Dementia with Lewy Bodies: What is it and how do I treat it ?

Dementia with Lewy Bodies:Dementia with Lewy Bodies:What is it and how do I treat it ? What is it and how do I treat it ?

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

How do you define a “disease” ?How do you define a “disease” ?

• Genetics > Pathology > Clinical ?Genetics > Pathology > Clinical ?

» mutation causes pathology leading to the clinical mutation causes pathology leading to the clinical presentationpresentation

• What about known pathogens ?What about known pathogens ?

» e.g. syphilis, mad cow disease (exposuree.g. syphilis, mad cow disease (exposure

superimposed on genetic risk).superimposed on genetic risk).

• Becoming difficult to define a “disease”Becoming difficult to define a “disease”

History of Parkinson’s DiseaseHistory of Parkinson’s Disease

138-201 138-201 Galen describes resting tremorGalen describes resting tremor

18171817 Initial description of disease by Initial description of disease by James ParkinsonJames Parkinson

1859/681859/68 Trousseau describes intellectual declineTrousseau describes intellectual decline

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




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

3. Supportive features: falls, syncope, LOC, neuroleptic 3. Supportive features: falls, syncope, LOC, neuroleptic sensitivity, delusions, non-visual hallucinationssensitivity, delusions, non-visual hallucinations

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)


• 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


• 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


PathologyPathology

• Essential for diagnosis of DLBEssential for diagnosis of DLB

» Lewy bodiesLewy bodies

• Associated but not essentialAssociated but not essential

» Lewy-related neuritesLewy-related neurites

» Plaques (all morphologic types)Plaques (all morphologic types)

» Neurofibrillary tanglesNeurofibrillary tangles

» 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%


Substantia nigra


Substantia nigra


CerebralCerebralCortex Cortex


HippocampalHippocampalCA-2 NeuritesCA-2 Neurites


AmygdalaAmygdala

The Clinical Diagnosis of The Clinical Diagnosis of Dementia with Lewy Bodies 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

3. Supportive features: falls, syncope, LOC, neuroleptic 3. Supportive features: falls, syncope, LOC, neuroleptic sensitivity, delusions, non-visual hallucinationssensitivity, delusions, non-visual hallucinations

Clinical Signs and Symptoms in DLBClinical Signs and Symptoms in DLB

• Early psychiatric symptomsEarly psychiatric symptoms

» Visual hallucinations, complex delusionsVisual hallucinations, complex delusions

• ParkinsonismParkinsonism

» Early gait and posture/stance difficultiesEarly gait and posture/stance difficulties

» Tremor less frequentTremor less frequent

» May never be clinically evidentMay never be clinically evident


• CognitionCognition

» Short-term memory lossShort-term memory loss

» Cortical dysfunctionCortical dysfunction

» Greater insightGreater insight

• Neuroleptic sensitivityNeuroleptic sensitivity


• ExaminationExamination

» Gait evaluation (arm swing, posture, Gait evaluation (arm swing, posture, postural stabilitypostural stability

» Frontal release signs (snout, glabellar, Frontal release signs (snout, glabellar, palmomental)palmomental)

• TestingTesting

» standard dementia w/ustandard dementia w/u

0.0

0.2

0.4

0.6

0.8

1.0

Sensitivity Specificity PPV NPV

PsychosisHallucinationsDelusionsParkinsonismParkinsonism + Psychosis

Diagnostic Accuracy in a Diagnostic Accuracy in a Community-Based Sample of DLBCommunity-Based Sample of DLB

Case Clinical Characteristics Neuropathology2

Parkinsonism Hallucinations1 Braak Stage LB Pathology

NFT SP SN Amygdala

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

Acetylcholinesterase (AChE)Acetylcholinesterase (AChE)

Butyrylcholinesterase (BuChE)Butyrylcholinesterase (BuChE)

• Alterations in nicotinic/muscarinic receptorsAlterations in nicotinic/muscarinic receptors

FC = Frontal cortexPC = Parietal cortexOC = Occipital cortexH = HippocampusB = Nucleus basalisS = Medial septal nucleus

Adapted from Coyle JT, et al. Science. 1983;219:1184-1190.

Cholinergic System Innervates Areas Cholinergic System Innervates Areas Associated With Memory and LearningAssociated With Memory and Learning

FC

PC

BH

OCS

Cholinergic Enhancement StrategiesCholinergic 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

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

AcetylCoA

CholineCholineACh

Presynaptic Presynaptic neuronneuron

Synaptic cleftSynaptic cleft

PostsynapticPostsynapticneuronneuron

Cholinergic receptorCholinergic receptor

AcetateAcetate

CholineCholineCholine+

++

AstrocyteAstrocyte

ACh

AChE

BuChEBuChE

BuChEBuChE

ChAT

Normal Cholinergic FunctionNormal Cholinergic Function

Effect of Tacrine on Cognition:Effect of Tacrine on Cognition:ADAS-Cog*ADAS-Cog*

*Alzheimer’s Disease Assessment Scale–Cognitive Subscale†P<0.001 vs placebo; ‡Observed mean treatment difference. Evaluable patients at week 30 = 263.Knapp MJ, et al, for the Tacrine Study Group. JAMA. 1994;271:985-991.

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22

33

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Mea

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a se l

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Mea

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h ang

e f r

o m B

a se l

ine

BaselineBaseline

WeeksWeeks30301818 2424121266

160 mg/d (n=238)160 mg/d (n=238)120 mg/d (n=174)120 mg/d (n=174)80 mg/d (n=60)80 mg/d (n=60)Placebo (n=181)Placebo (n=181)

BaselineBaseline

ImproveImprove

DeclineDecline

††

4.14.1‡‡

Is There a Cholinergic Deficit in DLB ?Is There a Cholinergic Deficit in DLB ?

• Depletion of acetylcholine (ACh) Depletion of acetylcholine (ACh) ??

• Decline in choline acetyltransferase (ChAT) activity Decline in choline acetyltransferase (ChAT) activity

• Loss of cholinergic neurons Loss of cholinergic neurons

Acetylcholinesterase (AChE) Acetylcholinesterase (AChE) ??

Butyrylcholinesterase (BuChE) Butyrylcholinesterase (BuChE) ??

• Alterations in nicotinic/muscarinic receptors Alterations in nicotinic/muscarinic receptors

Is There a Cholinergic Deficit in DLB ?Is There a Cholinergic Deficit in DLB ?

• Samuel et al (JNEN 1997) Samuel et al (JNEN 1997)

» 30% reduction of ChAT in AD30% reduction of ChAT in AD

» 75% reduction of ChAT in DLB75% reduction of ChAT in DLB

• Tiraboschi et al (Arch Psychiat 2002)Tiraboschi et al (Arch Psychiat 2002)

» ChAT preserved in mild ADChAT preserved in mild AD

» ChAT significantly lower in early DLBChAT significantly lower in early DLB

Cholinesterase Inhibitors:Cholinesterase Inhibitors:Treatment of DLBTreatment of DLB

• Multiple positive open-label trials Multiple positive open-label trials (tacrine, donepezil, rivastimine)(tacrine, donepezil, rivastimine)

• McKeith et al (Lancet 2000)McKeith et al (Lancet 2000)

» Double-blinded, 120 patientsDouble-blinded, 120 patients

» Rivastigmine up to 12 mg/dRivastigmine up to 12 mg/d

» Focus on behavioral symptoms using NPIFocus on behavioral symptoms using NPI



» NPINPI

– Positive - apathy, indifference, anxiety, Positive - apathy, indifference, anxiety, delusions, hallucinations and aberrant delusions, hallucinations and aberrant motor behaviormotor behavior

– No change - depression, No change - depression, agitation/aggression, irritability, sleepagitation/aggression, irritability, sleep



» MMSE trend positive (p = 0.07)MMSE trend positive (p = 0.07)

» 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

• Cholinesterase inhibitorsCholinesterase inhibitors

» apathy, psychosis in rivastigmine studyapathy, psychosis in rivastigmine study

• Lack of Treatment trialsLack of Treatment trials

» agitationagitation

» psychosispsychosis

Pharmacologic Approaches to Agitation in AD

• Anti-epileptics (mood stabilizers)» valproic acid (Depakote)

» carbamazepine (Tegretol)

• CNS-active beta-blockers» propranolol

• Other approaches» trazodone

» antiandrogens/estrogens

Antipsychotic MedicationsAntipsychotic Medications

• Avoid typical antipsychoticsAvoid typical antipsychotics

• Consider lowering dopaminergic Consider lowering dopaminergic agentsagents

• Atypical agentsAtypical agents

Agents for Psychotic SymptomsAgents for Psychotic Symptoms

AgentAgentHaloperidolHaloperidolThioridazineThioridazineRisperidoneRisperidoneOlanzapineOlanzapineQuetiapineQuetiapineClozapineClozapine

Starting DoseStarting Dose0.5 mg/day0.5 mg/day10-25 mg/day10-25 mg/day0.5-1.0 mg/day0.5-1.0 mg/day2.5 mg/day2.5 mg/day25-50 mg/day25-50 mg/day6.25 mg/day6.25 mg/day

Maximal DoseMaximal Dose2-5 mg/day2-5 mg/day50-100 mg/day50-100 mg/day2-6 mg/day2-6 mg/day2.5-15 mg/day2.5-15 mg/day400 mg/day400 mg/day50 mg/day50 mg/day

Treatment of Dementia with Lewy Bodies:Treatment of Dementia with Lewy Bodies:Motor SymptomsMotor Symptoms

Antiparkinsonian MedicationsAntiparkinsonian Medications

• No prospective treatment trialsNo prospective treatment trials

• Generally less responsive (non-Generally less responsive (non-dopaminergic motor symptoms)dopaminergic motor symptoms)

• Can elect not to treatCan elect not to treat

• L-dopa preferred to agonistsL-dopa preferred to agonists

Pharmacologic Approaches to DLB

• Cholinesterase inhibitors

• Atypical antipsychotics

• Limited dopaminergic agents

• Other approaches» ? AD agitation medications

» ? Vitamin E

» ? Estrogens, NSAIDS, vaccine, BACE inhibitors

DLB: Research DirectionsDLB: Research Directions

• Improvement in clinical diagnosisImprovement in clinical diagnosis» imaging, electrophysiologyimaging, electrophysiology

• Clinical trialsClinical trials» cognition, behavior, motorcognition, behavior, motor

• Clinical-pathologic studiesClinical-pathologic studies

• BiochemistryBiochemistry» ACh, DA, NE, 5HTACh, DA, NE, 5HT

• GeneticsGenetics» familial DLB, risk factors

• Bonner et al ‘03Bonner et al ‘03 (H&E, ASN) (H&E, ASN)» Research sampleResearch sample (25/36, (25/36, 70%70%))

mostly due to high frequency mostly due to high frequency isolated amygdala/brainstem LB isolated amygdala/brainstem LB

» Community-based sampleCommunity-based sample (10/32, (10/32, 31%31%)) non-significant increase of psychosis, EPSnon-significant increase of psychosis, EPS similar sensitivity/specificity to research similar sensitivity/specificity to research

samples (excl. fluctuation)samples (excl. fluctuation)

Clinical-pathologic Studies in DLB:Clinical-pathologic Studies in DLB:Sample BiasSample Bias

Comparison of Research and Community Samples

ResearchSample

CommunitySample

Significance(P-value)

Age at DeathMean (SD)

78.92 (8.47) 83.23 (8.05) 0.038

Duration ofDisease

Mean (SD)12.16 (6.70) 5.86 (2.58) <0.001

GenderM = 20F = 16

M = 11F = 21 0.080

Frequency of E4Allele in LB (+)

cases (CI)0.70 (0.56-0.84) 0.35 (0.14-0.56) 0.007

Braak Stage Mean (SD)

5.20 (0.58) 4.41 (0.95) <0.001

Frequency of LBPathology

LB (+) = 25LB (-) = 11

LB (+) = 10LB (-) = 22 0.002

Frequency of E4 Allele in Researchand Community Samples

0

0.2

0.4

0.6

0.8

1

Frequency of E4 Allele

ResearchSample

CommunitySample

LB (+)

LB (-)

*

* 2=7.17, p=0.007 # 2=8.96, p=0.003

#

Clinical and Pathological Characteristics in AD versus AD with LB (community-based sample)

NP AD (n = 22)

NP AD +LB's(n = 10)

Age at onset – Mean (SD) 77.3 (7.6) 77.4 (8.47)

Age at death – Mean (SD) 83.2 (8.42) 83.3 (7.70)

Duration of Disease – Mean (SD) 5.85 (2.83) 5.9 (2.13)

Mean Braak Stage – Mean (SD) 4.5 (0.91) 4.2 (1.03)

Gender Male Female

715

46

How do you define a “disease” ?How do you define a “disease” ?

• Genetics > Pathology > Clinical ?Genetics > Pathology > Clinical ?

» mutation causes pathology leading to the clinical mutation causes pathology leading to the clinical presentationpresentation

• What about known pathogens ?What about known pathogens ?

» e.g. syphilis, mad cow disease (exposuree.g. syphilis, mad cow disease (exposure

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

Documents

Dementia with Lewy Bodies: What is it and how do I treat it ?