What is Dementia with Lewy What is Dementia with Lewy Bodies? Bodies? James B. Leverenz, M.D. James B. Leverenz, M.D. Departments of Departments of Neurology and Psychiatry and Behavioral Neurology and Psychiatry and Behavioral Sciences Sciences University of Washington School of Medicine University of Washington School of Medicine and and VA Northwest Network Mental Illness and VA Northwest Network Mental Illness and Parkinson’s Disease Research, Education, and Parkinson’s Disease Research, Education, and Clinical Center Clinical Centers
What is Dementia with Lewy Bodies?. 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 Parkinson’s Disease Research, Education, and Clinical Center s. - PowerPoint PPT Presentation
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What is Dementia with Lewy Bodies? What is Dementia with Lewy Bodies?
James B. Leverenz, M.D.James B. Leverenz, M.D.
Departments of Departments of Neurology and Psychiatry and Behavioral SciencesNeurology and Psychiatry and Behavioral Sciences
University of Washington School of Medicine University of Washington School of Medicine
andandVA Northwest Network Mental Illness and Parkinson’s VA Northwest Network Mental Illness and Parkinson’s
Disease Research, Education, and Clinical CenterDisease Research, Education, and Clinical Centers
History of Parkinson’s DiseaseHistory of Parkinson’s Disease
1861-951861-95 Charcot and Brissaud emphasize rigidity, Charcot and Brissaud emphasize rigidity, bradykinesia and “psychic troubles”bradykinesia and “psychic troubles”
Clinical SymptomsClinical Symptoms in Parkinson’s Disease in Parkinson’s Disease
• Tremor (resting) Tremor (resting)
• RigidityRigidity
• BradykinesiaBradykinesia
• Postural instabilityPostural instability
Parkinson’s DiseaseParkinson’s Disease
Parkinson’s DiseaseParkinson’s Disease
Pathology in Parkinson’s DiseasePathology in Parkinson’s Disease
• Clinical history of parkinsonismClinical history of parkinsonism
• Neuronal loss and Lewy body Neuronal loss and Lewy body inclusions in the substantia nigra, inclusions in the substantia nigra, locus coeruleus, basal forebrain locus coeruleus, basal forebrain and cerebral cortexand cerebral cortex
Lewy Body InclusionsLewy Body Inclusions
• Characteristic inclusions in substantia nigra neurons of Characteristic inclusions in substantia nigra neurons of patients with Parkinson’s diseasepatients with Parkinson’s disease
• Immunoreactive for neurofilaments, ubiquitin and alpha-Immunoreactive for neurofilaments, ubiquitin and alpha-synuclein, but not tau (NFT are tau and ubiquitin positive)synuclein, but not tau (NFT are tau and ubiquitin positive)
• In substantia nigra it is cytoplasmic, round, eosinophilic with In substantia nigra it is cytoplasmic, round, eosinophilic with clear haloclear halo
• In cortex less distinct appearance, best visualized with In cortex less distinct appearance, best visualized with alpha-synuclein immunohistochemistryalpha-synuclein immunohistochemistry
Pathology in Parkinson’s DiseasePathology in Parkinson’s Disease
Pathology in Parkinson’s DiseasePathology in Parkinson’s Disease
Pathology in Parkinson’s DiseasePathology in Parkinson’s Disease
History of History of Dementia with Lewy BodiesDementia with Lewy Bodies
19611961 First report of cortical LB’s in dementia (Okazaki First report of cortical LB’s in dementia (Okazaki et al)et al)
19741974 Start of clinical reports of parkinsonism in ADStart of clinical reports of parkinsonism in AD
19861986 High frequency of LB in AD patients (Leverenz & High frequency of LB in AD patients (Leverenz & Sumi)Sumi)
19901990 “Lewy body variant” proposed (Hansen et al)“Lewy body variant” proposed (Hansen et al)
19901990 “Diffuse Lewy body disease” (Crystal et al)“Diffuse Lewy body disease” (Crystal et al)
19961996 “Dementia with Lewy bodies” (Consortium on “Dementia with Lewy bodies” (Consortium on DLB)DLB)
Consensus Criteria for Dementia with Lewy BodiesConsensus Criteria for Dementia with Lewy Bodies
1. Progressive cognitive decline with loss of normal 1. Progressive cognitive decline with loss of normal social and occupational function: loss of memory, social and occupational function: loss of memory, attention, frontal subcortical skills, visuospatial attention, frontal subcortical skills, visuospatial abilityability
2. Two of the following:2. Two of the following:
a. fluctuating cognition, attention, alertnessa. fluctuating cognition, attention, alertness
b. visual hallucinationsb. visual hallucinations
c. motor features of parkinsonismc. motor features of parkinsonism
Consensus Criteria for Consensus Criteria for Dementia with Lewy BodiesDementia with Lewy Bodies
““It is suggested that if dementia occurs It is suggested that if dementia occurs within 12 within 12 monthsmonths of the onset of extrapyramidal motor of the onset of extrapyramidal motor symptoms, the patient should be assigned a symptoms, the patient should be assigned a primary diagnosis of primary diagnosis of possible DLBpossible DLB … “ … “
““If the clinical history of parkinsonism is If the clinical history of parkinsonism is longer longer than 12 monthsthan 12 months, , PD with dementiaPD with dementia … will … will usually be a more appropriate diagnostic label usually be a more appropriate diagnostic label …”…”
Consensus Criteria for Consensus Criteria for Dementia with Lewy BodiesDementia with Lewy Bodies
• Criteria good predictor of Lewy body Criteria good predictor of Lewy body pathology (with or without concomitant AD pathology (with or without concomitant AD pathology) - pathology) - high positive predictive valuehigh positive predictive value
• Criteria poor predictor of the absence of Lewy Criteria poor predictor of the absence of Lewy body body pathology - pathology - low negative predictive valuelow negative predictive value
Lewy Body Frequency in Alzheimer’s DiseaseLewy Body Frequency in Alzheimer’s Disease
19861986 28% of AD (Leverenz and Sumi)28% of AD (Leverenz and Sumi)
19871987 55% of AD (Ditter and Mirra)55% of AD (Ditter and Mirra)
19951995 21% in CERAD registry (Hulette et al)21% in CERAD registry (Hulette et al)
1998 1998 23% in community based series (Lim et 23% in community based series (Lim et al)al)
19961996 Dementia with Lewy bodies, Dementia with Lewy bodies, largest largest pathological subgroup after pure ADpathological subgroup after pure AD
(Consortium on DLB)(Consortium on DLB)
Lewy Body Frequency in Alzheimer’s DiseaseLewy Body Frequency in Alzheimer’s Disease
• 1998 to 20001998 to 2000
» Using ASN immunohistochemistry and Using ASN immunohistochemistry and amygdala samplingamygdala sampling
» 63% PS-1/APP mutation AD63% PS-1/APP mutation AD
» 50% of Down syndrome50% of Down syndrome
» 61% of “sporadic” AD61% of “sporadic” AD
» 64% PS-2 mutation AD64% PS-2 mutation AD
Lewy Body Frequency in Alzheimer’s DiseaseLewy Body Frequency in Alzheimer’s Disease
• 20032003
» 33 % of AD cases in a community-33 % of AD cases in a community-based samplebased sample
alpha-synuclein stainingalpha-synuclein staining
amygdala samplingamygdala sampling
• There appears to be a sampling-There appears to be a sampling-bias in the frequency of LB bias in the frequency of LB pathologypathology
Consensus Criteria for Dementia with Lewy BodiesConsensus Criteria for Dementia with Lewy Bodies
PathologyPathology
• Essential for diagnosis of DLBEssential for diagnosis of DLB
» Lewy bodiesLewy bodies
• Associated but not essentialAssociated but not essential
» Regional neuronal loss (substantia nigra, locus coeruleus, Regional neuronal loss (substantia nigra, locus coeruleus, basal forebrain)basal forebrain)
» Microvacuolation and synapse lossMicrovacuolation and synapse loss
» Neurochemical abnormalities and neurotransmitter deficitsNeurochemical abnormalities and neurotransmitter deficits
Pathology in Pathology in Dementia with Lewy BodiesDementia with Lewy Bodies
• Neuronal loss and LB’s in substantia nigraNeuronal loss and LB’s in substantia nigra
• Cortical LB’s and CA-2 ubiquitinated fibersCortical LB’s and CA-2 ubiquitinated fibers
• Full AD pathology (SP/NFT), ~ 80%Full AD pathology (SP/NFT), ~ 80%
• Restricted AD pathology (diffuse SP and restricted Restricted AD pathology (diffuse SP and restricted NFT distribution), ~ 20%NFT distribution), ~ 20%
Pathology in Pathology in Dementia with Lewy BodiesDementia with Lewy Bodies
Substantia nigra
Pathology in Pathology in Dementia with Lewy BodiesDementia with Lewy Bodies
Substantia nigra
Pathology in Pathology in Dementia with Lewy BodiesDementia with Lewy Bodies
CerebralCerebralCortex Cortex
Pathology in Pathology in Dementia with Lewy BodiesDementia with Lewy Bodies
HippocampalHippocampalCA-2 NeuritesCA-2 Neurites
Pathology in Pathology in Dementia with Lewy BodiesDementia with Lewy Bodies
AmygdalaAmygdala
The Clinical Diagnosis of The Clinical Diagnosis of Dementia with Lewy Bodies Dementia with Lewy Bodies
Consensus Criteria for Dementia with Lewy BodiesConsensus Criteria for Dementia with Lewy Bodies
1. Progressive cognitive decline with loss of normal 1. Progressive cognitive decline with loss of normal social and occupational function: loss of memory, social and occupational function: loss of memory, attention, frontal subcortical skills, visuospatial attention, frontal subcortical skills, visuospatial abilityability
2. Two of the following:2. Two of the following:
a. fluctuating cognition, attention, alertnessa. fluctuating cognition, attention, alertness
b. visual hallucinationsb. visual hallucinations
c. motor features of parkinsonismc. motor features of parkinsonism
1 - - V C - +2 + VH V C + +3 - - V C + +4 + Present V C + +5 + Present III C + +6 + VH III B + +7 - Present V C + +8 - - III B - +9 - Present III B + +10 - Present V C + +
1 VH = Visual hallucinations; Present = Hallucinations present, type not specified2 CERAD criteria used for AD neuropathological diagnosis
Diagnostic Accuracy in a Diagnostic Accuracy in a Community-Based Sample of DLBCommunity-Based Sample of DLB
Treatment of Dementia with Lewy Bodies:Treatment of Dementia with Lewy Bodies:Cholinesterase InhibitorsCholinesterase Inhibitors
Major Changes in the CholinergicMajor Changes in the CholinergicSystem in Alzheimer’s DiseaseSystem in Alzheimer’s 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
» Individual cognitive data all “significantly Individual cognitive data all “significantly favoured rivastigmine.” and “...will be favoured rivastigmine.” and “...will be described more fully elsewhere.”described more fully elsewhere.”
Rivastigmine International Lewy Body Rivastigmine International Lewy Body Dementia Trial: Behavioural Changes (NPI)Dementia Trial: Behavioural Changes (NPI)
NPI 10-item Score–Mean Change from Baseline (OC)NPI 10-item Score–Mean Change from Baseline (OC)
-8-8
-7-7
-6-6
-5-5
-4-4
-3-3
-2-2
-1-1
00BaselineBaseline Week 12Week 12 Week 20Week 20
RivastigmineRivastigminePlaceboPlacebo
Impr
ovem
ent
I mp r
o vem
ent
*P<0.01 vs placebo (ANOVA/ANCOVA)McKeith IG, et al. American Academy of Neurology 52nd Annual Meeting. April 29-May 6, 2000. San Diego, California.
*
Treatment of Dementia with Lewy Bodies:Treatment of Dementia with Lewy Bodies:Behavioral DisturbancesBehavioral Disturbances
Treating Behavioral Disturbances in DLBTreating Behavioral Disturbances in DLB
superimposed on genetic risk).superimposed on genetic risk).
• Becoming difficult to define “a disease”Becoming difficult to define “a disease”
SummarySummary
• What is Dementia with Lewy bodies ?What is Dementia with Lewy bodies ?» Variant of Alzheimer’s diseaseVariant of Alzheimer’s disease
» Variant of Parkinson’s diseaseVariant of Parkinson’s disease
» Clinical syndrome with unique clinical Clinical syndrome with unique clinical presentation and management issuespresentation and management issues
» Common pathology in dementia (30 to 60%)Common pathology in dementia (30 to 60%)
» Additional study needed to fully characterize this Additional study needed to fully characterize this “second-leading” cause of dementia“second-leading” cause of dementia