1817 by James Parkinson First described in 1817 By 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)

MonozygoticDizygotic

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… Pesticides Herbicides Insectcides Well-Drinking Water Rural Living Higher incidence in agriculture workers…. Environmental… Metals: Manganese Copper Aluminum

Basal Ganglia Striatum Nigrostriatal Pathway Dopaminergic Cell bodies 80% die – degeneration of pathway..bingo NO Dopaminergic transmission

Parkinson’s Disease Disease of the Basal Ganglia Globus Pallidus Substantia Nigra Caudate & Putamen Sub Thalamic Nuclei Facilitates Movement D1 Inhibits Movement D2

Excitatory: green -- Inhibitory: red 1. Substantia Nigra axons inhibit the putamen 2. Axon loss increases excitation in Globus Pallidus 3. Globus Pallidus has increased inhibition to Thalamus 4. 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. Rigidity Symptoms 2. Hypokinesia & 3. Bradykinesia Hypokinesia: inability to initiate a voluntary movement Bradykinesia: slowness of movement Decrease in: Eyeblink Facial expression Eating 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 DA in 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

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 ) 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)