1. James Parkinson Born in 1755; died 1824. Lived entire life in London. Political reformer Paleontologist Physician

3. The Shaking Palsy Observations based on 6 cases 2 cases with follow-up 1 case with no follow-up 3 cases seen on the streets of London Observations Rest Tremor Gait and Posture (flexed posture and festination) Described bradykinesia but did not name Missed rigidity

4. “Before Concluding these pages, it may be proper to observe once more, that an important object proposed to be obtained by them is, the leading of the attention of those who humanely employ anatomical examination in detecting the causes and nature of diseases, particularly to this malady. By their benevolent labours its real nature may be ascertained, and appropriate modes of relief, or even of cure, pointed out.” James Parkinson An Essay on the Shaking Palsy, 1817

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7. Lewy Body Lewy, 1913 Described intraneuronal inclusions (Lewy bodies).

8. LEWY BODY NEURON

9. Substantia Nigra Von Economo, 1918 Noted involvement of substantia nigra in encephalitis lethargica. Tretiakoff, 1919 Described neuronal loss in substantia nigra in Parkinson’s disease.

11. Arvid Carlsson

12. Dopamine Carlsson, 1957 Found high concentrations of dopamine in striatum. Deduced that dopamine was a neurotransmitter and not a precursor for norepinephrine. Depletion of dopamine produced akinesia in rabbits which could be reversed by L-DOPA.

13. Oleh Hornykiewicz

14. Dopamine Hornykiewcz, 1960 Found that dopamine was depleted in striatum of people with PD.

15. CAUDATE PUTAMEN

17. L-DOPA Cotzias, 1967 First convincing evidence that D,L- DOPA, a precursor of dopamine, reversed parkinsonism.

18. Parkinson’s Disease: 20 th Century PD defined by motor symptoms (rest tremor, rigidity and bradykinesia). Loss of dopamine explained clinical features of the disease. Search for etiology of PD focused on unique features of dopamine neurons that led to their selective degeneration.

19. NAMELOCUSGENEINHERITANCE Park 14qSynucleinAD Park 26qParkinAR Park 32p?AD Park 44p-q Synuclein triplication AD Park 61pPINK-1AR Park 71pDJ-1 proteinAR Park 812pLRRK-2AD Single Gene Mutations and PD I

20. Genetics Discovering alpha-synuclein mutation or gene duplication as causes of PD Recognizing alpha-synuclein is a component of Lewy bodies

21. Braak et al., 2003 Interneuronal Lesions Related to Parkinson’s Disease

22. Braak et al., 2006 Braak’s Staging for Parkinson’s Disease

23. Li et al., 2002 NormalParkinson 08/25/9901/18/01 Myocardial 18 F-Dopamine Scans

24. Iwanga et al., 2000 Cardial Pexus in PD

25. Lewy Body Pathology in Autonomic Nervous System in PD Hypothalamus – 100% Intermediolateral columns – 96% Sympathetic ganglia – 96% Dorsal motor nucleus X – 100% ? Sacral parasympathetic ganglia – 100% Enteric nervous system (VIP neurons) – 93%

26. Autonomic Nervous System as Portal for Pathogen or Toxin? Braak et al., 2003

27. Parkinson’s Disease: 21 st Century PD recognized as a multisystem disorder with wide spread pathology. Loss of dopamine may occur later in disease process and primarily explains motor symptoms. Search for etiology of PD is no longer focused on unique features of dopamine neurons that lead to cell death.