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Parkinson’s Disease pg241;247 Pinel +lecture
Parkinson DiseaseFirst described by James Parkinson in 1817-English
Physician (b.1755 d.1824)
1805 wrote ‘Observations on the Nature and Cure of Gout’
1817 wrote ‘Essay on the Shaking Palsy’secured his place in history!
(No Likeness of Parkinson in existence)
One of the most common, most studied and best understood disorders of movement
Parkinson’s own description of condition is probably still the best and most complete:
‘……‘……‘……‘……involuntary tremulous motion, with lessened muscular power, involuntary tremulous motion, with lessened muscular power, involuntary tremulous motion, with lessened muscular power, involuntary tremulous motion, with lessened muscular power,
in parts not in action and even when supported, with a propensitin parts not in action and even when supported, with a propensitin parts not in action and even when supported, with a propensitin parts not in action and even when supported, with a propensity y y y
to bend the trunk forward, and to pass from walking to a to bend the trunk forward, and to pass from walking to a to bend the trunk forward, and to pass from walking to a to bend the trunk forward, and to pass from walking to a
running pace, the senses and intellects being uninjuredrunning pace, the senses and intellects being uninjuredrunning pace, the senses and intellects being uninjuredrunning pace, the senses and intellects being uninjured’’’’
Symptoms are:
Paucity of spontaneous movement- insufficiency of movement
Akinesia- no movements
Bradykinesia- very slow movements
Increased muscle tone- rigidity
Resting Tremor - @4-5Hz- ‘pill rolling’
Shuffling gait and flexed posture, impaired balance
Mask-like expression
Parkinson Disease is first example of a brain disorderresulting from a deficiency of a single neurotransmitter
Dopamine
Oleh Horynekiewicz found brains of Parkinson disease sufferers were deficient in DA in striatum.
1955-Arvid Carlson-80% brains dopamine in basal ganglia
2
basal ganglia-four nuclei
striatumcaudate
putamen
Globus pallidus Substantia nigra
Subthalamic nuclei
major inputs fromcortex, thalamus,brainstem
projection…
Major output
1960’s Parkinson disease shown to be result of degenerationof dopaminergic neurones within the substantia nigra pars
compacta
The Basal Ganglia
DA
Walter Brikmeyer and Horyenkiewicz found that IV L-dihydroxyphenylalanine (L-DOPA- a dopamine precursor) provided a dramatic albeit brief reversal of symptoms!
George Cotzias showed that gradual increases in oral L-DOPA provided significant and continuous benefits
Beneficial effects of L-DOPA only last for ~ 5 yrs side effects increase-motor response fluctuations and
drug related dyskinesias.
3
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)
William Langston
Found that drug abusers who accidentley took MPTP developed a profound Parkinsonian state
MPTP was found to be specifically targeting the dopamineproducing cells of the substantia nigra pars compacta.
Magic bullet!
MPTP was being converted to MPP+ a very damaging free radical.
MPTP MPP+MAO
? MAOI ?
This observation led to the intense investigation of the role of exogenous toxins in the pathogenesis of
Parkinson disease
Animal model required, but MPTP had no effect on rats……
MPTP 6-Hydroxydopamine
The Basal Ganglia
DA
GPe = globus pallidus external segmentGPi = globus pallidus internal segment
STN = subthalamic nucleus SNr = substantia nigra par reticulata
Striatum = caudate & putamen
D1+D2-
(Striatum)
And SNr
4
(Striatum)
And SNr
Disinhibition gating hypothesis: data with
glutamate injections in striatum
striatum
SNr
VM
SC
VM = ventromedial thalamus
SC =superior colliculus (midbrain sensory and
motor motor nucleus)
Alexander,et al. 1990
Why motor and not cognitive?
Why have a basal ganglia?
A1
A1 A1
A1
Distributed (all-to-all)
connectivity.
Number of connections ~ N2
A1
A1 A1
A1
S
Central switch
Number of connections ~
N
Central switch has a ‘wiring’ advantage over the ‘distributed’ alternative
Causes of Parkinson Disease?
Not much is know about the cause but there are some ideas.
Free radicals causing preature cell death
Certain pesticides and neurotoxins in the environment and our food-spouses of sufferers are mre likely to develop
Parkinson Disease- ‘shared exposure’ to toxins
Treatments
thalamus, subthalamicnucleus, and globuspallidusAlso lesions
Foetal Dopamine grafts and now Stem cells
Why are animal models not so good?
5
Why does DBS work? Oscillatory activity in BG
output
output nuclei
Coronalsection
putamen
head of caudate
tail of caudate
globuspallidus
Basal ganglia anatomy -
summary
GPe
GPi/SNr
Striatum
D1 Striatum
D2
STN
Cortex
GPe = globus pallidus external segmentGPi = globus pallidus internal segment
STN = subthalamic nucleus SNr = substantia nigra par reticulata
Inhibition
Excitation
Striatum = caudate & putamen
Thalamus
Tonic inhibition