What is Dementia with Lewy Bodies?

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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
  Parkinsons Disease Research, Education, and
  Clinical Centers

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History of Parkinsons Disease

• 138-201 Galen describes resting tremor
• 1817 Initial description of disease by
  James Parkinson
• 1859/68 Trousseau describes intellectual decline
• 1861-95 Charcot and Brissaud emphasize rigidity,
  bradykinesia and psychic troubles

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Clinical Symptoms in Parkinsons Disease

• Tremor (resting)
• Rigidity
• Bradykinesia
• Postural instability

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Parkinsons Disease
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Parkinsons Disease
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Pathology in Parkinsons Disease

• Clinical history of parkinsonism
• Neuronal loss and Lewy body inclusions in the
  substantia nigra, locus coeruleus, basal
  forebrain and cerebral cortex

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Lewy Body Inclusions

• Characteristic 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)
• In substantia nigra it is cytoplasmic, round,
  eosinophilic with clear halo
• In cortex less distinct appearance, best
  visualized with alpha-synuclein
  immunohistochemistry

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Pathology in Parkinsons Disease
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Pathology in Parkinsons Disease
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Pathology in Parkinsons Disease
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History of Dementia with Lewy Bodies
1961 First report of cortical LBs in dementia
(Okazaki et al) 1974 Start of clinical
reports of parkinsonism in AD 1986 High
frequency of LB in AD patients (Leverenz
Sumi) 1990 Lewy body variant proposed
(Hansen et al) 1990 Diffuse Lewy body disease
(Crystal et al) 1996 Dementia with Lewy bodies
(Consortium on DLB)
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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

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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
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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 poor predictor of the absence of Lewy
  body pathology - low negative predictive value

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Lewy Body Frequency in Alzheimers Disease

• 1986 28 of AD (Leverenz and Sumi)
• 1987 55 of AD (Ditter and Mirra)
• 1995 21 in CERAD registry (Hulette et al)
• 1998 23 in community based series (Lim et
  al)
• 1996 Dementia with Lewy bodies, largest
  pathological subgroup after pure AD
  (Consortium on DLB)

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Lewy Body Frequency in Alzheimers Disease

• 1998 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

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Lewy Body Frequency in Alzheimers Disease

• 2003
• 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 pathology

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Consensus Criteria for Dementia with Lewy Bodies

• Pathology
• Essential for diagnosis of DLB
• Lewy bodies
• Associated 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

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Pathology in Dementia with Lewy Bodies

• Neuronal loss and LBs in substantia nigra
• Cortical LBs and CA-2 ubiquitinated fibers
• Full AD pathology (SP/NFT), 80
• Restricted AD pathology (diffuse SP and
  restricted NFT distribution), 20

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Pathology in Dementia with Lewy Bodies
Substantia nigra
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Pathology in Dementia with Lewy Bodies
Substantia nigra
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Pathology in Dementia with Lewy Bodies
Cerebral Cortex
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Pathology in Dementia with Lewy Bodies
Hippocampal CA-2 Neurites
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Pathology in Dementia with Lewy Bodies
Amygdala
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The Clinical Diagnosis of Dementia with Lewy
Bodies
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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

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Clinical Signs and Symptoms in DLB

• Early psychiatric symptoms
• Visual hallucinations, complex delusions
• Parkinsonism
• Early gait and posture/stance difficulties
• Tremor less frequent
• May never be clinically evident

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Clinical Signs and Symptoms in DLB

• Cognition
• Short-term memory loss
• Cortical dysfunction
• Greater insight
• Neuroleptic sensitivity

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Clinical Signs and Symptoms in DLB

• Examination
• Gait evaluation (arm swing, posture, postural
  stability
• Frontal release signs (snout, glabellar,
  palmomental)
• Testing
• standard dementia w/u

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Diagnostic Accuracy in a Community-Based Sample
of DLB
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Diagnostic Accuracy in a Community-Based Sample
of DLB
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Treatment of Dementia with Lewy
BodiesCholinesterase Inhibitors
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Major Changes in the CholinergicSystem in
Alzheimers Disease

• Depletion of acetylcholine (ACh)
• Decline in choline acetyltransferase (ChAT)
  activity
• Loss of cholinergic neurons
• ? Acetylcholinesterase (AChE)
• ? Butyrylcholinesterase (BuChE)
• Alterations in nicotinic/muscarinic receptors

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Cholinergic System Innervates Areas Associated
With Memory and Learning
PC
FC
OC
S
B
H
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.
19832191184-1190.
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Is There a Cholinergic Deficit in DLB ?

• Depletion of acetylcholine (ACh) ?
• Decline in choline acetyltransferase (ChAT)
  activity ?
• Loss of cholinergic neurons ?
• ? Acetylcholinesterase (AChE) ?
• ? Butyrylcholinesterase (BuChE) ?
• Alterations in nicotinic/muscarinic receptors ?

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Is There a Cholinergic Deficit in DLB ?

• Samuel et al (JNEN 1997)
• 30 reduction of ChAT in AD
• 75 reduction of ChAT in DLB
• Tiraboschi et al (Arch Psychiat 2002)
• ChAT preserved in mild AD
• ChAT significantly lower in early DLB

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Cholinesterase InhibitorsTreatment of DLB

• Multiple positive open-label trials (tacrine,
  donepezil, rivastimine)
• McKeith et al (Lancet 2000)
• Double-blinded, 120 patients
• Rivastigmine up to 12 mg/d
• Focus on behavioral symptoms using NPI

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Cholinesterase InhibitorsTreatment of DLB

• McKeith et al (Lancet 2000)
• NPI
• Positive - apathy, indifference, anxiety,
  delusions, hallucinations and aberrant motor
  behavior
• No change - depression, agitation/aggression,
  irritability, sleep

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Cholinesterase InhibitorsTreatment of DLB

• McKeith et al (Lancet 2000)
• MMSE trend positive (p 0.07)
• Individual cognitive data all significantly
  favoured rivastigmine. and ...will be
  described more fully elsewhere.

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Rivastigmine International Lewy Body Dementia
Trial Behavioural Changes (NPI)
NPI 10-item ScoreMean Change from Baseline (OC)

-8
Rivastigmine
-7
Placebo
-6
-5
Improvement
-4
-3
-2
-1
0
Baseline
Week 12
Week 20
Plt0.01 vs placebo (ANOVA/ANCOVA) McKeith IG, et
al. American Academy of Neurology 52nd Annual
Meeting. April 29-May 6, 2000. San Diego,
California.
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Treatment of Dementia with Lewy
BodiesBehavioral Disturbances
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Treating Behavioral Disturbances in DLB

• Cholinesterase inhibitors
• apathy, psychosis in rivastigmine study
• Lack of Treatment trials
• agitation
• psychosis

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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

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Antipsychotic Medications

• Avoid typical antipsychotics
• Consider lowering dopaminergic agents
• Atypical agents

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Agents for Psychotic Symptoms
Agent Haloperidol Thioridazine Risperidone Olanzap
ine Quetiapine Clozapine
Starting Dose 0.5 mg/day 10-25 mg/day 0.5-1.0
mg/day 2.5 mg/day 25-50 mg/day 6.25 mg/day
Maximal Dose 2-5 mg/day 50-100 mg/day 2-6
mg/day 2.5-15 mg/day 400 mg/day 50 mg/day
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Treatment of Dementia with Lewy BodiesMotor
Symptoms
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Antiparkinsonian Medications

• No prospective treatment trials
• Generally less responsive (non-dopaminergic motor
  symptoms)
• Can elect not to treat
• L-dopa preferred to agonists

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Pharmacologic Approaches to DLB

• Cholinesterase inhibitors
• Atypical antipsychotics
• Limited dopaminergic agents
• Other approaches
• ? AD agitation medications
• ? Vitamin E
• ? Estrogens, NSAIDS, vaccine, BACE inhibitors

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DLB Research Directions

• Improvement in clinical diagnosis
• imaging, electrophysiology
• Clinical trials
• cognition, behavior, motor
• Clinical-pathologic studies
• Biochemistry
• ACh, DA, NE, 5HT
• Genetics
• familial DLB, risk factors

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How do you define a disease ?

• Genetics gt Pathology gt Clinical ?
• mutation causes pathology leading to the
  clinical presentation
• What about known pathogens ?
• e.g. syphilis, mad cow disease (exposure
• superimposed on genetic risk).
• Becoming difficult to define a disease

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Summary

• 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