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Parkinson’s Disease !!

Caroline M. Tanner, M.D., Ph.D.

Disclosures: Consultant: Ultragenyx, Neurocrine; DSMC Service: Biotie, Voyager, Intec

Parkinson’s Disease: outline

� PD – the clinical syndrome � Descriptive epidemiology � Pathology of PD � Treatments for PD � Etiology

1817 – James Parkinson -  6 people: 3 seen only on the street -  First complete description of motor

syndrome

Jean-Martin Charcot, 1888 Sir William Gowers, 1888

-  Insidious onset -  Late life

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Parkinson’s Disease: The Motor Syndrome

Resting Tremor Bradykinesia

Rigidity Postural Reflex Impairment

PD Descriptive Epidemiology

o  PD occurs everywhere in the world

o  95% of cases begin after age 50

o  Incidence increases with age at least through the 9th decade

o  Men > women

o  Risk may be related to ethnicity or geography

o  Unclear if incidence (proportion of new cases) is increasing over time

o  Absolute number of cases is expected to double world wide as population ages

Parkinson’s disease: pathology – classical

Lewy bodies, Lewy neurites: Protein aggregates; alpha-synuclein Substantia nigra

depigmentation: Loss of dopaminergic neurons Healthy Parkinson’s

disease

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Parkinson’s disease: clinical course

�  Stage 1: Unilateral involvement à �  Stage 2: Mild bilateral involvement à �  Stage 3: Mild to moderate bilateral involvement,

Some postural instability, independent à Stage 4: Severe disability, Able to walk/stand unassisted à�  Stage 5: Wheelchair bound or bedridden à

Hoehn and Yahr Scale

Langston 2006

PD non-motor symptoms: categories �  Autonomic

�  Orthostasis�  Constipation�  Urinary urgency�  ED

�  Sleep�  RBD�  Poor sleep maintenance

�  Sensory�  Loss of smell�  Loss of taste�  Pain

�  Psychiatric�  Fatigue�  Depression�  Anxiety�  Apathy�  Psychosis

�  Cognitive�  Executive dysfunction�  Impaired attention�  Impaired visuospatial

function�  Relative preservation of

anterograde memory�  PD-MCI�  PDD

Barrone et al. 2009, Mov Disord

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è Midlife olfactory deficits predict Lewy bodies Ross et al, 2000

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è Midlife constipation predicts PD Abbott et al, 2001

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Incidence

è Midlife obesity predicts PD Ross et al, 2000

Some Clues from the Honolulu Asian Aging Study

Are the first signs non-motor features?

Does PD Start in Midlife?

Neurodegeneration Begins Before Onset of Motor

Signs

Constipation

??

Hyposmia

Braak Stages of CNS Pathology for PD

Prodromal features may identify an “at risk”

population

Substantia nigra not first site of injury in PD Lewy neurites found in olfactory bulb & autonomic nervous system

REM Sleep BD ↓Heart Rate Variability

Stri

atal

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

Parkinson’s Disease – Clinical Course

4 – 20+ years as long as 30 + years

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PD Treatment Overview

Goals of therapy: Parkinson’s disease � Slow or halt progression

� Relieve signs and symptoms of disease

� Avoid side effects

PD Treatment: medications

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Drug Therapies for Parkinson’s Disease Levodopa (Sinemet) Immediate Release (IR)

COMT Inhibitors Entacapone (Comtan), Tolcapone (Tasmar)

Long-acting Levodopa Controlled Release (CR) Rytary

Dopamine agonists

Amantadine Trihexyphenidyl (Artane) MAO-B inhibitor

Selegiline or Rasagaline

DuopaLevodopa Continuous Infusion

PD Treatment: medication adverse effects �  Levodopa (Sinemet/Rytary): nausea, orthostasis, psychiatric, dyskinesias

�  Dopamine Agonists: impulse control disorders, edema, psychosis, confusion, orthostasis, dyskinesias, sleep attacks

�  MAO-B inhibitors: hypertension, insomnia, drug interactions

�  Anticholinergics: dry mouth, sedation, delirium, confusion, hallucinations, constipation, urinary retention

�  Entacapone: diarrhea, orange urine

�  Tolcapone: liver failure

�  Amantadine: confusion/hallucinations, nightmares, anticholinergic effects, livedo reticularis

PD Treatment: motor fluctuations

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Video

PD Treatments: Deep Brain Stimulation (DBS)

Permanently implanted brain pacemaker1.  Lead2.  Extension Wire3.  IPG

•  Increases the best “on-medication” state by 4-5 hours daily

•  Improves motor function by 25-50%

•  Raises the ceiling for off-medication times

•  Reduction in medication dosing (30-50%)

Deep Brain Stimulation: GPi vs. STN

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Videos

PD Treatments: role of exercise

•  SHOW DATA ON THIS

Parkinson’s Disease Etiology

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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

Video

Some Factors Associated with a Higher Risk of Parkinson’s Disease

Pesticides

Head Injury

Solvents

Male Gender

♂

AgeMetals?

Polychlorinated Biphenyls

Air Pollution

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Physical activity

Tobacco Use/Exposure Coffee & Tea

Drinking

Higher serum urate

Female gender; Estrogens??

Anti-inflammatory drugs (ibuprofen)

Ca channel blockers

Higher Vitamin D

Statins?

PUFAs? Flavonoids?

Some Factors Associated with a Lower Risk of Parkinson’s Disease: Clues for Preventative Therapies?

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

PD

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

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?

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Gene-Environment Interaction in PD Goldman, Tanner, et al, Annals of Neurology 2012

Gene: α-synuclein

Environment: Head injury Lewy Bodies

are mostly aggregated α-synuclein protein

10

1 Risk from

gene Risk if BOTH

PD

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5

2

Gene- Environment Interaction: 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

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Purely  Gene*c  PD  is  Rare  Purely  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 Preventing PD Possible?

Primary Prevention: Remove causative factors: disease process never initiated

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Paraquat   Permethrin  

Increased  Risk  of  PD  Was  Not  Observed  in  Farmers  Using  Gloves  During  Pesticide  

Application      

GLOVES   NO  GLOVES  

Odd

s R

atio

Furlong, Tanner, Goldman, et al, 2015

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Research  (NETPR)  

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