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 Parkinson’s
Disease Research, Education, and Clinical Centers
How do you define a “disease” ?
• Genetics > Pathology > 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”
History of Parkinson’s 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”
Clinical Symptoms
in Parkinson’s Disease
• Tremor (resting)
• Rigidity
• Bradykinesia
• Postural instability
Parkinson’s Disease
Parkinson’s Disease
Pathology in Parkinson’s Disease
• Clinical history of parkinsonism
• Neuronal loss and Lewy body
inclusions in the substantia nigra,
locus coeruleus, basal forebrain
and cerebral cortex
Lewy Body Inclusions
• Characteristic inclusions in substantia nigra neurons of
patients with Parkinson’s disease
• Immunoreactive for neurofilaments, ubiquitin and alphasynuclein, 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
Pathology in Parkinson’s Disease
Pathology in Parkinson’s Disease
Pathology in Parkinson’s Disease
History of
Dementia with Lewy Bodies
1961
First report of cortical LB’s 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)
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
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
…”
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
Lewy Body Frequency in Alzheimer’s 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)
Lewy Body Frequency in Alzheimer’s 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
Lewy Body Frequency in Alzheimer’s Disease
• 2003
» 33 % of AD cases in a communitybased sample

alpha-synuclein staining

amygdala sampling
• There appears to be a samplingbias in the frequency of LB
pathology
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
Pathology in
Dementia with Lewy Bodies
• Neuronal loss and LB’s in substantia nigra
• Cortical LB’s and CA-2 ubiquitinated fibers
• Full AD pathology (SP/NFT), ~ 80%
• Restricted AD pathology (diffuse SP and restricted
NFT distribution), ~ 20%
Pathology in
Dementia with Lewy Bodies
Substantia nigra
Pathology in
Dementia with Lewy Bodies
Substantia nigra
Pathology in
Dementia with Lewy Bodies
Cerebral
Cortex
Pathology in
Dementia with Lewy Bodies
Hippocampal
CA-2 Neurites
Pathology in
Dementia with Lewy Bodies
Amygdala
The Clinical Diagnosis of
Dementia with Lewy Bodies
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
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
Clinical Signs and Symptoms in DLB
• Cognition
» Short-term memory loss
» Cortical dysfunction
» Greater insight
• Neuroleptic sensitivity
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
Diagnostic Accuracy in a
Community-Based Sample of DLB
Psychosis
Hallucinations
Delusions
Parkinsonism
Parkinsonism + Psychosis
1.0
0.8
0.6
0.4
0.2
0.0
Sensitivity
Specificity
PPV
NPV
Diagnostic Accuracy in a
Community-Based Sample of DLB
Case
Clinical Characteristics
Parkinsonism
1
2
3
4
5
6
7
8
9
10
+
+
+
+
-
Hallucinations 1
VH
Present
Present
VH
Present
Present
Present
Neuropathology 2
Braak Stage
LB Pathology
NFT
SP
SN
Amygdala
V
V
V
V
III
III
V
III
III
V
C
C
C
C
C
B
C
B
B
C
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
1 VH = Visual hallucinations; Present = Hallucinations present, type not specified
2 CERAD criteria used for AD neuropathological diagnosis
Treatment of Dementia with Lewy Bodies:
Cholinesterase Inhibitors
Major Changes in the Cholinergic
System in Alzheimer’s Disease
• Depletion of acetylcholine (ACh)
• Decline in choline acetyltransferase (ChAT)
activity
• Loss of cholinergic neurons
•  Acetylcholinesterase (AChE)
•  Butyrylcholinesterase (BuChE)
• Alterations in nicotinic/muscarinic receptors
Cholinergic System Innervates Areas
Associated With Memory and Learning
PC
FC
OC
S
B
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.
H
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
Normal Cholinergic Function
Presynaptic
neuron
Acetyl
CoA
Astrocyte
+
Choline
Choline
ChAT
BuChE
ACh
Synaptic cleft
ACh
AChE
Postsynaptic
neuron
Cholinergic receptor
Choline
+
Acetate
AChE
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.
BuChE
Effect of Tacrine on Cognition:
ADAS-Cog*
–3
†
–2
Improve
–1
 4.1‡
0
1
2
Baseline
160 mg/d (n=238)
120 mg/d (n=174)
80 mg/d (n=60)
Placebo (n=181)
Decline
3
Baseline
6
12
18
24
30
Weeks
*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.
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 
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
Cholinesterase Inhibitors:
Treatment 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
Cholinesterase Inhibitors:
Treatment 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
Cholinesterase Inhibitors:
Treatment 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.”
Rivastigmine International Lewy Body
Dementia Trial: Behavioural Changes (NPI)
NPI 10-item Score–Mean Change from Baseline (OC)
-8
-7
Rivastigmine
Placebo
*
-6
-5
-4
-3
-2
-1
0
Baseline
Week 12
Week 20
*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:
Behavioral Disturbances
Treating Behavioral Disturbances in DLB
• Cholinesterase inhibitors
» apathy, psychosis in rivastigmine study
• Lack of Treatment trials
» agitation
» psychosis
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 Medications
• Avoid typical antipsychotics
• Consider lowering dopaminergic
agents
• Atypical agents
Agents for Psychotic Symptoms
Agent
Haloperidol
Thioridazine
Risperidone
Olanzapine
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
Treatment of Dementia with Lewy Bodies:
Motor Symptoms
Antiparkinsonian Medications
• No prospective treatment trials
• Generally less responsive (nondopaminergic motor symptoms)
• Can elect not to treat
• L-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 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
Clinical-pathologic Studies in DLB:
Sample Bias
•
Bonner et al ‘03 (H&E, ASN)
»
Research sample (25/36, 70%)

»
mostly due to high frequency
isolated amygdala/brainstem LB
Community-based sample (10/32, 31%)

non-significant increase of psychosis, EPS

similar sensitivity/specificity to research
samples (excl. fluctuation)
Comparison of Research and
Community Samples
Age a t Death
Mean (SD)
Duration of
Disease
Researc h
Sam ple
Community
Sam ple
Significa nce
(P-value)
78.92 (8.47)
83.23 (8.05)
0.038
12.16 (6.70)
5.86 (2.58)
<0.001
M = 20
F = 16
M = 11
F = 21
0.080
Mean (SD)
Gender
Frequency of E4
Allele i n LB (+)
cases (CI)
Braak S tage
Mean (SD)
Frequency of LB
Pathology
0.70 (0.56-0.84) 0.35 (0.14-0.56)
0.007
5.20 (0.58)
4.41 (0.95)
<0.001
LB (+) = 25
LB (-) = 11
LB (+) = 10
LB (-) = 22
0.002
Frequency of E4 Allele in Research
and Community Samples
1
0.8
Frequency of
E4 Allele
*
0.6
LB (+)
LB (-)
#
0.4
0.2
0
Research
Sample
* c2=7.17, p=0.007
Community
Sample
#
c2=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)
7
15
4
6
Gender
Male
Female
How do you define a “disease” ?
• Genetics > Pathology > 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”
Summary
• What is Dementia with Lewy bodies ?
» Variant of Alzheimer’s disease
» Variant of Parkinson’s 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