1817 by James Parkinson First described in 1817 By English MD James Parkinson Parkinson’s Disease...
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•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
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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
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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)
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Monozygotic Dizygotic
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Parkinson's Disease •Lewy body in a substantia nigra neuron
Caused by alpha synuclein & Parkin: gene responsible for making these proteins suspect early onset
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Environmental…
PesticidesHerbicidesInsectcidesWell-Drinking WaterRural Living
Higher incidence inagriculture workers….
Environmental…
Metals:ManganeseCopper Aluminum
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Basal Ganglia
Striatum
Nigrostriatal Pathway
DopaminergicCell bodies
80% die – degeneration of pathway..bingo NO Dopaminergic transmission
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Parkinson’s Disease
Disease of the Basal Ganglia
Globus PallidusSubstantia NigraCaudate & PutamenSub Thalamic Nuclei
FacilitatesMovement D1
InhibitsMovement D2
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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
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•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
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•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
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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
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Treatment…..
HEY LETS JUST GIVE DOPAMINE!!!
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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
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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)
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“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/
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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.
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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”
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Animal Models of PD
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Substania Nigra
Striatum
Lesioning – Neurotoxicity
Parkinson’s Disease (long-term)
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Fluphenazine – D2 Dopaminergic Antagonist
HYPOKINESIA
TARGET STRIATUM (D2)
Blockade of receptor
Parkinson’s Disease – (acute: manipulation of pharmacological agent)
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