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?