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L

Lewy Body Disease Average course of disease is generally 5–7 years


from diagnosis to death (Schoenberg and Duff
Sarah E. Cook 2011). An examination of risk factors for DLB
Duke University, Durham, NC, USA by Boot and colleagues (2013) found that a clin-
ical diagnosis of DLB (as opposed to pathologi-
cal) was associated with history of depression or
Synonyms anxiety, family history of Parkinson’s disease,
history of stroke, and being an APOE 4 homozy-
Parkinsonism; Parkinson’s disease dementia; gote. Protective factors were noted to be history of
Mild cognitive impairment due to Parkinson’s cancer and caffeine use, although the exact mech-
disease anism by which they protect against DLB is not
known.
This entry will provide a broad overview of
Definition DLB, starting with the relevant neuropathology.
This will provide a framework for understanding
Dementia with Lewy bodies (DLB, also referred the common clinical presentation of DLB, includ-
to as Lewy Body Dementia) is a progressive neu- ing the neurologic, psychiatric and cognitive signs
rodegenerative disease with fluctuations in atten- and symptoms, diagnostic criteria, and treatment
tion and arousal, changes in cognition and sleep, considerations.
psychotic features, and development of problems
with voluntary movement. It has commonalities
with Parkinson’s disease dementia making diag- Neuropathology of Dementia with Lewy
nostic differentiation challenging. It has only been Bodies
recognized as a separate condition since the 1960s
(Troster 2008). DLB is now considered the second On neuropathological examination, DLB is char-
most common form of progressive dementia, fol- acterized by abnormal aggregates of alpha
lowing Alzheimer’s disease (AD) (Latoo and Jan synuclein protein which were called Lewy bodies,
2008), accounting for about 15–35 % of all named after Friederich Lewy who discovered
dementia cases depending on the study (Troster them in the early 1900s in patients with
2008). DLB often manifests earlier in life than Parkinson’s disease (Latoo and Jan 2008). Lewy
some of the other dementias, often with onset bodies are almost universally found in the
between age 50–70 (Schoenberg and Duff 2011). brainstem of individuals with DLB (most often
It affects up to 5 % of older adults (Troster 2008). in substantia nigra and locus ceruleus) and may
# Springer Science+Business Media Singapore 2016
N.A. Pachana (ed.), Encyclopedia of Geropsychology,
DOI 10.1007/978-981-287-080-3_344-1
2 Lewy Body Disease

account for the parkinsonian and sleep symptoms pathology might be identified (Simard
often seen in DLB which will be reviewed later. It et al. 2000).
is believed that this area is the site of initial neu- In distinguishing DLB from Parkinson’s dis-
ropathological change in DLB and that aggrega- ease dementia (PDD), there are some differences
tion of alpha synuclein then ascends sequentially in the pathological changes in the two conditions.
rostrally to the limbic area (including the amyg- According to Donaghy and McKeith who provide
dala, anterior cingulate, entorhinal cortex) and a thorough discussion of the pathological changes
neocortex (frontal, temporal, and parietal lobes) in DLB (Donaghy and McKeith 2014), while both
(Donaghy and McKeith 2014). It is believed that LBD and PDD can have diffuse presence of Lewy
the neuropathological changes in these areas may bodies in certain subcortical and cortical areas,
account for the changes in behavior and cognition there is often more amyloid deposition in the
that are often part of DLB which will be described striatum, alpha synuclein deposition in the hippo-
later. All of these areas of the central nervous campal area, and greater serotonin receptor den-
system are investigated for Lewy bodies during sity in the frontal lobes in DLB compared to
postmortem analysis to assist with making a defin- PDD. Individuals with DLB have less necrosis
itive diagnosis. In addition, Lewy bodies can also in the substantia nigra and less striatal dopamine
be found in the autonomic branch of the peripheral receptor upregulation than those with PDD.
nervous system, which may be related to the In addition to the presence of Lewy bodies,
orthostatic dysfunction that can be seen in DLB. DLB has been associated with other neuropatho-
The pattern of Lewy body involvement within the logical changes, most notably decreased acetyl-
central nervous system is important in diagnosis choline available in the basal forebrain and
(McKeith et al. 2005), but research has found that decreased dopamine in the basal ganglia (Morra
the amount of Lewy bodies present is not strongly and Donovick 2014). Neuroimaging studies sug-
correlated with disease severity or duration of gest that there could be atrophy of cortical and
disease since onset (McKeith et al. 2004). subcortical areas in DLB, including temporal,
It is important to note that the presence of frontal, and parietal lobes as well as in the amyg-
Lewy bodies in the central nervous system is not dala and hippocampus. However, the atrophy is
specific only to DLB. In fact, depending on the not as pronounced as in AD making detection by
study, between 24 % and 55 % of cognitively structural imaging more challenging (Morra and
normal (nondemented) older adults have signifi- Donovick 2014). According to Donaghy and
cant Lewy body burden on autopsy. There is also a McKeith (2014), there are no radioligands avail-
high degree of comorbidity of LBD and other able yet to detect alpha synulcein deposition on
neurodegenerative conditions, especially AD but neuroimaging, as is the case for imaging amyloid
also with vascular disease (Zupancic et al. 2011). deposition in vivo in AD.
McKeith and colleagues (2005) state that the like-
lihood of DLB is directly related to the amount of
Lewy body pathology and inversely related to the Neurologic Presentation of Dementia
amount of AD pathology. But others have recog- with Lewy Bodies
nized the high degree of comorbidity of DLB with
other neurodegenerative conditions by dividing Diagnostic Criteria for Dementia with Lewy
pathological cases into two groups: “common” Bodies
LBD in which both Lewy body and AD pathology DLB is a neurodegenerative process that by defi-
(amyloid plagues and neurofibrillary tangles) are nition includes a progressive cognitive decline
present and both meet neuropathological criteria that interferes with daily functioning (i.e., must
and the second group is called a “pure” DLB in have dementia), with motor features starting after,
which only Lewy bodies are of sufficient severity concurrently, or within 1 year of these cognitive
to meet neuropathological criteria but other symptoms (Donaghy and McKeith 2014). If
motor features are present for longer than 1 year
Lewy Body Disease 3

before cognitive symptoms first present, then has shown >75 % sensitivity and 90 % spec-
Parkinson’s disease dementia is typically diag- ificity for detecting DLB from other cause
nosed rather than DLB (Rongve et al. 2015). Clin- dementia; Zupancic et al. 2011)
ical diagnosis is accomplished with history of
signs and symptoms as well as physical and neu- In addition to the core and suggestive features
rological examinations, usually by a neurologist. already mentioned above, there are other signs
As with some several other dementias, definitive that are frequently seen in DLB, including: auto-
confirmation of diagnosis is not possible until nomic dysfunction which can lead to falls and/or
pathological examination postmortem. syncopal episodes, delusional beliefs and/or hal-
According to the most widely accepted criteria lucinations in modalities other than visual, incon-
for DLB by McKeith and the DLB Consortium tinence, mood disturbance, and slow wave
(McKeith et al. 2005), there are core features of activity on EEG with temporal sharps (Donaghy
DLB and then features that help support the diag- and McKeith 2014).
nosis, often called suggestive features. In order to If psychotic symptoms are present, the possi-
meet criteria for probable DLB, in addition to the bility of antiparkinsonian medications causing
progressive cognitive decline/dementia, an indi- hallucinations needs to be ruled out, as several of
vidual needs to have either two or more core these medications can induce hallucinations
features or one core feature and one suggestive among myriad other potential side effects. The
feature. timeline of onset of symptoms should help clarify
if this is the case, but if the hallucinations persist
Core Features of DLB after discontinuation and clearance of the possibly
1. Fluctuations in attention or arousal leading to offending medication, then DLB should remain
disorientation and mental status changes over on the differential (Zupancic et al. 2011).
hours or days (least common core feature;
Donaghy and McKeith 2014) Differentiation from Other
2. Visual hallucinations, most often well-formed Neurodegenerative Conditions
but not threatening to the patient and often DLB is often mistaken for AD or other neurode-
images of people or animals (70–85 % of generative conditions due to commonalities in
DLB cases; Morra and Donovick 2014) clinical presentation. Given the high rate of
3. Parkinsonism, most often bradykinesia, rigid- dementia in Parkinson’s disease (see Parkinson’s
ity, or postural changes as opposed to the disease entry in this volume by Cook for review
tremor commonly seen in PD (60–92 % of on Parkinson’s disease dementia; Cook 2016) and
DLB cases; Zupancic et al. 2011) overlapping clinical features, it is important to
differentiate DLB from Parkinson’s disease
Suggestive Features of DLB dementia (PDD). If the onset of cognitive prob-
1. REM sleep behavior disorder, which is an lems occurs more than a year, and most often
enacting of dreams during rapid eye movement several years, after the onset of motor symptoms,
sleep, can start decades before other clinical it is considered to be PDD and not DLB. If the
manifestations, up to 93 % of individuals cognitive symptoms present first, then it is more
with this disorder go on to develop a form of likely DLB (Rongve et al. 2015). In addition to
synucleinopathy, including DLB, if followed examining onset of symptoms, individuals with
long enough (Donaghy and McKeith 2014) PDD often respond to levodopa therapy better
2. Sensitivity to neuroleptic (antipsychotic) med- than individuals with DLB (Zupancic
ications marked by the development of extra- et al. 2011). There is increasing speculation that
pyramidal signs in mild cases but sedation and PDD and DLB may be syndromes along one
fever possible with more severe reaction continuum for a few reasons. First, some authors
3. Low uptake of dopamine transporter in basal have suggested that the 1 year rule between cog-
ganglia on SPECT or PET imaging (research nitive and motor symptoms is arbitrary. Second,
4 Lewy Body Disease

there are not well-accepted definitive diagnostic leading to more descriptive labels (e.g., amnestic
criteria for diagnosing PDD in vivo to assist with MCI, nonamnestic MCI) and acknowledgement
separating them. Third, they have striking neuro- that not all MCI will lead to AD, but that some will
pathological similarities postmortem. Fourth, progress to other dementias including DLB
cognitive domains impacted are relatively similar. (Molano et al. 2010). There has been very little
And lastly, therapeutically, there appears to be research about a possible prodromal phase in
little difference in medication efficacy between DLB, although some preliminary information
them (Rongve et al. 2015). has been provided from studies looking at conver-
Distinguishing DLB from an Alzheimer’s sion of MCI to dementia. As outlined in Troster
dementia (AD) is best done by examining the (2008), one study found that in a group of 34 indi-
clinical history of symptoms and if available, neu- viduals with amnestic MCI that later converted to
ropsychological testing data. Specifically, AD dementia and came to autopsy, three had a patho-
most often does not present with parkinsonism, logical diagnosis of DLB and one had a final
nor are visual hallucinations common early in the clinical diagnosis of DLB. Another study of
disease course of AD. Individuals with DLB are 440 cognitively normal individuals and 141 indi-
more likely to have autonomic signs, such as viduals with MCI were followed for 30 months
orthostatic hypotension and constipation (Morra and found possible DLB in 10 participants, 4 who
and Donovick 2014). On neuropsychological test- had normal test findings at baseline, 4 who had
ing, AD affects the medial temporal lobes and nonamnestic MCI at baseline, and two with
typically begins with progressive short-term amnestic MCI at baseline.
memory loss, with memories not being triggered In another related study, researchers at the
by cueing. In DLB, if there are changes in mem- Mayo Clinic (Molano et al. 2010) examined
ory, it is often much later in the disease course and their databases to find cases of MCI that later
qualitatively different, such that a patient with progressed to DLB to find clinical correlates of a
DLB will often benefit from repetition and cueing. pathological diagnosis of DLB at autopsy. Only
Generally speaking, cognitive symptoms in DLB eight cases were identified, including six males.
would be considered more subcortical in nature Seven of the cases had REM sleep behavior dis-
(i.e., attention, processing speed, and/or executive order with onset preceding cognitive symptoms in
deficits), as opposed to the cortical features in six patients by a median of 10 years. Six patients
AD. However, many studies have noted that indi- had visual hallucinations, six patients had prob-
viduals with DLB have more problems with con- lems with executive functioning, and six patients
structional skills than individuals with AD. A had problems with visuospatial functioning on
matched study of decline in individuals with formal testing. Seven patients had parkinsonism,
DLB and AD by Stavitsky and colleagues with a median onset of 3 years after cognitive
(2006) also confirmed this finding, but also symptoms. They provide clinical history includ-
found that those with DLB had more problems ing progression and course of symptoms for some
with carrying out everyday skills earlier than indi- of these cases to show the heterogeneity in DLB.
viduals with AD. According to Donaghy and McKeith (2014), a
study is now underway to learn more about not
Is There a Prodrome to Dementia with Lewy only the prodromal phase but also clinical markers
Bodies? of those who eventually develop DLB using an
In Alzheimer’s disease, the most common form of at-risk group, those with REM sleep behavior
dementia, there is a large literature about a pro- disorder.
drome, which has been called mild cognitive
impairment (MCI). While initially conceived to Treatment in Dementia with Lewy Bodies
be the prodrome for AD, research has found that Since DLB is a progressive neurodegenerative
there is heterogeneity in clinical symptoms and condition, the prognosis is poor. As noted earlier,
neuropsychological test performance in MCI, survival following diagnosis is often relatively
Lewy Body Disease 5

short compared to AD, with estimates of about (PD), some of these medications can cause or
5–7 years from diagnosis (Morra and Donovick worsen hallucinations. In general, individuals
2014). The cognitive deficits in DLB are thought with DLB tend to respond less to such treatment
to arise at least partially from the cholinergic than patients with PD, which can help in the
decline, and therefore research has examined if differential diagnosis. If such a treatment is con-
acetylcholinesterase inhibitors, mostly used in sidered in DLB, dosing is often started low with
Alzheimer’s disease, would be beneficial for indi- titration being slow with regular monitoring of
viduals with DLB and PDD. In a recent Cochrane symptoms (Zupancic et al. 2011).
review on this topic by Rolinski and others
(2012), a total of six clinical trials were consid-
ered. However, there was only one study with Neuropsychological Presentation
exclusively DLB patients (McKeith et al. 2000). of Dementia with Lewy Bodies
The Cochrane review suggested that in PDD, the
use of acetylcholinesterase inhibitors significantly There are several neuropsychological deficits seen
improved global assessment, cognition, behavior, in individuals with DLB, with deficits primarily in
and activities of daily living. In the single trial attention, working memory, and other executive
with only DLB cases randomized to treatment functions as well as visual perception and con-
with rivastigmine or placebo by McKeith and struction. Memory is much less impacted early in
colleagues (2000), those on rivastigmine had the course of disease, and semantic knowledge is
symptomatic benefit, primarily with respect to often intact (Schoenberg and Duff 2011). Each of
decreasing apathy, anxiety, and hallucinations. these cognitive domains will be discussed in more
Once the drug was withdrawn, these benefits detail.
washed out. In a review by Troster (2008), the specific
In a more recent meta-analysis by Stinton and impairments that have been found in literature
colleagues (2015) on pharmacological treatment are discussed, particularly as it relates to AD and
of DLB, they too found that acetylcholinesterase PDD. For attention, individuals with DLB often
inhibitors (donepezil and rivastigmine) were help- have significant problems with attention skills,
ful for cognitive symptoms, delusions, and activ- including tasks of basic attention, complex or
ities of daily living. They concluded that divided attention, sustained attention, and cancel-
memantine, a different class of medication used ation/visual search. Such skills have been found to
in AD, had limited effectiveness in treating symp- often be worse for DLB than for AD. Other higher
toms of DLB but was tolerated well. In terms of level executive skills such as abstraction, thinking
antipsychotics for psychiatric symptoms, they flexibly, and judgment follow a similar pattern in
found that most agents had a high degree of that they are more impacted in DLB compared to
adverse events or were generally ineffective. AD. It is posited that the dysfunction of basal
Instead of using antipsychotics for the neuropsy- forebrain cholinergic system is responsible for
chiatric symptoms often seen in DLB, which can these deficits in DLB (Troster 2008).
include depression, anxiety, as well as psychotic Individuals with DLB often have deficits on
symptoms, treatment with selective serotonin tests of visual perception and construction. For
reuptake inhibitors (SSRIs) and/or serotonin- example, they often have problems copying a
norepinephrine reuptake inhibitors (SNRIs) is picture accurately, matching figures, or
often considered. Psychiatric medications that conducting a visual search. Given the possibility
reduce acetylcholine should be avoided so as to of motor problems in individuals with DLB, one
not increase cognitive problems (Morra and might think that such deficits could simply be
Donovick 2014). related to the motor demands of testing. However,
While dopamine agonists, such as levodopa, on deeper examination of the deficits across a
that increase the amount of dopamine in the brain wide array of tests, it is more likely that the deficits
are the first line treatment for Parkinson’s disease may be secondary to problems with praxis and
6 Lewy Body Disease

perceptual processing. Individuals with DLB with Cross-References


visual hallucinations may have particularly poor
visual processing even compared to others with ▶ Dementia with Lewy Bodies
DLB but without visual hallucinations. It is ▶ Parkinson's Disease
believed that the deficits in visual processing are
related to dysfunction in the two visual streams,
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