James Parkinson

Born in 1755; died 1824.

Lived entire life in London.

• Political reformer

• Paleontologist

• Physician

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

“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 BODYLEWY BODY

NEURONNEURON

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

CAUDATE

PUTAMEN

PUTAMEN

L-DOPA

Cotzias, 1967

First convincing evidence that D,L-DOPA, 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.

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

Genetics

Discovering alpha-synuclein mutation or gene duplication as causes of PD

Recognizing alpha-synuclein is a component of Lewy bodies

Braak et al., 2003

Interneuronal Lesions Related to Parkinson’s Disease

Braak et al., 2006

Braak’s Staging for Parkinson’s Disease

Li et al., 2002

Normal Parkinson08/25/99 01/18/01

Myocardial 18F-Dopamine Scans

Iwanga et al., 2000

Cardial Pexus in PD

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%

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.