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Update on LBD Research: A Focus on Genetics
James B. Leverenz, MDCleveland Lou Ruvo Center for Brain Health
Neurological InstituteCleveland Clinic
Disclosures
Consulting
• Axovant
• GE Healthcare
• Navidea Biopharmaceuticals
• Piramal Healthcare
• Teva
Grant Support
• Axovant
• Genezyme/Sanofi
• Lundbeck
Overview
Definitions
Genetics 101
Genetics of Lewy Body Dementia (LBD)
• Cognition in Parkinson’s disease (PD)
• Dementia with Lewy Bodies (DLB)
What is a Lewy body?
Alpha-Synuclein in Lewy Bodies
a-synuclein immunohistochemistry
Neuropathology of Community Based Dementia
Normal
(n=2)
HS+Vasc
(n=5)
HS+DLB
(n=2)HS
(n=10)HS+AD+Vasc
(n=1)
Vasc
(n=20)
PSP
(n=4)
Other
(n=12)
AD
(n=37)
AD+Vasc
(n=33)
DLB
(n=15)AD+Other
(n=1)
AD/DLB
(n=52)
DLB+Vasc
(n=17)
AD/DLB+Vasc
(n=31)
AD/DLB+Other
(n=1)
HS+AD/DLB
(n=5)
7%
21%
13%
2%
15%
8%
4%
5%
2%
13%
6%
Neuropathology of Community Based Dementia
Dementia
McKhann et al., Alzheimer’s & Dementia, 1-7, 2011.
NIA/AA: “Dementia is diagnosed when there is
A change in at least two cognitive domains:
Memory
Executive function
Visuospatial
Language
Behavior
A decline from previous levels of functioning
A decline in the ability to function at work or at usual
activities
The Lewy Body Dementias
Parkinson’s Disease Dementia
Dementia with Lewy Bodies
Emre M, et al. Mov Disord, 22:1689-1707, 2007
CLINICAL DIAGNOSIS OF PD DEMENTIA
2007 Clinical Diagnostic Criteria
Diagnosis of PD
Dementia syndrome within the context of
established PD
impairment in more than one cognitive domain
decline from premorbid level
deficits severe enough to impair daily life
McKeith et al, Neurology 65:1863-72, 2005.
Consensus Criteria for Dementia with Lewy Bodies
1. Progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function…
2. Core features (2 = “probable”, 1 = “possible”)
• a. fluctuating cognition, attention, alertness
• b. recurrent visual hallucinations
• c. spontaneous features of parkinsonism
3. Suggestive features (plus one core = “probable” DLB)
• a. REM sleep behavior disorder
• b. severe neuroleptic sensitivity
• c. low dopamine transporter uptake (PET/SPECT)
4. One year rule for PDD vs. DLB
Common clinical symptoms
Parkinsonism
Visual hallucinations
Fluctuations
REM Sleep Disorder
Is it all timing?
For criteria, yes
Just a variant of same disease?
PDD vs.DLB
Genetics 101
Human Chromosomes
Human Chromosomes
Inheritance Patterns
The Complexity of Genetics
The Complexity of Genetics
Most genetics are related to RISK
APOE e4 in Alzheimer’s disease
Increased riskCan have two
copies and never get AD
Can get AD without
carrying this gene
We carry gene “variants” that increase or decrease our risk
Likely it’s the combination that
determines disease
Genetics of LBD
Common clinical symptoms
Parkinsonism
Visual hallucinations
Fluctuations
REM Sleep Disorder
Is it all timing?
For criteria, yes
Just a variant of same disease?
PDD vs.DLB
Neuropathology of Community Based Dementia
Lewy Body Pathology in Alzheimer’s Disease
Leverenz et al, Arch Neurol, 2006
DLB, PDD and
Alzheimer’s Disease
Is DLB just a variant of
PD/PDD?Is DLB just a variant of
AD?
AD LBD-AD
DLB
PD & PD-D
Genetics of the LBDs
Tsuang, JAMA Neurol, 2013
APOE e4 and the LBDs
Tsuang et al, JAMA Neurol, 2013
Bras et al, Hum Mol Genet, 2014
APOE e4 and the LBDs
Bras et al, Hum Mol Genet, 2014
APOE e4 and the LBDs
Bras et al
APOE finding just an association with Ab deposition?• Why are other AD genes not associated?
Bras et al, Hum Mol Genet, 2014
APOE e4 and the LBDs
• 140 autopsied cases
• Links to dementia
» Lewy pathology
» APOE e4
» AD (~ 30%)
Genetics of PD
Risk FactorSmall Effect
Risk FactorLarge Effect
Pathogenic Mutation
(reduced penetrance)
Pathogenic Mutation
(complete penetrance)
Risk
<───── 6 Causal Genes ─────><─── 20+ Susceptibility Genes ── ─>
LRRK2(G2019S)
LRRK2(R1441C)
SNCA(A53T)
PARK2
SNCA(SNPs)
MAPT
LRRK2(SNPs)
GBA(N370S)
HIP1R
HLA
BST1
RAB25
Genetics of the LBDs
Glucocerebrosidase (GBA)o Homozygotes associates with Gaucher’s diseaseo Clear link to PD risk in heterozygoteso ~ 7x increase risk in carriers
Genetics of the LBDs
Tsuang et al, Neurology, 79:1944-50, 2012
DLB, PDD and Alzheimer’s Disease
Is DLB just a variant of PD/PDD?
• Similar Lewy body pathology
• Some shared genetics (e.g., GBA)
Is DLB just a variant of AD?
• Frequent AD pathology in DLB
• Some shared genetics (e.g., APOE)
AD LBD-AD
DLB
PD & PD-D
AD LBD-AD
DLB
PD & PD-D
Seattle:–Pinky Agarwal, MD
–Lynn Bekris, PhD
–Daniel Burdick, MD
–Marie Davis, MD, PhD
–Karen Edwards, PhD
–Brooke Gerton, MD
–Alida Griffith, MD
–Gene Hu, MD, PhD
–Mike Kim, MD
–Katelan Longfellow, MD
–Erica Martinez
–Ignacio Mata, PhD
–Tom Montine, MD, PhD
–John Roberts, MD
–Debby Tsuang, MD, MS
–G. Stennis Watson, PhD
–Dora Yearout
–Jia Yin, MS
– Cyrus Zabetian, MD, MSc
Emory University–Stewart Factor, DO
–Julia Land, PsyD
Johns Hopkins University–Liana Rosenthal, MD
–Ted Dawson, MD, PhD
–Marilyn Albert, PhD
Mayo Clinic, FL–Zbigniew K. Wszolek, MD
–Ryan Uitti, MD
–Dennis Dickson, MD
OHSU-PVAMC–Joe Quinn, MD
–Kathy Chung, MD
–John Nutt, MD
–Susan O'Connor
Rush University–Jennifer Goldman, MD
–Glenn Stebbins, PhD
–Bryan Bernard, PhD
UCLA–Beate Ritz, MD, PhD
–Rebecca Rausch, PhD
University of Cincinnati –Alberto Espay, MD
–Fredy Revilla, MD
–Johnna Devoto, PhD
University of Pennsylvania–Daniel Weintraub, MD
–John Trojanowski, MD, PhD
–Howard Hurtig, MD
–Alice Chen-Plotkin, MD
–Vivianna Van Deerlin, MD, PhD
AD LBD-AD
DLB
PD & PD-D
Questions?