1. www.wemove.org Parkinson’s Disease Slide Library Version 2.0 - All Contents Copyright © WE MOVE 2001 Parkinson’s Disease: Epidemiology, Etiology, and Pathogenesis Part 1 of 7

2. www.wemove.org Clinical Features/Cardinal Signs 1817: James Parkinson “An Essay on the Shaking Palsy” Diagnosis requires 2 of 3: –Bradykinesia; rigidity; tremor (primarily at rest) Other signs: Masked face, hypovolemic speech, swallowing difficulty, micrographia, flexed posture, shuffling gait, start hesitancy and freezing Onset: Insidious, unilateral progressing to bilateral

3. Epidemiological Considerations Idiopathic PD = Lewy body disease Misdiagnosis common Neurofibrillary tangle parkinsonism with distribution sites similar to Lewy body in PD is clinically indistinguishable from PD Therefore, for incidence and prevalence studies, all variants of PS should be included Studies of etiology should be restricted to single pathological entity-Lewy body disease www.wemove.org

4. Classification of Parkinson Syndromes in a Community Idiopathic PD ~ 85% of all PS cases Neuroleptic-induced parkinsonism (DIP) 7% - 9% MSA (SDS, SND, OPCD) ~ 2.5% PSP ~ 1.5% Vascular parkinson syndrome ~ 3% PS due to MPTP, CO, Mn, recurrent head trauma is extremely rare No new cases of postencephalitic parkinsonism since l960s www.wemove.org

5. Descriptive Epidemiology of Parkinson Syndrome Incidence –5-24/ 10 5 worldwide (USA: 20.5/10 5 ) –Incidence of PS/PD rising slowly with aging population Prevalence –57-371/10 5 worldwide (USA/Canada 300/10 5 ) –35%-42% of cases undiagnosed at any time Onset –mean PS 61.6 years; PD 62.4 years –rare before age 30; 4-10% cases before age 40 www.wemove.org

6. Morbidity in Parkinsonism Progressive (except drug-induced and vascular) –More rapid in MSA and PSP than in PD –Non-linear, wide individual variations Prognosis is best in non-demented PD cases Symptomatic and QOL improvement with L-dopa www.wemove.org

7. Mortality in PS Reduced life expectancy –Mean survival after onset ~ 15 years –longer in non-demented PD cases –longer with L-dopa use PD survival >MSA, PSP The most common causes of death: –pulmonary infection/aspiration, urinary tract infection, pulmonary embolism and complications of falls and fractures www.wemove.org

8. Survival in Parkinsonism Prior to Levodopa

9. Pathology of Parkinson’s Disease

10. Main Biochemical Abnormality Marked striatal DA depletion –“Striatal dopamine deficiency syndrome” At death, DA loss > 90% <50% DA loss is asymptomatic ~70% DA loss for symptom manifestations Severity of DA loss best correlates with bradykinesia in PD www.wemove.org

11. Normal Basal Ganglia Functional Anatomy

12. Function Anatomy of Parkinson’s Disease

13. Parkinson’s Disease 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 www.wemove.org

14. Cause of PD Unknown in most cases; not accelerated aging Genes –AD inheritance very rare; mutation unknown –mutation of Alpha synuclein gene (chromosome 4q) identified in one large Italian (Contursi) and 5 Greek autosomal dominant families –mutation of parkin gene in autosomal-recessive juvenile parkinsonism Environment –Majority of cases believed caused by environmental factor (s) but none identified so far Genes plus environment? www.wemove.org

15. Environmental Toxin Model: MPTP Reproduces all the major motor features of PD MAO-B MPTP MPP+ (In astrocytes) Dopaminergic neuron mitochondria Inhibits NADH--CoQ1 (Complex I) of mitochondrial respiratory chain ATP production falls Cell death www.wemove.org

16. Twin Studies Tanner et al., 1999: WWII Veterans Twins Registry –Pairwise concordance similar for all MZ and DZ twins; equal for onset > age 50 –“... suggests that typical PD diagnosed after age 50 years has no genetic component." Piccini et al., 1999: Longitudinal PET study –Concordance for dopaminergic dysfunction 75% for MZ, 22% DZ –"These data point to a significant genetic role in the development of nigrostriatal dopaminergic dysfunction." –Necessity of concomitant environmental factor not ruled out www.wemove.org

17. Hypotheses of SN Pathogenesis Apoptosis; mitochondrial?  oxidative stress,  antioxidant capacity –  iron in neuromelanin,  free radical formation –  complex I and glutathione in SNc Slow or weak excitotoxicity –ATP loss  Membrane potential decline  persistent activation of NMDA receptors  calcium influx, nitric oxide, superoxide, peroxynitrite formation Inadequate neurotrophic factor(s) www.wemove.org

18. Preclinical Parkinson’s Disease No specific clinical markers known 4-13% of autopsies in elderly showing incidental Lewy bodies are regarded as preclinical cases Increased risk of neuroleptic parkinsonism Duration of preclinical phase unknown (several years to several decades?) PET studies may identify preclinical cases www.wemove.org

19. Faculty for the WE MOVE Parkinson’s Disease Teaching Slide Set Mark Stacy, MD Barrow Neurological Institute Phoenix, Arizona, USA Charles H. Adler, MD, PhD Mayo Clinic Scottsdale Scottsdale, Arizona, USA Kathleen Albany, PT, MPH WE MOVE New York, USA Richard B. Dewey, Jr., MD University of Texas Southwestern Medical Center Dallas, Texas, USA William G. Ondo, MD Baylor College of Medicine Houston, Texas, USA Rajesh Pahwa, MD University of Kansas Medical Center Kansas City, Kansas, USA Ali H. Rajput, MD Royal University Hospital Saskatoon, Saskatchewan, Canada Lisa M. Shulman, MD Health Policy Fellow U.S. House of Representatives Washington, DC, USA Celia Stewart, PhD Mount Sinai Medical Center New York, New York, USA Reviewed by the Education Committee of the Movement Disorder Society www.wemove.org