James Parkinson Born in 1755; died 1824. Lived entire life in London. Political reformer...
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James Parkinson
Born in 1755; died 1824.
Lived entire life in London.
• Political reformer
• Paleontologist
• Physician
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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
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“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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Lewy Body
Lewy, 1913
Described intraneuronal inclusions (Lewy bodies).
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LEWY BODYLEWY BODY
NEURONNEURON
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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.
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Arvid Carlsson
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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.
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Oleh Hornykiewicz
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Dopamine
Hornykiewcz, 1960
Found that dopamine was depleted in striatum of people with PD.
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CAUDATE
CAUDATE
PUTAMEN
PUTAMEN
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L-DOPA
Cotzias, 1967
First convincing evidence that D,L-DOPA, a precursor of dopamine, reversed parkinsonism.
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Parkinson’s Disease: 20th 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.
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NAME LOCUS GENE INHERITANCE
Park 1 4q Synuclein AD
Park 2 6q Parkin AR
Park 3 2p ? AD
Park 4 4p-q Synuclein triplication AD
Park 6 1p PINK-1 AR
Park 7 1p DJ-1 protein AR
Park 8 12p LRRK-2 AD
Single Gene Mutations and PD I
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Genetics
Discovering alpha-synuclein mutation or gene duplication as causes of PD
Recognizing alpha-synuclein is a component of Lewy bodies
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Braak et al., 2003
Interneuronal Lesions Related to Parkinson’s Disease
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Braak et al., 2006
Braak’s Staging for Parkinson’s Disease
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Li et al., 2002
Normal Parkinson08/25/99 01/18/01
Myocardial 18F-Dopamine Scans
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Iwanga et al., 2000
Cardial Pexus in PD
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Lewy Body Pathology in Autonomic Nervous System in
PDHypothalamus – 100%
Intermediolateral columns – 96%
Sympathetic ganglia – 96%
Dorsal motor nucleus X – 100% ?
Sacral parasympathetic ganglia – 100%
Enteric nervous system (VIP neurons) – 93%
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Autonomic Nervous System as Portal for Pathogen or Toxin?
Braak et al., 2003
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Parkinson’s Disease: 21st 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.