into CBD-like or PSP-like movement disorders. This overlap is apparent anatomically, as PSP, CBD, PNFA and FTD all affect basal ganglia and frontal structures.50 Tau pathology and genetics also link these syndromes. Nearly all PSP, CBD and PNFA and some FTD cases show overexpression of the 4R tau isoform in neurons and glia. Over 90% of PSP and CBD patients, but only 57% of controls, are homozygous for the H1 tau haplotype.32,5153 Although PSP, CBD and FTD are usually sporadic, in familial cases tau mutations might lead to CBD in one generation, FTD in another, or a syndrome similar to PSP.15,54,55 On the basis of clinical and pathological data, it now seems that PNFA usually represents an asymmetric, dominant-hemisphere, cortically predominant manifestation of CBD or PSP.3,56,57 Significant differences still remain, however, between CBD, PSP and FTD. First, the three disorders have distinct anatomical patterns of degeneration: PSP is associated with extensive pathological changes in the cerebellum and pons, whereas CBD, PNFA and FTD generally spare this region. CBD is much more likely than FTD to affect the basal ganglia and parietal regions. In FTD the most prominent atrophy is generally frontal, temporal or both. Second, the inclusions found in each of the disorders are reliably differentiable on pathology: whereas the insoluble tau form in CBD and PSP is 4R

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Pathology: Ballooned neurons Astrocytic plaques Achromatic neurons 4R tau Anatomy: Mesial frontal Frontal opercular More parietal CBD Movement: Asymmetric parkinsonism Ocular apraxia Myoclonus Alien limb Dystonia Parietal atrophy H1 tau haplotype A0 tau allele

Pathology: Neurofibrillary tangles Globose neurons

Anatomy: More dorsal midbrain More widespread brainstem PSP Movement: Axial rigidity Falls Vertical gaze Early dysphagia

Nonfluent aphasia Tau inclusions Tau mutations Basal ganglia Frontal executive deficits Apathy

FTLD Genetics: Pathology: Progranulin mutations Ubiquitin inclusions Frontotemporal dementia Behavioral symptoms: Anatomy: Emotional blunting More orbital frontal Spared memory Overeating Disinhibition Semantic dementia Behavioral symptoms: Anatomy: Loss of knowledge for Anterior words, faces, objects temporal

Figure 1 Venn diagram summarizing the similarities and differences between corticobasal degeneration, progressive supranuclear palsy and frontotemporal lobar degeneration. Abbreviations: 4R, fourmicrotubule repeat; CBD, corticobasal degeneration; FTLD, frontotemporal lobar degeneration; PSP, progressive supranuclear palsy.

tau, FTD tau inclusions are commonly 3R tau. Furthermore, although tau links some FTD cases to CBD and PSP, most patients with FTD do not in fact show tau inclusions. Third, genetic factors provide additional distinctions: even though there are occasional families with tau mutations in whom FTD, CBD and PSP overlap, there are many more in which the FTD or PSP phenotype remains constant across many generations. Last, there are still substantial clinical differences between the disorders: by definition FTD does not begin with aphasia, whereas it is now evident that many PSP and CBD patients start with PNFA. Cognitive impairment is also more common in CBD than

in PSP; eye-movement abnormalities are more prominent in PSP than in CBD; and manifestations of parietal damage such as graphesthesia and astereognosis are much more frequent in CBD than in PSP. FTD is differentiable from CBD and PSP when behavioral impairments are dominant and the patient shows relatively spared language and memory function. Although the overlap between CBD, PSP and FTD is extensive, careful attention to clinical findings and advances in neuroimaging techniques have enhanced the differential diagnosis. Taken together, these differences are sufficient to support continued separation of the disorders.

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CONCLUSION

Currently, PSP, CBD and FTLD can be distinguished on the basis of clinical and pathological observations. The overlapping characteristics of these disorders, however, will continue to create controversy with respect to their classification2,58,59 until the etiologies are better understood. Little is known about the epidemiological and genetic factors that cause these disorders. Recent data support strong links between CBD, PSP, PNFA and some cases of FTD via their common tau pathology. Most cases of SD and many cases of FTD are, however, associated with ubiquitin rather than tau pathology, and appear to be etiologically distinct from CBD and PSP. As biochemical, pathological and genetic discoveries are made, new and better nomenclature systems might become possible. Beyond pathology and genetics, the effectiveness of treatments that focus on the underlying pathological mechanisms will be important in refining taxonomies.60 For example, if an anti-tau therapy was available that benefited patients with CBD, PSP, PNFA and FTD equally, consideration of these disorders as a single entity would be more compelling. At present, however, no such therapy exists, and many questions remain with regard to the anatomical, genetic and pathological variability of these disorders. The rapid evolution of knowledge regarding CBD, PSP, PNFA and FTD offers hope not only for understanding these disorders, but also for finding effective therapies with which to treat them.
KEY POINTS
Traditionally, frontotemporal lobar degeneration (FTLD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) have been distinguishable on the basis of presenting clinical symptoms Recently, molecular and genetic findings have suggested a link between the three disorders PSP and CBD cases show tau inclusions post-mortem, as do some FTLD cases Progressive nonfluent aphasia, a subtype of FTLD, often leads to PSP and CBD Not all FTLD cases are tauopathies As there are currently no treatments available that target the molecular and genetic etiologies of these three disorders, they should continue to be considered distinct

References 1 Kertesz A et al. (2003) Frontotemporal degeneration, Picks disease, Pick complex, and Ravel. Ann Neurol 54 (Suppl 5): S1S2 2 Kertesz A (2006) Progress in clinical neurosciences: frontotemporal dementiaPicks disease. Can J Neurol Sci 33: 141148 3 Josephs KA et al. (2006) Clinicopathologic analysis of frontotemporal and corticobasal degenerations and PSP. Neurology 66: 4148 4 Rebeiz JJ et al. (1968) Corticodentatonigral degeneration with neuronal achromasia. Arch Neurol 18: 2033 5 Gibb WRG et al. (1989) Corticobasal degeneration. Brain 112: 11711192 6 Leiguarda R et al. (1994) The nature of apraxia in corticobasal degeneration. J Neurol Neurosurg Psychiatry 57: 455459 7 Kertesz A et al. (2000) The corticobasal degeneration syndrome overlaps progressive aphasia and frontotemporal dementia. Neurology 55: 13681375 8 Leiguarda RC et al. (2003) Limb-kinetic apraxia in corticobasal degeneration: clinical and kinematic features. Mov Disord 18: 4959 9 Grimes DA et al. (1999) Dementia as the most common presentation of corticalbasal ganglionic degeneration. Neurology 53: 19691974 10 Pillon B et al. (1995) The neuropsychological pattern of corticobasal degeneration: comparison with progressive supranuclear palsy and Alzheimers disease. Neurology 45: 14771483 11 Dubois B et al. (2000) The FAB: a frontal assessment battery at bedside. Neurology 55: 16211626 12 Frattali CM et al. (2000) Language disturbances in corticobasal degeneration. Neurology 54: 990992 13 Graham NL et al. (2003) Corticobasal degeneration as a cognitive disorder. Mov Disord 18: 12241232 14 Dickson DW et al. (2002) Office of Rare Diseases neuropathologic criteria for corticobasal degeneration. J Neuropathol Exp Neurol 61: 935946 15 Bugiani O et al. (1999) Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol 58: 667677 16 Morris HR et al. (1999) The tau gene A0 polymorphism in progressive supranuclear palsy and related neurodegenerative diseases. J Neurol Neurosurg Psychiatry 66: 665667 17 Steele JC et al. (1964) Progressive supranuclear palsy: a heterogeneous degeneration involving the brain stem, basal ganglia and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia and dementia. Arch Neurol 10: 333359 18 Troost BT and Daroff RB (1977) The ocular motor defects in progressive supranuclear palsy. Ann Neurol 2: 397403 19 Rivaud-Pechoux S et al. (2000) Longitudinal ocular motor study in corticobasal degeneration and progressive supranuclear palsy. Neurology 54: 10291032 20 Maher ER and Lees AJ (1986) The clinical features and natural history of the SteeleRichardsonOlszewski syndrome (progressive supranuclear palsy). Neurology 36: 10051008 21 Litvan I et al. (1996) Natural history of progressive supranuclear palsy (SteeleRichardsonOlszewski syndrome) and clinical predictors of survival: a clinicopathological study. J Neurol Neurosurg Psychiatry 60: 615620 22 Santacruz P et al. (1998) Progressive supranuclear palsy: a survey of the disease course. Neurology 50: 16371647

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REVIEW
www.nature.com/clinicalpractice/neuro

23 Litvan I et al. (1996) Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele RichardsonOlszewski syndrome): report of the NINDSSPSP international workshop. Neurology 47: 19 24 Belfor N et al. (2006) Clinical and neuropsychological features of corticobasal degeneration. Mech Ageing Dev 127: 203207 25 Davis PH et al. (1985) Atypical presentation of progressive supranuclear palsy. Ann Neurol 17: 337343 26 Gearing M et al. (1994) Progressive supranuclear palsy: neuropathologic and clinical heterogeneity. Neurology 44: 10151024 27 Albert ML et al. (1974) The subcortical dementia of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry 37: 121130 28 Maher ER et al. (1985) Cognitive deficits in the SteeleRichardsonOlszewski syndrome (progressive supranuclear palsy). J Neurol Neurosurg Psychiatry 48: 12341239 29 Grafman J et al. (1990) Frontal lobe function in progressive supranuclear palsy. Arch Neurol 47: 553558 30 Hauw JJ et al. (1994) Preliminary NINDS neuropathologic criteria for SteeleRichardson Olszewski syndrome (progressive supranuclear palsy). Neurology 44: 20152019 31 Wszolek ZK et al. (1998) Clinical neurophysiologic findings in patients with rapidly progressive familial parkinsonism and dementia with pallido-ponto-nigral degeneration. Electroencephalogr Clin Neurophysiol 107: 213222 32 Conrad C et al. (1997) Genetic evidence for the involvement of tau in progressive supranuclear palsy. Ann Neurol 41: 277281 33 Baker M et al. (1999) Association of an extended haplotype in the tau gene with progressive supranuclear palsy. Hum Mol Genet 8: 711715 34 Flament S et al. (1991) Abnormal tau proteins in progressive supranuclear palsy: similarities and differences with the neurofibrillary degeneration of the Alzheimer type. Acta Neuropathol (Berl) 81: 591596 35 Gotz J et al. (2001) Formation of neurofibrillary tangles in P301l tau transgenic mice induced by A42 fibrils. Science 293: 14911495 36 Roy S et al. (1974) Electron microscopic study of neurofibrillary tangles in SteeleRichardsonOlszewski syndrome. Acta Neuropathol (Berl) 29: 175179 37 Pick A (1892) On the relationship between senile brain atrophy and aphasia [German]. Prager Medizinische Wochenschrift 17: 165167 38 Alzheimer AC (1911) On peculiar cases of disease at higher age [German]. Zeitschrift fr die gesamte Neurologie und Psychiatrie 4: 356385 39 Onari K and Spatz H (1926) Anatomical contributions on Picks circumscribed cerebral cortex atrophy (Picks disease) [German]. Zeitschrift fr die gesamte Neurologie und Psychiatrie 101: 470511 40 [No authors listed] (1994) Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester groups. J Neurol Neurosurg Psychiatry 57: 416418 41 Neary D et al. (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51: 15461554

42 Mott RT et al. (2005) Neuropathologic, biochemical, and molecular characterization of the frontotemporal dementias. J Neuropathol Exp Neurol 64: 420428 43 McKhann GM et al. (2001) Clinical and pathological diagnosis of frontotemporal dementia: report of the Work Group on Frontotemporal Dementia and Picks Disease. Arch Neurol 58: 18031809 44 Foster NL et al. (1997) Frontotemporal dementia and parkinsonism linked to chromosome 17: a consensus conference. Conference Participants. Ann Neurol 41: 706715 45 Wilhelmsen KC et al. (1994) Localization of disinhibitiondementiaparkinsonismamyotrophy complex to 17q21-22. Am J Hum Genet 55: 11591165 46 Baker M et al. (2006) Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 442: 916919 47 Morita M et al. (2006) A locus on chromosome 9p confers susceptibility to ALS and frontotemporal dementia. Neurology 66: 839844 48 Hughes A et al. (2003) Tau haplotype frequency in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Exp Neurol 181: 1216 49 Panegyres PK and Zafiris-Toufexis K (2002) Polymorphisms in the tau gene in sporadic frontotemporal dementia and other neurodegenerative disorders. Eur J Neurol 9: 485489 50 Gorno-Tempini ML et al. (2004) Clinical, cognitive and anatomical evolution from nonfluent progressive aphasia to corticobasal syndrome: a case report. Neurocase 10: 426436 51 Houlden H et al. (2001) Corticobasal degeneration and progressive supranuclear palsy share a common tau haplotype. Neurology 56: 17021706 52 Di Maria E et al. (2000) Corticobasal degeneration shares a common genetic background with progressive supranuclear palsy. Ann Neurol 47: 374377 53 Feany MB and Dickson DW (1996) Neurodegenerative disorders with extensive tau pathology: a comparative study and review. Ann Neurol 40: 139148 54 Soliveri P et al. (2003) A case of dementia parkinsonism resembling progressive supranuclear palsy due to mutation in the tau protein gene. Arch Neurol 60: 14541456 55 Tsuboi Y et al. (2005) Increased tau burden in the cortices of progressive supranuclear palsy presenting with corticobasal syndrome. Mov Disord 20: 982988 56 Kertesz A et al. (2005) The evolution and pathology of frontotemporal dementia. Brain 128: 19962005 57 Hodges JR et al. (2004) Clinicopathological correlates in frontotemporal dementia. Ann Neurol 56: 399406 58 Neary D (1997) Frontotemporal degeneration, Pick disease, and corticobasal degeneration. One entity or 3? 3. Arch Neurol 54: 14251427 59 Boeve BF et al. (2003) Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 54 (Suppl 5): S15S19 60 Noble W et al. (2005) Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Proc Natl Acad Sci USA 102: 69906995

Acknowledgments
This work was supported by the Larry L Hillblom Foundation, National Institute on Aging grant P01-AG1972403, and an Alzheimers Disease Research Center grant P50-AG023501.

Competing interests
The authors declared they have no competing interests.

DECEMBER 2006 VOL 2 NO 12 SHA ET AL.

2006 Nature Publishing Group

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