Studies in Parkinson’s Disease Studies in Parkinson’s Disease and Dystonia: An Epidemiologic and Dystonia: An Epidemiologic

Perspective Perspective

Caroline M Tanner MD PhDDirector, Parkinson’s Disease Research, Education and Clinical

Center, San Francisco Veterans Affairs Medical Center,&

Professor, Neurology, University of California-San Francisco, CA, USA

Presented at Parkinson’s Australia, Adelaide, May 2015

Topics Topics • Primary torsion dystonia (PTD)

– Incidence of PTD

– Risk factors for PTD

– Diagnostic error in PTD

• Parkinson’s Disease

– World wide distribution

– Studies of causes

– Next steps: treatment, prevention

Challenges in Studying DystoniaChallenges in Studying Dystonia

• Rare • Many causes• Many syndromes • Requires expert identification• No biomarkers• No definitive post-mortem findings

How Common is Dystonia? Selected Prevalence Studies

Prevalence Study Nation Study Design CasesPrevalence/ 100,000

Li et al, 1985 China Door-to-door 2 3.0

Nutt et al, 1988 USAMedical records

linkage17 29.5

Kandil et al, 1994 Egypt Door-to-door 4 10.0

Nakashima et al, 1995 Japan Neurology clinics 15 6.1

Duffey et al, 1998 EnglandNeurology clinics; population survey

335 12.9

ESDE, 2000 8 Euro. Countries Neurology clinics 677 11.7

Muller et al, 2002 Italy Population sample 6 732

Castelon-Konkiewitz et al, 2002

Germany Neurology clinics 182 10.1

Butler et al, 2004 England Medial records linkage 43 43.0

Sugawara et al, 2006 Japan Medical clinics 169 15.1

Das et al, 2007 India Population sample 23 49

Problems with Studying Prevalent CasesProblems with Studying Prevalent Cases

May not accurately represent all disease:

Persons with long survival , more benign course over-represented

SOLUTION: Investigate incident cases• # of new cases of disease in a population • More accurate estimate of disease frequency

PROBLEM: Few Incidence studies of PTD:1980: Israel 8 cases, est. .042/100,000 & 1985,88, 2003: Minnesota, 36 cases, est. 0.2/100,000 – 1.2/100,000

• Fresno

• San Francisco• San Jose

• Sacramento

Serves 30% of population in the geographic region

Group practice prepaid HMO with > 3 million members

21 hospitals, 43 outpatient clinics

Physicians work only for KPMCP (> 65 neurologists)

Uniform health care coverage

Representative of underlying population for ethnicity, age, SES

Kaiser Permanente Northern California Medical Plan

Computerized utilization report

(n = 7711)

BIDS-m Questionnaire;

exam

Incident casesExpert medical record review

Case Ascertainment Methods

Stage 1

Neurologist utilization reviewStage 2

Stage 3

Incidence period 2003-2007

Stage 4

MD Permission to contact

Cannot contact / Refused

Expert diagnosis

Incidence of Dystonia by Subtype / 100,000 p-y Incidence of Dystonia by Subtype / 100,000 p-y adjusted for age, gender to US Census 2000 2003-adjusted for age, gender to US Census 2000 2003-2007 KPNC2007 KPNC

0

1

2

3

4

5

AllWomenMen

N=288

N=192

N=139

N=747

COMPARISON: Nutt et al: Blepharospasm: 0.46/105 p-y; Torticollis: 1.1/105 p-y; Spasmodic dysphonia: 0.27 /105 p-y;

1.71 3x

0.82 ;3x1.33

4.43

4.12

4.75

1.11

1.45

3.42

2.88

1.51

1.91

1.06

1.39

0.59

0.38

1.52

1.14

1.20

0.870.67

0.36

0.95

0.68

0.55

0.80

0.85

0.60

0.20

0.09

Risk Factors for Dystonia Risk Factors for Dystonia Some Proposed Nongenetic Risk FactorsSome Proposed Nongenetic Risk Factors

• Physical activity/overuse

• Antecedent trauma: local; head injury

• Infection, fever

• Smoking (inverse)

• Elevated serum homocysteine

• Antecedent or comorbid anxiety disorder (vs. hemifacial spasm patients)

• Very little risk factor investigation to date

Preliminary Assessment: Medically Documented Trauma Preliminary Assessment: Medically Documented Trauma and Risk of Primary Dystonia in Kaiser Permanente N and Risk of Primary Dystonia in Kaiser Permanente N

California 2003-2007California 2003-2007

2.91

1.78 1.76

00.5

11.5

22.5

33.5

44.5

OD

DS

RA

TIO

S*

*Adjusted for age, gender, membership time before ref date

Cases: 617Controls: 6009

Risk Factors in Incident Laryngeal Dystonia: Risk Factors in Incident Laryngeal Dystonia: Case Control - N CA Kaiser Case Control - N CA Kaiser

• LD Cases & Controls Matched for Age, Gender• Questionnaire & Telephone Interview • Self-reported Medical history, lifestyle, family history, job & hobby with

repetititve tasks

Key Results:

Ever Held a Job or Hobby Requiring Repetitive Use if Voice?: SD 56% , Controls 44%

OR*: 8.1 (95% CI: 3.1, 21.2)

Ever smoked // smoked 100 or more cig:

SD 32%, Controls 68%; OR*: 0.44 (95% CI: 0.22,0.90)

* Adjusted age, gender

Diagnostic Error in Dystonia Diagnostic Error in Dystonia STUDY GOALSSTUDY GOALS

• To identify the frequency of incorrect diagnosis of dystonia.

• To describe the characteristics of diagnostic error associated with primary dystonia

Methods:• Interview incident cases with PTD• Analyze health care contacts prior to diagnosis of dystonia in cases & index date in matched controls (1 case:10 controls)

Consequences of Diagnostic Error in Consequences of Diagnostic Error in Dystonia – Response to InterviewDystonia – Response to Interview

1. From the time you first started noticing symptoms, how long did it take to be diagnosed with dystonia?

Mean: 5.1 years (Range: 1 week – 50 years)

Median: 2 years

2. How many MD visits before correct diagnosis?

Mean: 4.2 (Range: 0 - 90) ; Median: 2

3. How many M.D.s? 50% saw >1 specialty ; 24% > 3

4. Other diagnosis? 54% given some other diagnosis before dystonia; 33% psychiatric diagnoses

Consequences of Diagnostic Error in Consequences of Diagnostic Error in Dystonia – Interview QuestionsDystonia – Interview Questions

Did you have any unpleasant/harmful effects from the delay in the correct diagnosis of dystonia ? 64% Yes

Types of unpleasant/harmful effects:

95% Personal worry/anxiety93% Emotional well-being 77% Job/occupation69% Recreation/ community activities59% Family relationships51% Friendships

Consequences of Diagnostic Error in Consequences of Diagnostic Error in Dystonia – Interview QuestionsDystonia – Interview Questions

Have you needed to change your job duties or activities as a result of dystonia symptoms? Yes 39%

Have the treatments you received for dystonia allowed you to resume job activities? Yes 75%

Sy

mp

tom

ati

c

Ascertainment of Dystonia: The Iceberg Problem

Asymptomatic

Symptoms, Not Diagnosed:

• Misdiagnosed

• Did not seek care

No Rx

Rx

Iden

tified

clin

ically

How many cases are missed?

Future Directions in Epidemiologic Future Directions in Epidemiologic Investigation of Dystonia Investigation of Dystonia

• Improved case recognition

• Risk factor studies – are there environmental triggers? Is there gene-environment interaction? Risk factors determining expression in gene carriers?

• Animal models – what mechanisms?

• Better treatments

• Prevention

What Causes Parkinson’s Disease?

Why Study Etiology?

- May lead to better treatments

- May identify persons at risk

- May lead to prevention of disease or slowing of disease progression

Estimated Age-Specific PD Incidence Kaiser Permanente of N. California, 1994 - 1995

0

50

100

150

200

250

<30 30-39 40-49 50-59 60-69 70-79 80+

PD

In

cid

en

ce p

er

100,0

00 p

-y

Male

Female

Age (years)

PD Incidence Increases with Age

Life Expectancy Is Expected to Increase World Wide

AGE 60+

2015

22

Consequently, the global burden of Parkinson’s disease is expected to increase

Change in number of people with Parkinson’s disease in the world’s most populous nations from 2005 to 2030*

Source: Dorsey et al, Neurology 2007;68:384-6

*Among individuals over 50 in the world’s ten most and Western Europe’s five most populous nations

Consequences for Society

Costs: –Direct costs of health care–Indirect costs:

• Loss of years worked, lost societal contributions

• Mental & physical costs • Affects person with PD & family members, colleagues, friends

Can We Bridge the Gap ?

Unmet needs

Knowledge gaps

What Causes Parkinson’s Disease?

MPTP-Induced Parkinsonism

The First Big Clue Langston, Ballard, Tetrud 1983

Cluster of subacute parkinsonism

in young narcotics addicts

Similar to PD:

BUT• MPTP injection is rare

N

CH3

• Same signs as PD

• Progressive worsening in some

• Improves with l-dopa

• Same side effects from l-dopa

• Not a likely cause of PD

The toxicologic effects of MPTP suggested that similar

chemicals, present in the environment, could cause PD

Is Parkinson’s disease an

environmental disorder?

“These findings favor monogenic autosomal dominant inheritance and show reason to argue against a multifactorial etiology or heteroplasmy.”

Duvoisin & Johnson Brain Pathology 1992

Is Parkinson’s Disease a monogenic disorder?

Is Parkinson’s disease an inheriteddisorder?

Twins: Mother Nature's Controlled Study

•MZ twins share ~100% of genes

•DZ twins share ~50% of genes

Hypothesis: If Parkinson’s disease is primarily a genetic disorder, then concordance in MZ twins should be > than in DZ twins.

NAS/NRC WWIIVETERAN TWINS ROSTER

31,848 TWINS BORN 1917 - 1927

Results: MZ & DZ concordance similar ; Except young onset MZ > DZ

Conclusion: Environment is an important contributor to the cause of PD

Tanner, et al, JAMA, 1999

Inherited parkinsonism is rare, but yields clues to the cause of typical Parkinson’s Disease

• Current evidence suggests only ~ 10 % of all PD is caused by a single genetic defect

• In many, inherited parkinsonism begin at an earlier than expected age • In many, inherited parkinsonism has different clinical features than “typical”

PD

Normal protein products of these genes are all likely involved in protein degradation & /or cellular response to toxicant injury or oxidative stress

Studying Twin Pairs Discordant for PD Can Yield Clues Regarding

Causes

OR 95% CI p-value*

Overall 3.0 1.14-9.2 0.023

MZ 3.3 0.86-19 0.092

DZ 2.7 0.64-16 0.23

Head Injury and PD Risk in WWII Veteran TwinsGoldman, Tanner et al, Annals of Neurology 2006

Subjects: 93 discordant pairs with complete information 26 pairs with at least one head injury

Results: 14.7% with head injury; 7.8% hospitalized Head injury 37.4 yrs (mean) before PD onset Increased Risk of PD with head injury

*McNemar’s

PD risk further increased with > 1 head injury: 1 injury: OR 2.6 (1.07,6.5; p = 0.035)2 injuries: OR 5.1 (0.54, 48; p = 0.16)

Test for trend 0.042

Head Injury & PD

Mild-moderate head injury associated with PD in >70% of studies.

2-3 fold increased risk Biologic Plausibility:• Triggers chronic

inflammatory process• Oxidative stress• Protein aggregation• Mitochondrial damage• Disrupts Blood Brain Barrier

BUT only some people with head

injuries develop PD Why?

Gene-Environment Interaction in PD

Goldman, Tanner, et al, Annals of Neurology 2012

Gene: -synuclein

Environment: Head injury

PD Pathology: Lewy Bodies

Lewy Bodies are mostly aggregated -synuclein protein

Blo

od

-bra

in b

arri

er

bre

akd

ow

n

Complex I↑ROS

Infla

mm

ator

y

casc

ade

α-Synuclein aggregation

Microglial activation

Release Inflammatory cytokines: Interleukins IL-1, IL-6;TNF-α; COX-2

Head-Injury

-synuclein in human brain after injury -synuclein in mouse striatum after moderate cortical impact

Research Question

Does -synuclein gene variant modify the effect of head injury

on PD risk?

Alpha-Synuclein Gene Variant is Associated with Small Increase in PD Risk

Gene Variant 2 makes more alpha-synuclein protein than Variant 1

10

1Risk from

geneRisk if BOTH

PD

Ris

k

5

2

BOTH Head Injury & Synuclein Gene Variant

Goldman, Tanner, et al, Ann Neurol, 2012

Risk from head injury

50%70%

1000%

Parkinson’s Disease : A Complex Disorder

Genetics loads the gun

Environment pulls the trigger

Environmental Chemical Exposures and Parkinson’s

Disease

Since the 1990s, over 20 case-control studies have shown an association of PD and pesticides. PD risk is usually

about twice as high in pesticide exposed persons.

BUT

•Broad chemical categories

•Few specific agents identified

SEARCH Study: Case Control Study of Occupational Risk Factors

Tanner et al, Arch Neurol, 2009;66(9):1106-1113

Mechanism

↑ROS*adjusted for age, gender , smoking

N+

CH3

Cl -

N+

CH3

Cl -

519 PD cases, 511 controls in 8 MD centers

Lifelong, job-task-based occupational histories; other risk factors

Paraquat: OR* = 2.8 (95% C.I.: 0.8, 9.7)

Cl

ClO

O OH

2,4-Diphenoxyacetic acid (2,4-D) : OR* = 2.6 (95% C.I.: 1.03, 6.48)

? Alpha Synuclein

aggregation

Mechanism:

July 2009: Agent Orange Linked to Parkinson's & Heart Disease

Institute of Medicine Study finds "suggestive but limited evidence" of increased risk of both conditions among Vietnam vets.

Agent Orange & Parkinson’s Disease Risk

2,4-D 2,4,5-T

2,3,7,8 tetrachlorodibenzodioxin

Operation Ranch Hand: 1962-1971 20 x 106 gallons Agent Orange

FAME Study: PD in Agricultural Health Study Tanner, Kamel et al, 2011

52,000 farmers, 32,000 spouses in Iowa & N Carolina screened for PD

In-person examination, videotape, blood, dust, soil

Lifelong history: occupation, pesticides, other risks

112 PD cases, 368 controls

ParaquatParaquat Increased Risk of PD: All OR = 2.3 (95% C.I. 1.45, 4.3) Men OR = 2.5 (95% C.I. 1.3, 4.7)

Models adjusted for age, gender, state, ever smoking, ever pesticide use

N+

CH3

Cl -

N+

CH3

Cl -RotenoneRotenone Increased Risk of PD: All OR = 2.3 (95% C.I.: 1.2, 4.3) Men OR = 2.8 (95% C.I.: 1.4, 5.8)

H

H

O

Paraquat, GST-T1 and PDGene-Environment Interaction

1

4

7

10

13

Normal Gene Mutant

Risk of PD Associated with Joint Occurrence of Paraquat Exposure and a Variant of the GST-T1

Gene

Ris

k of

PD

Goldman et al, 2012

Compound Odds ratio95%

Confidence Interval

P-value

N-hexane 1.27 0.40-4.07 0.69

Toluene 1.28 0.49-3.31 0.61

Xylene 2.24 0.43-11.6 0.34

CCl4 2.32 0.88-6.11 0.088

TCE 6.11 1.15-32.5 0.034

PERC 10.5 0.97-113 0.053

TCE or PERC

8.94 1.70-47.0 0.010

Solvent Exposures in 99 Twin Pairs Discordant for PD Goldman et al , 2010

Complex I

Cl Cl C=CCl H

Consistent with occupational cluster (Gash et al 2008) & TCE rat model (Liu et al, 2010)

Can Combined Effects of Several

Environmental Factors Influence

Risk of Parkinson’s Disease ?

Head injury Paraquat Use Odds Ratio

No No 1.0 (ref)

Yes No 1.2

No Yes 1.8

Yes Yes 4.2

83 PD and 328 controls with complete data in FAME • Head injury in 19% • Paraquat used by 17%, all men

Head injury and paraquat use were synergistically associated with increased PD risk

Both cause oxidative stressJoint effects are synergistic in a recent animal model (Hutson, 2011).

Head Injury, Paraquat Use and Risk of PDGoldman et al 2012

Purely Genetic PD is RarePurely Environmental PD is Rare

Most PD is likely due to the combined effects of genetic predisposition and environmental

exposures

This is a hopeful finding, because environment can be

changed!

Is Secondary Prevention of Parkinson’s Disease Possible?

Identify persons “at risk” for PD before symptoms manifest

Intervene to prevent the development of PD

Some Factors Associated with a Lower Risk of Parkinson’s Disease – Possible

Disease Modifying Treatments?

Physical activity

Cigarette smoking

Coffee & Tea Drinking

Higher serum urate

Female gender; Estrogens?

Anti-inflammatory drugs

(ibuprofen)

Ca channel blockers

Higher Vitamin D

Statins?

PUFAs?Flavonoids?

Why Have Trials of Disease Modifying Therapies Been Inconclusive?

Is the experimental treatment ineffective?

Is the intervention too late?

Str

iata

l dop

amin

e

0%

80%

100%

20%

60%

40%

PARKINSON’S DISEASE

PRODROMAL

At PD diagnosis:

• 50% neuron loss in the substantia nigra

•80% striatal dopamine deficit

PRECLINICAL

Who May Be “At Risk” for PD ?

• Persons with clinical features highly predictive of the onset of PD in the future: “prodromal” PD: e.g., RBD, hyposmia

• Persons with genetic susceptibility: primary

& “risk” genotypes

• Persons exposed to certain toxicants

DILEMMA: PREDICTIVE VALUE VERY LOW FOR MOST FEATURES

Reliable Biomarkers Needed!

Next Steps

Systematic Prospective Follow-up of Well-

Characterized Populations

PPMI The Parkinson’s Progression Markers Initiative: A

Prospective Biomarkers Study

OBJECTIVES

Ideal to identify a biomarker tool set to inform decisions at early stages of drug development and clinical testing

Frasier et al, 2010; Marek et al 2011

Early Untreated PD

POPULATIONS

Matched Controls

RBD

LRRK2, SNCA Families

Hyposmia

Is Preventing PD Possible? Preliminary Results

Primary Prevention:

– Remove causative factors

– Disease process never initiated

Odd

s R

atio

1

Furlong, Tanner, Goldman,et al 2014

1Adjusted for age, sex, state, smoking

The Next Step:Identifying Risk in Populations: California Parkinso

n’s Disease Registry [AB 2248, Frommer, Ch. 945, 2004]

Pilot project in 4 counties funded by NETRPAll PD cases –> reduce bias , findings generalizable Identify incidence, prevalence, disease clusters Link to environmental toxinsIdentify PD subgroups Identify biomarkers

Examples of Toxicant Monitoring in CA

http://www.epa.gov/espp/litstatus/effects/redleg-frog/paraquat/analysis.pdfhttp://www.atsdr.cdc.gov/substances/SubstanceMapResults.asp Accessed 3/14/2012

Understanding Parkinson’s Disease

Clinical Research: Epidemiology, Clinical Trials

Basic Scientists:

Laboratory studies

Clinicians:Diagnosis, treatment

DISEASEDISEASE PREVENTIONPREVENTION

A Dynamic Multidisciplinary Process

Our Supporters

Research Study Participants & Families

Neurotoxin Exposure Treatment (Parkinson’s)

Research (NETPR)

The Valley Foundation

James & Sharron Clark

THANK YOU !