Studies in Parkinson’s Disease and Dystonia: An Epidemiologic Perspective Caroline M Tanner MD PhD...
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Transcript of Studies in Parkinson’s Disease and Dystonia: An Epidemiologic Perspective Caroline M Tanner MD PhD...
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
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
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
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
“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?
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
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
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
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%
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)
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