Parkinson Disease

First described by James Parkinson in 1817-English Physician (b.1755 d.1824)

(No Likeness of Parkinson in existence)

1805 wrote Observations on the Nature and Cure of Gout 1817 wrote Essay on the Shaking Palsy secured his place in history! Parkinsons Disease pg241;247 Pinel +lecture

One of the most common, most studied and best understood disorders of movement Parkinsons own description of condition is probably still the best and most complete:

Symptoms are: Paucity of spontaneous movement- insufficiency of movement Bradykinesia- very slow movements Akinesia- no movements Increased muscle tone- rigidity

involuntary involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported, with a propensity propensity to bend the trunk forward, and to pass from walking to a running pace, the senses and intellects being uninjured uninjured

Resting Tremor - @4-5Hz- pill rolling Shuffling gait and flexed posture, impaired balance Mask-like expression

Parkinson Disease is first example of a brain disorder resulting from a deficiency of a single neurotransmitter

Dopamine

1955-Arvid Carlson-80% brains dopamine in basal ganglia Oleh Horynekiewicz found brains of Parkinson disease sufferers were deficient in DA in striatum.

basal ganglia-four nuclei striatum

caudate

1960s Parkinson disease shown to be result of degeneration of dopaminergic neurones within the substantia nigra pars compacta

putamen
projection

major inputs from cortex, thalamus, brainstem

Globus pallidus Subthalamic nuclei

Substantia nigra

Major output

The Basal Ganglia

L-dihydroxyphenylalanine (L-DOPA-

Walter Brikmeyer and Horyenkiewicz found that IV 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 DA Beneficial effects of L-DOPA only last for ~ 5 yrs side effects increase-motor response fluctuations and drug related dyskinesias.

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 dopamine producing cells of the substantia nigra pars compacta.

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

Magic bullet! MPTP MPTP was being converted to MPP+ a very damaging free radical. 6-Hydroxydopamine

MPTP

MAO

MPP+

? MAOI ?

The Basal Ganglia D1+ D2-

(Striatum)

DA
GPi = globus pallidus internal segment STN = subthalamic nucleus

Striatum = caudate & putamen GPe = globus pallidus external segment SNr = substantia nigra par reticulata

And SNr

Disinhibition gating hypothesis: data with glutamate injections in striatum

VM = ventromedial thalamus

(Striatum)
striatum VM

SC =superior colliculus (midbrain sensory and motor motor nucleus)

And SNr

Alexander,et al. 1990 SC SNr

Why have a basal ganglia?

Central switch has a wiring advantage over the distributed alternative

A1

A1

A1

A1

A1

A1

A1
Distributed (all-to-all) connectivity. Number of connections ~ N2

A1
Central switch Number of connections ~ N

Why motor and not cognitive?

Causes of Parkinson Disease? Not much is know about the cause but there are some ideas. Free radicals causing preature cell death

Treatments

Certain pesticides and neurotoxins in the environment and our food-spouses of sufferers are mre likely to develop Parkinson Disease- shared exposure to toxins

thalamus, subthalamic nucleus, and globus pallidus Also lesions

Foetal Dopamine grafts and now Stem cells Why are animal models not so good?

Why does DBS work? Oscillatory activity in BG

output
globus pallidus

Coronal section

putamen

head of caudate tail of caudate

output nuclei

Basal ganglia anatomy summary

Cortex Striatum D1 Thalamus GPe GPi/SNr
Tonic inhibition
Excitation Inhibition Striatum = caudate & putamen GPi = globus pallidus internal segment STN = subthalamic nucleus GPe = globus pallidus external segment SNr = substantia nigra par reticulata

STN Striatum D2