Dementia with Lewy Bodies: What is it and how do I treat it ?
James B. Leverenz, M.D. Departments of Neurology and Psychiatry and
Behavioral Sciences University of Washington School of Medicine and
VA Northwest Network Mental Illness and Parkinsons Disease
Research, Education, and Clinical Center VA Northwest Network
Mental Illness and Parkinsons Disease Research, Education, and
Clinical Centers Slide 2 How do you define a disease ? Genetics
> Pathology > Clinical ? Genetics > Pathology >
Clinical ? mutation causes pathology leading to the clinical
presentation What about known pathogens ? What about known
pathogens ? e.g. syphilis, mad cow disease (exposure superimposed
on genetic risk). Becoming difficult to define a disease Becoming
difficult to define a disease Slide 3 Slide 4 Slide 5 History of
Parkinsons Disease 138-201 Galen describes resting tremor
1817Initial description of disease by James Parkinson
1859/68Trousseau describes intellectual decline 1861-95Charcot and
Brissaud emphasize rigidity, bradykinesia and psychic troubles
Slide 6 Clinical Symptoms in Parkinsons Disease Tremor
(resting)Tremor (resting) RigidityRigidity BradykinesiaBradykinesia
Postural instabilityPostural instability Slide 7 Parkinsons Disease
Slide 8 Slide 9 Pathology in Parkinsons Disease Clinical history of
parkinsonismClinical history of parkinsonism Neuronal loss and Lewy
body inclusions in the substantia nigra, locus coeruleus, basal
forebrain and cerebral cortexNeuronal loss and Lewy body inclusions
in the substantia nigra, locus coeruleus, basal forebrain and
cerebral cortex Slide 10 Lewy Body Inclusions Characteristic
inclusions in substantia nigra neurons of patients with Parkinsons
diseaseCharacteristic inclusions in substantia nigra neurons of
patients with Parkinsons disease Immunoreactive for neurofilaments,
ubiquitin and alpha- synuclein, but not tau (NFT are tau and
ubiquitin positive)Immunoreactive for neurofilaments, ubiquitin and
alpha- synuclein, but not tau (NFT are tau and ubiquitin positive)
In substantia nigra it is cytoplasmic, round, eosinophilic with
clear haloIn substantia nigra it is cytoplasmic, round,
eosinophilic with clear halo In cortex less distinct appearance,
best visualized with alpha-synuclein immunohistochemistryIn cortex
less distinct appearance, best visualized with alpha-synuclein
immunohistochemistry Slide 11 Pathology in Parkinsons Disease Slide
12 Slide 13 Slide 14 History of Dementia with Lewy Bodies 1961First
report of cortical LBs in dementia (Okazaki et al) 1974Start of
clinical reports of parkinsonism in AD 1986High frequency of LB in
AD patients (Leverenz & Sumi) 1990Lewy body variant proposed
(Hansen et al) 1990Diffuse Lewy body disease (Crystal et al)
1996Dementia with Lewy bodies (Consortium on DLB) Slide 15
Consensus Criteria for Dementia with Lewy Bodies 1. Progressive
cognitive decline with loss of normal social and occupational
function: loss of memory, attention, frontal subcortical skills,
visuospatial ability 2. Two of the following: a. fluctuating
cognition, attention, alertness b. visual hallucinations c. motor
features of parkinsonism 3. Supportive features: falls, syncope,
LOC, neuroleptic sensitivity, delusions, non-visual hallucinations
Slide 16 Consensus Criteria for Dementia with Lewy Bodies It is
suggested that if dementia occurs within 12 months of the onset of
extrapyramidal motor symptoms, the patient should be assigned a
primary diagnosis of possible DLB If the clinical history of
parkinsonism is longer than 12 months, PD with dementia will
usually be a more appropriate diagnostic label Slide 17 Consensus
Criteria for Dementia with Lewy Bodies Criteria good predictor of
Lewy body pathology (with or without concomitant AD pathology) -
high positive predictive value Criteria good predictor of Lewy body
pathology (with or without concomitant AD pathology) - high
positive predictive value Criteria poor predictor of the absence of
Lewy body pathology - low negative predictive value Criteria poor
predictor of the absence of Lewy body pathology - low negative
predictive value Slide 18 Lewy Body Frequency in Alzheimers Disease
198628% of AD (Leverenz and Sumi) 198755% of AD (Ditter and Mirra)
199521% in CERAD registry (Hulette et al) 1998 23% in community
based series (Lim et al) 1996Dementia with Lewy bodies, largest
pathological subgroup after pure AD (Consortium on DLB) Slide 19
Lewy Body Frequency in Alzheimers Disease 1998 to 20001998 to 2000
Using ASN immunohistochemistry and amygdala sampling 63% PS-1/APP
mutation AD 50% of Down syndrome 61% of sporadic AD 64% PS-2
mutation AD Slide 20 Slide 21 Lewy Body Frequency in Alzheimers
Disease 20032003 33 % of AD cases in a community- based sample
alpha-synuclein staining amygdala sampling There appears to be a
sampling- bias in the frequency of LB pathologyThere appears to be
a sampling- bias in the frequency of LB pathology Slide 22
Consensus Criteria for Dementia with Lewy Bodies Pathology
Essential for diagnosis of DLBEssential for diagnosis of DLB Lewy
bodies Associated but not essentialAssociated but not essential
Lewy-related neurites Plaques (all morphologic types)
Neurofibrillary tangles Regional neuronal loss (substantia nigra,
locus coeruleus, basal forebrain) Microvacuolation and synapse loss
Neurochemical abnormalities and neurotransmitter deficits Slide 23
Pathology in Dementia with Lewy Bodies Neuronal loss and LBs in
substantia nigraNeuronal loss and LBs in substantia nigra Cortical
LBs and CA-2 ubiquitinated fibersCortical LBs and CA-2
ubiquitinated fibers Full AD pathology (SP/NFT), ~ 80%Full AD
pathology (SP/NFT), ~ 80% Restricted AD pathology (diffuse SP and
restricted NFT distribution), ~ 20%Restricted AD pathology (diffuse
SP and restricted NFT distribution), ~ 20% Slide 24 Pathology in
Dementia with Lewy Bodies Substantia nigra Slide 25 Pathology in
Dementia with Lewy Bodies Substantia nigra Slide 26 Pathology in
Dementia with Lewy Bodies CerebralCortex Slide 27 Hippocampal CA-2
Neurites Slide 28 Pathology in Dementia with Lewy Bodies Amygdala
Slide 29 The Clinical Diagnosis of Dementia with Lewy Bodies Slide
30 Consensus Criteria for Dementia with Lewy Bodies 1. Progressive
cognitive decline with loss of normal social and occupational
function: loss of memory, attention, frontal subcortical skills,
visuospatial ability 2. Two of the following: a. fluctuating
cognition, attention, alertness b. visual hallucinations c. motor
features of parkinsonism 3. Supportive features: falls, syncope,
LOC, neuroleptic sensitivity, delusions, non-visual hallucinations
Slide 31 Clinical Signs and Symptoms in DLB Early psychiatric
symptomsEarly psychiatric symptoms Visual hallucinations, complex
delusions ParkinsonismParkinsonism Early gait and posture/stance
difficulties Tremor less frequent May never be clinically evident
Slide 32 Clinical Signs and Symptoms in DLB CognitionCognition
Short-term memory loss Cortical dysfunction Greater insight
Neuroleptic sensitivityNeuroleptic sensitivity Slide 33 Clinical
Signs and Symptoms in DLB ExaminationExamination Gait evaluation
(arm swing, posture, postural stability Frontal release signs
(snout, glabellar, palmomental) TestingTesting standard dementia
w/u Slide 34 Diagnostic Accuracy in a Community-Based Sample of DLB
Slide 35 Slide 36 Treatment of Dementia with Lewy Bodies:
Cholinesterase Inhibitors Slide 37 Major Changes in the Cholinergic
System in Alzheimers Disease Depletion of acetylcholine
(ACh)Depletion of acetylcholine (ACh) Decline in choline
acetyltransferase (ChAT) activityDecline in choline
acetyltransferase (ChAT) activity Loss of cholinergic neuronsLoss
of cholinergic neurons Acetylcholinesterase (AChE)
Acetylcholinesterase (AChE) Butyrylcholinesterase (BuChE)
Butyrylcholinesterase (BuChE) Alterations in nicotinic/muscarinic
receptorsAlterations in nicotinic/muscarinic receptors Slide 38 FC
= Frontal cortex PC = Parietal cortex OC = Occipital cortex H =
Hippocampus B = Nucleus basalis S = Medial septal nucleus Adapted
from Coyle JT, et al. Science. 1983;219:1184-1190. Cholinergic
System Innervates Areas Associated With Memory and Learning FC PC B
H OC S Slide 39 Cholinergic Enhancement Strategies Analogous to
dopaminergic enhancement strategies for Parkinson's disease
Cholinesterase inhibitor therapy inhibits AChE
(BuChE-tacrine/rivastigmine), degradative enzyme for acetylcholine
results in increase of acetylcholine available to postsynaptic
neurons increases cholinergic neurotransmission Slide 40 ACh =
acetylcholine; AChE = acetylcholinesterase; BuChE =
butyrylcholinesterase; ChAT = choline acetyltransferase; CoA =
coenzyme A. Adapted from Adem A. Acta Neurol Scand. 1992;85(suppl
139):69-74. AChE Acetyl CoA Choline ACh Presynapticneuron Synaptic
cleft Postsynaptic neuron Cholinergic receptor Acetate Choline
Choline + + Astrocyte ACh AChE BuChE BuChE ChAT Normal Cholinergic
Function Slide 41 Effect of Tacrine on Cognition: ADAS-Cog*
*Alzheimers Disease Assessment ScaleCognitive Subscale P How do you
define a disease ? Genetics > Pathology > Clinical ? Genetics
> Pathology > Clinical ? mutation causes pathology leading to
the clinical presentation What about known pathogens ? What about
known pathogens ? e.g. syphilis, mad cow disease (exposure
superimposed on genetic risk). Becoming difficult to define a
disease Becoming difficult to define a disease Slide 62 Summary
What is Dementia with Lewy bodies ?What is Dementia with Lewy
bodies ? Variant of Alzheimers disease Variant of Parkinsons
disease Clinical syndrome with unique clinical presentation and
management issues Common pathology in dementia (30 to 60%)
Additional study needed to fully characterize this second-leading
cause of dementia
