Parkinson’s Disease

Paul Tuite, MDUniversity of Minnesota

Director of Movement Disorders

Parkinson’s disease (PD)

Early Clinical FeaturesTremorSlownessStiffnessStooped postureAltered gaitSmall handwritingSoftened voiceOthers

Epidemiology of PD

• Incidence– 5-24/ 105 worldwide (USA: 20.5/105)– Incidence of PD rising slowly with aging population

• Prevalence– 57-371/105 worldwide (USA/Canada 300/105)– 35%-42% of cases undiagnosed at any time

• Onset– mean PD 62.4 years– rare before age 30; 4-10% cases before age 40

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Risk Factors

• Definite: Old age

• Highly likely: MZ co-twin with early-onset PD

• Probable: Positive family history

• Possible: Herbicides, pesticides, heavy metals, proximity to industry, rural residence, well water, repeated head trauma, etc.

• Possible protective effect: Smoking

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Black line is age related loss

A. Toxin causes rapid loss of neurons at exposure

B. Genetic cause with variable rates of loss of neurons depending on the gene

C. Genetic and toxic model A H V Schapira; BMJ 1999;318:311-314

Genetics of PD

• PARK1: (dominant), 4q21: alpha-synuclein • PARK2: (mainly recessive) 6q25-q27: Parkin • PARK3: (dominant, reduced penetrance) 2p13 • PARK4: (dominant, early onset) 4p15 • PARK5: (susceptibility gene) 4p14: UCH-L1 • PARK6: (recessive) 1p35-p36 • PARK7: (recessive) 1p36 • PARK8: (dominant) 12p11 • PARK9: (Kufor-Rukeb syndrome; recessive) 1p36 • PARK10: (susceptibility gene) 1p32 • FTDP17: (susceptibility gene) 17q21: Tau

The Scientist 1997

PD & Environmental Factors

Increased Risk– Pesticides

• Paraquat• Organochlorines• Carbamates

– Welding– Miners

Decreased Risk– Coffee consumption

• ?Caffeine

– Smoking• Nicotine

– MAO B inhibition

– CYP2D6

Genetics Environment

Mitochondria Complex I Defects

Protein Accumulation

OxidativeStress

ExcitotoxicityAbnormal

ProteinDegradation

Cell Death

Betarbet et al. Brain Path 2002;12:499-510.

Mitochondria

Complex I Mitochondrial Inhibitors

Betarbet et al. Brain Path 2002;12:499-510.

ROTENONE

Betarbet et al. Brain Path 2002;12:499-510.

GAO 2003 inflamm in PD TIPS

Neurorestoration

Neuroprotection

Rate of development of disease

A H V Schapira; BMJ 1999;318:311-314

THERAPIES UNDER DEVELOPMENT