•1817 by James Parkinson

First described in 1817By English MD

James Parkinson

Parkinson’s Disease

“…involuntary tremulous motion, with lessened muscular power, in parts not in action and even when supported, with a propensity to bend the trunk forwards, and pass from a walking to a running pace, the senses and intellects being uninjured.” J. Parkinson

PD: Motor System Disorder

• Chronic• Progressive• Non Fatal

-1 to 1.5 million cases in the US strikes 1 in every 100 over 50

- Equal opportunity disease… men, women all ethnicities slightly higher rate among whites vs blacks Disease of Aging – onset 55 (idiopathic) Early Onset: 5-10%

diagnosed

Idiopathic

400,000 nigral cells in SN

2,400 cells die each year (Apoptosis)…100 X 2,400 = 240,000

…50% cell death = mild symptomolgy

So PD accelerated…why?

• environmental?• genetic?

• Head injury (parkinsonism)

Monozygotic Dizygotic

Parkinson's Disease •Lewy body in a substantia nigra neuron

Caused by alpha synuclein & Parkin: gene responsible for making these proteins suspect early onset

Environmental…

PesticidesHerbicidesInsectcidesWell-Drinking WaterRural Living

Higher incidence inagriculture workers….

Environmental…

Metals:ManganeseCopper Aluminum

Basal Ganglia

Striatum

Nigrostriatal Pathway

DopaminergicCell bodies

80% die – degeneration of pathway..bingo NO Dopaminergic transmission

Parkinson’s Disease

Disease of the Basal Ganglia

Globus PallidusSubstantia NigraCaudate & PutamenSub Thalamic Nuclei

FacilitatesMovement D1

InhibitsMovement D2

Excitatory: green -- Inhibitory: red1. Substantia Nigra axons inhibit the putamen2. Axon loss increases excitation in Globus Pallidus3. Globus Pallidus has increased inhibition to Thalamus4. Then decreased excitation from the Thalamus to Cortex

D2 receptors

neurons from putamen fire excessively…loss of control of motor function

•Muscular stiffness and increased muscle tone•Patients usually unaware of rigidity, but troubled with slowness•More apparent to doctor than patient•Cogwheeling – ratchet like movement

1. RigiditySymptoms

2. Hypokinesia & 3. Bradykinesia

•Hypokinesia: inability to initiate a voluntary movement

•Bradykinesia: slowness of movementDecrease in: EyeblinkFacial expressionEating and chewing

•An involuntary movement: head, limbs, or entire body•Most apparent when limb is rested and supported •Increases with stress •Ceases during sleep

•Decreases with intentional movements •'Pill rolling tremor' if most prominent in fingers & hand

•Most bothersome, yet least disabling of all symptoms

4.Tremor

Stage 1•Symptoms mild - inconvenient•Unilateral•Tremor- leans to affected side•Affected arm in semiflexed position with tremor

Stage 2•Symptoms mod – disability min•Bilateral •Early postural changes•Slow, shuffling gait•Toe-gait walk

Stage 3•Symptoms mod severe•Major posture problems - stooped, knees flexed while walking •Major balance problems - unsteadiness while turning•Falls•Severe tremor, rigidity or bradykinesia

Stage 4•Significant disability•Institutionalization

Stage 5•Loss of global ability•Bradykinesia very severe•Cannot walk or stand

Treatment…..

HEY LETS JUST GIVE DOPAMINE!!!

Dopamine doesn’t cross the blood brain barrier….But levodopa does (l-dopa)!

Phenylalanine

Tyrosine

L- Dopa

Dopamine

Aromatic L amino acid decarboxylase

Problems: 1. doesn’t address the cell death 2. in time l-dopa is not effective (good for early to intermediate stages)

•Sinemet (l-dopa+carbidopa)l-dopa quickly converted to DAin PNS decarboxylase inhibtor 75% respond to drug

Selegiline (MAOI)

•Delays Parkinsonian disability and the need for levodopa therapy by 9-12 months

•Inhibits dopamine degradation •allows for 20% smaller doses of levodopa

•Exacerbation of levodopa-associated side effects •Insomnia, postural hypotension

•inhibiting monoamine oxidase-B morepre-synaptic dopamine

Also…inhibits this enzyme …converts MPTP to MPP+ (bad stuff)

“on-off” of PD

“I need to explain the "on-off" phenomenon. This Jekyll and-Hyde melodrama is a constant vexation for the P.D. patient, especially one as determined as I was to remain closeted. "On" refers to the time when the medication is telling my brain everything it wants to hear. I'm relatively loose and fluid, my mind clear and movements under control. Only a trained observer could detect my Parkinson's. During one of my "off" periods, even the most myopic layperson, while perhaps not able to diagnose P.D. specifically, can recognize that I am in serious trouble.” -Michael J. Fox, an excerpt from Lucky Man

http://www.michaeljfox.org/

New Treatment Strategy…..DBS (deep brain stimulation)

- US Food and Drug Administration recently approved (Jan. 15, 2002)- Tiny electrodes on the scalp – connecting wire to implanted pulse generator under the collarbone - 80% reduction of tremor & bradyk.- can modify stimulation based on severity of symptoms

Thalamotomy: remove thalamus (M.J. Fox - 1998)Pallidotomy: remove the globus pallidus Helps the symptoms of tremor, dyskinesia, rigidity & bradykinesia-however, irreversible destruction of brain tissue-Overtime the benefits decline-May compromise other intact brain processes: speech, vision etc.

DBS •Thalamus•Globus pallidus •Sub Thalamic (best)

Thalamus: tremor, safer then lesion •Globus pallidus: dyskinesia safer than lesion•Sub Thalamic: improve all Symptoms improvement of motor scores 40-60% during “off” 10% during “on”

Animal Models of PD

Substania Nigra

Striatum

Lesioning – Neurotoxicity

Parkinson’s Disease (long-term)

Fluphenazine – D2 Dopaminergic Antagonist

HYPOKINESIA

TARGET STRIATUM (D2)

Blockade of receptor

Parkinson’s Disease – (acute: manipulation of pharmacological agent)