|
Overview
Dementia with Lewy Bodies (DLB) is the second most common form of
neurodegenerative dementia after Alzheimer's disease (AD), comprising
10-15% cases of dementia. Rather than a single entity, DLB consists
of a heterogenous group of disorders that are characterized clinically
by a progressive decline in cognitive function and pathologically
by the presence of Lewy bodies (LBs) in the cerebral cortex. The following
review will attempt to clear much of the misconception about DLB as
well as describe the associated clinical and pathologic features. What
is a Lewy Body?
View
Lewy Body Neuropathology The Lewy body (LB) was first described by Dr. Freidrich Lewy in 1912
in the brain of a patient with Parkinson's disease (PD). Since that
time, LBs have been described in virtually all PD cases in the large
neurons (brain cells) that produce the neurochemical dopamine located
in a part of the brainstem called the substantia nigra. In addition
to the substantia nigra neurons, LBs may be found in other populations
of neurons that degenerate in PD in the cerebral cortex and brainstem.
LBs are filamentous inclusions within neurons. They are composed of
a protein known as alpha-synuclein. The normal function of alpha-synuclein
is unknown at the present time. Other proteins have been described
in LBs but are not thought to be the major building blocks. LBs in
the substantia nigra typically have a characteristic spherical appearance
with a loose radiating array of filaments in the periphery or "corona"
surrounding a matted meshwork of filaments in the center or "core". It was not until almost 50 years later that LBs were described in
cortical neurons in a severely demented patient. This is due to the
more inconspicuous appearance of cortical LBs by light microscopy.
In contrast to the characteristically round nigral LBs, LBs in cortical
neurons generally assume a more irregular geometry and extend into
the proximal segments of the neuronal processes. Today LBs in the brain are best demonstrated with the use of specific
antibodies against the alpha-synuclein protein. These antibodies have
helped to greatly understand the vast spectrum of neurodegenerative
disorders that contain LBs, most of which lead to eventual cognitive
impairment and dementia.
View Pictures of Lewy
Body Neuropathology What are Lewy Body Dementias? Parkinson's disease (PD) is the most common neurodegenerative movement
disorder affecting more than 500,000 people in the US. The cardinal
features of PD include resting tremor, slowness of movement (bradykinesia),
increased muscle tone (cogwheel rigidity) and a tendency to lose one's
balance (postural instability). Dementia is a variable presentation
in PD, typically occurring late in the course of the disease. Statistics
vary, with reports ranging from 20-60% of patients eventually developing
some cognitive decline. The dementia that occurs in PD has not been
extensively characterized but is thought to involve retrieval of previously
learned information and slowed processing of new information. Alzheimer's disease (AD) is an irreversible, progressive brain disorder
that occurs gradually and results in memory loss, unusual behavior,
personality changes, and a decline in thinking abilities. It is the
most common form of dementing illness among middle and older adults,
affecting over 4 million Americans and many millions worldwide. The
earliest symptoms often include loss of recent memory, faulty judgment,
and changes in personality. Often, people in the initial stages of
AD think less clearly and forget the names of familiar people and
common objects. Later in the disease, they may forget how to do simple
tasks like washing their hands. Eventually, people with AD lose all
reasoning abilities and become dependent on other people for their
everyday care. Approximately 25% of AD patients develop PD-like symptoms
during the course of their illness. Thus there is a common but still
enigmatic overlap between AD and PD. Increasing interest in understanding the clinical and pathologic
basis of DLB has in part been driven by the expanding spectrum of
LB-related disorders. LBs similar to the nigral LBs found in PD patients
have been detected in cortical neurons of PD patients with dementia.
The presence of numerous cortical and subcortical LBs, senile plaques
and neurofibrillary tangles defines a subtype of AD with parkinsonian
features sometimes referred to as the LB variant of AD. Furthermore
there is a smaller percentage of demented patients who present with
extrapyramidal (Parkinsonian) features, visual hallucinations and
an AD-like dementia who pathologically have only cortical LBs without
significant plaques and tangles. These patients have previously been
classified as having "pure" diffuse LB disease. To compound
the problem even further, LBs are found in brain regions of patients
with familial (hereditary) forms of AD and in older individuals with
Down's syndrome. LB-like inclusions have also been found in the brains
of patients with Amyotrophic Lateral Sclerosis (Lou Gehrig's Disease)
and several other rare neurodegenerative disorders (see
Table 1). In recognition of the fact that LB dementias are the second most
common form of dementia after AD and because of the confusion about
the nomenclature and diagnostic criteria, a consortium formalized
the clinical and pathologic diagnosis of these diverse disorders under
the general term of DLB. Incidence and Prevalence
of DLB Dementia is a major public health problem crossing gender, socioeconomic
and ethnic lines. The incidence of dementia increases with age and
the prevalence increases every decade after age 65, so that by age
85 nearly 50% of the population may be affected. While AD is the most
common form of dementia, accounting for 65% of cases, it is not the
only cause of dementia. DLB is the second leading cause of dementia
and is thought to be responsible for 10-15% of all cases of dementia.
The true prevalence of LB-related dementias may be substantially greater,
however. For example, 25% of AD patients develop PD-like symptoms
and many of these patients will have LBs on autopsy. PD is the most
common form of movement disorder affecting 1 in 100 persons over the
age of 60. Estimates of the yearly incidence of dementia in PD (most
highly correlated with the presence of cortical LBs) increases with
age from 2.7%/year (ages 55-64) to 13.7%/year (ages 70-79). Therefore
the combined sum of patients with dementia and Parkinsonism may approach
2 million individuals. In general, DLB affects a similar age group to AD patients with a
mean age of 74.7 years. The male to female ratio approaches 1. There
has been a suggestion that DLB patients progress at a more rapid rate
to severe stages of dementia compared to AD, although this is difficult
to fully substantiate. Compared to PD, DLB is also thought to be more
rapidly progressive. Clinical Symptoms of DLB Following a consensus consortium in 1996, diagnostic criteria for
DLB were devised. Clinical features that were most characteristic
of DLB were a progressive dementia and at least 2 of the following
three characteristics: (1) extrapyramidal (Parkinsonian) signs (typically
bradykinesia, rigidity and postural instability, but rarely tremor);
(2) fluctuating course; and (3) prominent visual hallucinations. Other
features that are supportive but not required for diagnosis include:
(1) increased sensitivity to neuroleptics (antipsychotic medications
such as haloperidol); (2) repeated falls; (3) syncope (fainting spells)
or transient loss of consciousness; (4) systematized delusions (discussed
below); and (5) hallucinations in other modalities (auditory, olfactory,
etc). The fluctuation in cognition has been the most confusing aspect of
the diagnosis and the most difficult feature to identify and agree
on. Cognitive fluctuation has been defined as the spontaneous impairment
of alertness and concentration (appear drowsy but awake, look dazed,
not be aware of what is going on) that varies from day to day or week
to week (i.e. become worse for a while then improved, up and down
course). Suggestions have been made that fluctuation of 5 points or
more in the Mini-mental State Exam (a commonly used psychological
test) total score over 3 administrations in a 6-month period can be
considered significant fluctuation. Of course, the problem with this
recommendation is that it would be rare to evaluate a patient so often
in a clinician's office unless the patient was part of a specific
research protocol. More recently, several rating scales have been
proposed to quantify the presence and severity of fluctuation, one
of which can be administered by the caregiver. Extrapyramidal (Parkinsonian) signs have been correlated with the
severity of dementia in DLB. There are several features that may help
distinguish DLB from PD: 1) myoclonus (an irregular jerking movement),
2) absence of rest tremor, 3) no response to levodopa or 4) no perceived
need to treat with levodopa. These signs were 10 times more likely
to be associated with DLB than PD and are not characteristic of AD.
Although clinicians tend to think of DLB only in the presence of Parkinsonian
signs, these features are not absolutely required for the diagnosis.
Several clinicopathological studies have demonstrated that in the
presence of a progressive dementia, fluctuation and visual hallucinations,
the clinical diagnosis of DLB can be made. Neuropsychiatric Spectrum
of DLB Studies retrospectively examining the psychometric profile of patients
with DLB using Mini-mental State Exam (MMSE) scores, the information-memory-concentration
scores of the Blessed scale or the Mattis Dementia rating scale have
demonstrated that patients with DLB perform worse than AD patients
in tests of visual tracking and visual attention shifting. DLB patients
also performed worse with respect to verbal and motor initiation capacities
and in comparison of the ability to perform similarities. With regard
to visuospatial abilities, DLB patients perform more poorly than AD
patients on visuospatial tests such as block design and clock draw
testing do. DLB patients also perform worse on the copying portion
of tasks such as construction subtests. Patients with DLB performed
equally as poor as AD patients in regards to verbal and semantic memory,
naming, abstraction and episodic memory tasks. When these same tasks were applied prospectively to patients who
met clinical criteria for DLB, these patients were found to be more
impaired than AD patients in areas of visuospatial working memory,
timed attention tasks, and copying two- and three- dimensional drawings
and the clock draw. When followed longitudinally, DLB patients tended to experience a
more rapid decline than seen in AD, especially when motor symptoms
were present. Patients with extrapyramidal motor symptoms deteriorated
67% faster on the MMSE (4.5 points per year) than patients without
motor symptoms (2.7 points per year). Another study comparing DLB
and AD patients reported that the average rate of MMSE decline in
DLB was 5.8 points per year compared to 4.1 points per year in AD.
One study looking at patients with AD and extrapyramidal symptoms
demonstrated greater deficits on tests of verbal comprehension, automatic
speech, semantic fluency and praxis than AD alone. In summary, longitudinal studies have demonstrated a significantly
faster functional or cognitive decline in DLB or in AD patients with
Parkinsonism compared to AD. The exact profile of decline and the
time period for this decline is still lacking. Behavioral Spectrum of DLB Visual hallucinations are the most frequently reported psychotic
symptom in DLB followed by delusions. Compared with AD, DLB patients
are more likely to experience hallucinations and delusions early in
the course of the illness. Hallucinations are commonly well-formed
visual hallucinations although auditory hallucinations can also be
seen more commonly in DLB compared to AD. Hallucinations in other
modalities (olfactory, gustatory, tactile) are much less common. The visual hallucinations are more prominent in those patients with
poor eyesight. Those patients who experienced hallucinations early
in the course of their illness, regardless of visual acuity were more
likely to show cortical LBs on autopsy than those with hallucinations
of late onset. Hallucinations generally appear prior to the 4th
year of symptoms and may persist till death in 71% of cases. The most common form of delusions in DLB are misidentification delusions
(i.e. delusions that someone is in the home, delusions that the patient's
home is not his/her own or that TV or movie personalities are actually
present in the room) followed by persecutory/ paranoid delusions (delusions
that people are stealing things or conspiring against the patient),
phantom boarder delusions (the belief that an unwanted person is living
in the house) and abandonment delusions. Depression is significantly more common in DLB compared to AD at
any stage of illness. Other behavioral manifestations include anxiety,
irritability, apathy, violent behavior/aggressivity, nocturnal confusion/insomnia
and restlessness/agitation. In summary, behavioral disturbances, especially psychosis are much
more common in DLB than in AD. It appears that at the onset, the DLB
patient is more likely to experience visual hallucinations, delusions,
visual misperceptions, major depression and depressive symptoms (apathy,
anxiety or irritability) than patients with AD. Pathologic Diagnosis of DLB LB disorders can be divided into three groups on the basis of LB
pathology: 1) Type A, diffuse type; 2) Type B, transitional type and
3) Type C, brainstem type related to Parkinson's disease. The diffuse
type has been further classified into two subgroups: 1) the "common"
form in which senile plaques and neurofibrillary tangles in sufficient
quantity to meet criteria for AD are present in addition to cortical
LBs and 2) the "pure" form in abundant cortical Lewy bodies
are present but plaques and tangles are not of sufficient quantity
to meet criteria for the diagnosis of AD. It should be noted that
the "common" form is indeed more common comprising up 90%
of cases. This nomenclature can be confusing and this lead to the
formation of a consensus committee to devise pathologic criteria to
standardize the diagnosis and classified all the subgroups under the
generic term DLB. The defined pathologic criteria for DLB requires LBs as essential
for the diagnosis. Associated but not essential features
includes Lewy-related dystrophic (degenerate) neurites, plaques, tangles,
regional neuronal loss especially in the brainstem areas associated
with PD (substantia nigra) and basal forebrain (nucleus basalis of
Meynert), microvacuolation (spongiform changes or "holes" found in the brain substance), synapse loss (loss of communication
connections between neurons) and neurochemical deficits. In order to substantiate the pathologic diagnosis, the consensus
criteria recommends examination of at least three cortical brain regions
(frontal, parietal and temporal), two limbic (associative, related
to behavior) regions (anterior cingulate and transentorhinal cortices)
and brainstem regions (substantia nigra, locus ceruleus and dorsal
vagal nucleus) to establish a definite neuropathological diagnosis.
In addition, several other areas may show substantial LB pathology
including the amygdala, insula, anterior (ventral) striatum and basal
forebrain. Cortical LBs are found in small and mid-sized neuron, in predominantly
deeper layers of the cortex of every lobe with a predilection for
limbic structures (cingulate, insula, anterior frontal, medial temporal
areas). Neuritic degeneration of the hippocampal neurons (in the CA2/3
region) is associated with LB disorders but is not seen in AD or normal
aging. These dystrophic neurites can also been in other areas of the
cortex and in subcortical structures. Synaptic loss can be seen in the medial temporal lobe structures
important in memory and behavior (perforant pathway). These degenerate
synaptic terminals contain aggregations of the same proteins that
are found in LBs and the dystrophic Lewy neurites (alpha-synuclein).
In addition, two closely related proteins (beta-synuclein and gamma-synuclein)
aggregate in the perforant pathway in LB disorders but not in AD or
normal aging. There are significant neurochemical deficits in DLB. There is a reduction
in the cortical cholinergic enzyme choline acetyltransferase that
has been found to be more severe in persons with hallucinations (80-85%
reduction) than in those without (50-55%). These reductions were greatest
in neocortical areas (parietal, temporal) and were more marked in
hippocampus and entorhinal cortex than seen in AD. Unlike AD however,
there appears to be at least some attempt at compensation for this
deficit as the post-synaptic acetylcholine receptors are increased
in DLB. In addition to reductions in acetylcholine, deficits in dopamine
have been described. Losses of 40-60% of dopamine in DLB brains have
been reported compared with an 80% loss of dopamine seen in PD. There
is also a significant loss of the ventral tegmental neurons in DLB.
These neurons are the source of dopamine projections to the limbic
areas that are vulnerable to LB formation. Of all these potential markers, it is the presence of cortical LBs
that correlates most closely with the severity of dementia. In an
analysis of patients with DLB, the presence of 3 or more cortical
LBs per high power microscopic field is a more sensitive and specific
marker of dementia that the presence of plaques, tangles, dystrophic
neurites or even the combination of all markers of dementia pathology.
The most sensitive tool to examine for LBs is staining of brain sections
with an antibody against the alpha-synuclein protein. Evaluation of DLB The evaluation of DLB is dependent on an informed source of
history in order to establish and determine the time-course of dementia,
motor symptoms, hallucinations and fluctuations. This can best be
accomplished by a clinician with experience in neurodegenerative disorders.
The physical examination often will give clues to the presence of
Parkinsonian signs as well as rule out other potential medical and
neurologic causes of dementia. There is no laboratory test specific for the diagnosis of DLB. Laboratory
evaluation is used to exclude other potential causes of dementia and
can include an evaluation of thyroid hormone, vitamin B12 levels,
liver function tests and a test for syphilis. Neuroimaging with magnetic resonance imaging (MRI) may reveal cerebral
atrophy. Several studies looking at functional imaging with positron
emission tomography (PET) showed a more severe glucose hypometabolism
in DLB compared with AD in the cerebellar hemispheres and the temporal-parietal-occipital
association cortices, especially in the medial and lateral occipital
lobes. This is in contrast to AD where the greatest deficits have
been found in the medial temporal and cingulate regions. Psychometric testing, although varying from center to center
should include tests for verbal and non-verbal memory, attention,
concentration, abstraction, visuospatial abilities and construction.
Another useful tool in evaluating the patient would include an assessment
of activities of daily living including personal hygiene/grooming,
ambulation, dressing and feeding. Treatment of DLB Because of the known deficits in the cholinergic system and the knowledge
of compensatory mechanisms, there has been interest in the use of
the centrally active cholinesterase inhibitors for the treatment of
the cognitive symptoms of DLB. Studies with donepezil have demonstrated
improvements in hallucinations with some suggestion of improvement
in cognition and overall function. More recently, trials with rivastigmine
have suggested that there may be greater improvement in cognition
and neuropsychiatric symptoms than similarly treated patients with
AD. Behavioral domains that improved on rivastigmine included apathy,
indifference, anxiety, delusions, hallucinations and aberrant motor
behavior. These effects were lost once the medication was withdrawn.
Studies looking at the role of galanthamine in DLB are underway. Perhaps even more disturbing than the cognitive symptoms
(particularly to the caregiver) are the psychotic and behavior manifestations
of DLB. As mentioned above, these symptoms can include agitation,
delusions, and hallucinations. Management of these issues has been
problematic because of problems with DLB patients taking antipsychotic
medications. The early clinical diagnosis of DLB is critical given
that DLB patients are more likely to experience an adverse reaction
to classic neuroleptics such as haloperidol compared to AD patients
(81% compared to 29%). In order to lessen the risk of potential side
effects, treatment strategies have focused on the use of atypical
neuroleptics such as olanzapine, risperidone, and quetiapine. These
newer agents have significantly less binding to dopamine receptors
that the classic neuroleptics however, an exacerbation of extrapyramidal
symptoms can be seen with risperidone and olazapine which still have
an anti-dopamine mode of action. Quetiapine works on the serotonin
system and does not appear to worsen motor symptoms. Depressive features also need to be addressed. Many of the antidepressant
medications available today are safe and effective for the treatment
of depression in the geriatric population. Among the most commonly
prescribed antidepressants are the serotonin reuptake inhibitors such
as sertraline, fluoxetine and paroxetine. References Fernandez HH, Freidman JH, Jaques C, Rosenfeld M. Quetiapine for
the treatment of drug induced psychosis in Parkinson's disease. Movement
Disorders 1999;14:484-487. Galvin JE, Lee VM-Y, Trojanowski JQ. Synucleinopathies: Clinical
and pathological implications. Archives of Neurology 2001;58:186-190. Galvin JE, Uryu K, Lee VM-Y, Trojanowski JQ. Axonal pathology in
Parkinson's disease and Lewy body dementia hippocampus contains alpha-,
beta- and gamma-synuclein. Proceedings of the National Academy of
Science 1999;96:13450-13455. Galvin JE, Lee VM-Y, Schmidt ML, Tu PH, Iwatsubo, T, Trojanowski
JQ. Pathobiology of the Lewy body. Advances in Neurology 1999;80:313-324. Hirono N, Mori E, Tanimukai S, Kazui H, Hashimoto M, Hanihara T,
Imamura T. Distinctive neurobehavioral features among the neurodegenerative
dementias. Journal of Neuropsychiatry and Clinical Neurosciences 1999;11:498-503. Hurtig HI, Trojanowski JQ, Galvin JE et al. Alpha-synuclein cortical
Lewy bodies are markers for dementia. Neurology 2000;54:1916-1921.
McKeith I, Del Ser T, Spano P, Emre M, Wesnes K, Anand R, Cicin-Sain
A, Ferrara R, Spiegel R. Efficacy of rivastigmine in dementia with
Lewy bodies: a randomised, double-blind, placebo-controlled international
study. Lancet 2000;356:2024-2025. McKeith IG, Galasko D, Kosaka K et al. Consensus guidelines for the
clinical and pathologic diagnosis of dementia with Lewy bodies. Neurology
1996;47:1113-1124. Simard M, van Reekum R, Cohen T. A review of the cognitive and behavioral
symptoms in dementia with Lewy bodies. Journal of Neuropsychiatry
and Clinical Neurosciences 2000;12:425-450.
For more information
Contact your local Alzheimer's
Association chapter or American
Parkinson's Disease Association chapter. For evaluation of Dementia with Lewy bodies in St. Louis, contact
the Memory Diagnostic Center at Washington University at 314-286-1967.
For more information on DLB research, see:
Dr. Galvin's Home Page or NINDS
Dementia With Lewy Bodies Information Page
|
