Download Parkinson's Disease

Survey
yes no Was this document useful for you?
   Thank you for your participation!

* Your assessment is very important for improving the work of artificial intelligence, which forms the content of this project

Document related concepts

Premovement neuronal activity wikipedia, lookup

Molecular neuroscience wikipedia, lookup

Neuroanatomy wikipedia, lookup

Clinical neurochemistry wikipedia, lookup

Metastability in the brain wikipedia, lookup

Time perception wikipedia, lookup

Neuroeconomics wikipedia, lookup

Basal ganglia wikipedia, lookup

Aging brain wikipedia, lookup

Biochemistry of Alzheimer's disease wikipedia, lookup

Alzheimer's disease wikipedia, lookup

Allochiria wikipedia, lookup

Sports-related traumatic brain injury wikipedia, lookup

Parkinson's disease wikipedia, lookup

Substantia nigra wikipedia, lookup

Transcript
Parkinson’s Disease
First described in 1817
By English MD
James Parkinson
•1817 by James Parkinson
“…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…
Pesticides
Herbicides
Insectcides
Well-Drinking Water
Rural Living
Higher incidence in
agriculture workers….
Environmental…
Metals:
Manganese
Copper
Aluminum
Basal Ganglia
Striatum
Dopaminergic
Cell bodies
Nigrostriatal
Pathway
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
D2 receptors
neurons from putamen fire
excessively…loss of control
of motor function
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
Symptoms
1. Rigidity
•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
2. Hypokinesia & 3. Bradykinesia
•Hypokinesia: inability to initiate a voluntary movement
•Bradykinesia: slowness of movement
Decrease in:
Eyeblink
Facial expression
Eating and chewing
4.Tremor
•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
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
Problems:
1. doesn’t address the cell death
2. in time l-dopa is not effective
(good for early to intermediate
stages)
L- Dopa
Aromatic L amino acid
decarboxylase
Dopamine
•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
http://www.michaeljfox.org/
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.
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
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
Parkinson’s Disease (long-term)
Striatum
Substania Nigra
Lesioning – Neurotoxicity
Parkinson’s Disease – (acute:
manipulation of pharmacological
agent)
Fluphenazine – D2 Dopaminergic Antagonist
Blockade of receptor
TARGET STRIATUM (D2)
HYPOKINESIA