Adina feldman doctoral thesis defence presentation

IF I ONLY HAD A BRAIN - Epidemiological Studies

of Parkinson’s disease

Adina L. Feldman

Doctoral Dissertation Defence

10 January 2014

The Brain

10 January 2014 Adina L. Feldman 2

Source: Sobotta’s Atlas of Human Anatomy (1908)

Midbrain

Motor

cortex

Parkinson’s disease (PD)

Clinical Symptoms

(parkinsonism)

Resting Tremor

Rigidity

Bradykinesia



Neuropathology

Degeneration of dopaminergic neurons in substantia nigra

Deficiency of dopamine in neuronal pathway controlling movement

Lewy bodies - Intracellular aggregation of α-synuclein


Incidence of PD

De Lau & Breteler, Lancet Neurology (2006)

Lifetime risk ≈ 1.3% (women) 2.0% (men)


Etiology of PD

Genetic risk factors

Heritability: 40% (Wirdefeldt, 2011)

Familial aggregation in first-degree

relatives: RR 2.9 (2.2-3.8) (Thacker, 2008)

Rare autosomal dominant

or recessive mutations (Lill, 2012)

11 risk loci (Lill, 2012)

Environmental risk factors

Smoking ↓risk (Hernan, 2002)

Caffeine (?) ↓risk (Hernan, 2002)

Socioeconomic and

Occupational risk factors

Pesticides ↑risk (Pezzoli, 2013)

Farmers (?) ↑risk (Van Maele-Fabry, 2012)

High education (?) ↑risk (Wirdefeldt, 2005)

Teachers, phycisians (?) ↑risk (Goldman, 2005)

Other non-PD parkinsonian disorders



With differential neuropathology and

parkinsonian symptoms

Multiple System Atrophy

Progressive Supranuclear Palsy

Corticobasal Degeneration

Cerebrovascular Parkinsonism

With dementia

Lewy Body Dementia

(Parkinson’s Disease Dementia)


Clinical overlap between PD and dementia

Cognitive impairment

Mo

tor

fun

ctio

n im

pai

rmen

t

PD

PDD

CvP LBD

VaD

AD Healthy

Aging

Comorbidity of PD and dementia

Relative risk of dementia in PD:

RR 1.7-5.9 (Aarsland, 2010)

Prevalence of dementia in PD:

24.5% (Aarsland, 2005)

Lifetime risk of dementia in PD:

≈ 60% (Aarsland, 2010)

PD: Parkinson’s disease AD: Alzheimer’s disease

CvP: Cerebrovascular parkinsonism VaD: Vascular dementia

PDD: Parkinson’s disease dementia LBD: Lewy body dementia


Comorbidity of PD and dementia - Hypotheses

1. PD-related pathological protein

aggregation of α-synclein and its

downstream effects cause

dementia-related pathology and

consequent cognitive symptoms. (Crews, 2009; Mandal, 2006; Iwai, 2000)

2. Overlap in environmental and/or

genetic risk factors for PD and

dementia (”shared familial risk”).

Familial

co-aggregation

of PD and

dementia


Familial coaggregation of PD and dementia

Van Duijn, Int J Epidemiol (1991)


Aims

Study I

To study the validity of register-based

PD case ascertainment

Study II

To explore the association between

incident PD and occupational

exposures to 14 compounds

Study III, IV & IVtw

To elucidate whether there is shared

familial risk for PD and dementia

To systematically review and synthesize

published studies on familial coaggregation

of PD and dementia

To investigate familial coaggregation of PD

and dementia in first-degree relatives

To investigate familial coaggregation of PD

and dementia in twins

To increase the understanding of the etiology of PD and

the causes of comorbidity of PD and dementia


Study I: The Validation Study


Methods

National Patient Register Sensitivity (1964-2009) PPV (1964-screening)

Cause of Death Register Sensitivity (screening-2008) PPV (within 3 years from screening)


Study I: The Validation Study


Study II: The Occupational Exposure Study


Methods

Old

cohort

Age (

years

)

Calendar year

Middle

cohort

Incidence / 100,000 PYR

1,000 5,000 10,000

PD


Methods & Results

Outcome

PD in NPR and CDR

Exposure

14 occupational exposures

ascertained by a Job Exposure

Matrix

Covariates

Educational status at baseline

Smoking status at baseline

Age in time-scale

(Sex)

Analysis

Cox proportional hazard

regression


Study III: The Systematic Review and Meta-Analysis


Methods

PubMed search

parkinson

AND

dementia OR alzheimer

AND

risk OR epidemiology

AND

familial

(risk / history / aggregation)

OR

parent / sibling / twin / relative


Study III: The Systematic Review and Meta-Analysis

Outcome

Dementia or AD

Exposure

First-degree family

history of PD

Covariates

Age, sex +

study specific

Analysis

DerSimonian & Laird

random effects model


Study IV: The Family-based Study


Methods

Outcome

Incident PD

Incident dementia

Exposure

At least one first-degree relative

ever affected by:

PD

Dementia

Covariates

Sex, Age in time-scale,

Number of informative relatives

Analysis

Cox proportional hazard regression

with robust SE


Study IV & IVtw

Dementia


1,000 5,000 10,000

PD

Dementia


1,000 5,000 10,000

PD

Study IV Study IVtw


Study IV & IVtw


What if Study IV had been published before

the systematic review and meta-analysis…?


Meta-analysis with Study IV included

Without study IV

Pooled HR 1.18 (1.00-1.39)

Outcome

Dementia or AD

Exposure

First-degree family

history of PD

Covariates

Age, sex +

study specific

Analysis

DerSimonian & Laird

random effects model


Conclusions

Study I

PD register-based case ascertainment

in the NPR and CDR is valid for use in

epidemiological studies, although not

perfect.

The most optimal PD case definition is

achieved when using primary hospital

discharge diagnoses.

Study II

Occupational exposure to inorganic

dust may be a risk factor for PD in

Swedish men who were of working age

in the 1960’s and 1970’s.

Study III, IV & IVtw

There may be an association of modest

magnitude between dementia risk and

positive first-degree family history of

Parkinson’s disease, indicating the

presence of some familial coaggregation

of these disorders.


Thank You!!

By Jorge Cham of Piled Higher and Deeper (www.phdcomics.com)

Adina feldman doctoral thesis defence presentation

Health & Medicine

Transcript of Adina feldman doctoral thesis defence presentation