James Parkinson
Born in 1755; died 1824.
Lived entire life in London.
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Political reformer
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Paleontologist
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Physician
The Shaking Palsy
Observations based on 6 cases
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2 cases with follow-up
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1 case with no follow-up
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3 cases seen on the streets of London
Observations
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Rest Tremor
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Gait and Posture
(flexed posture and festination)
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Described bradykinesia but did not name
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Missed rigidity
“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).
LEWY BODY
NEURON
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.
Arvid Carlsson
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.
Oleh Hornykiewicz
Dopamine
Hornykiewcz, 1960
Found that dopamine was depleted
in striatum of people with PD.
CAUDATE
PUTAMEN
L-DOPA
Cotzias, 1967
First convincing evidence that D,LDOPA, a precursor of dopamine,
reversed parkinsonism.
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.
Single Gene Mutations and PD I
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
Genetics
Discovering alpha-synuclein
mutation or gene duplication as
causes of PD
Recognizing alpha-synuclein is a
component of Lewy bodies
Interneuronal Lesions Related
to Parkinson’s Disease
Braak et al., 2003
Braak’s Staging for Parkinson’s Disease
Braak et al., 2006
Myocardial
Normal
18F-Dopamine
Scans
Parkinson
08/25/99
01/18/01
Li et al., 2002
Cardial Pexus in PD
Iwanga et al., 2000
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%
Autonomic Nervous System as
Portal for Pathogen or Toxin?
Braak et al., 2003
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.