2) Parkinson's Disease

Front 1

"paralysis agitans"

Back 1

first described by James Parkinson in 1817

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Who renamed "paralysis agitans" to Parkinsons Disease

Back 2

Charcot

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Parkinsonism

Back 3

Cluster of same symptoms caused by known factors

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Causes of Parkinsonism

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1. Virus, 1918 Spanish Flu, followed by a post-encephalitic form of Parkinsonism, "encephalitic lethargica"
2. Drug-induced Parkinsonism: MPTP
3. Other less common causes: coal gas poisoning, manganese poisoning, vascular problems, tumors, syphilis

Front 5

Idiopathic Parkinsonism

Back 5

The second most common form of neurodegenerative disease
The most common degenerative disease affecting the motor system

Front 6

Parkinson's Disease Prevalence

Back 6

1 per 1000
1 per 200 (over age 50)
1% over 65
10% over 80

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Survival Time

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9 years, but varies
PD patients have a mortality rate three times higher than their age-matched controls

Front 8

Clinical Features of PD

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1. Rigidity
2. bradykinesa, hypokinesa, akinesia
3. Tremor
4. Postural instability (ataxia)
5. Intellectual and personality changes

Front 9

Rigidity

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- muscles constantly innervate contraction, even when patient is purposefully relaxed
- Intermittent character to passive resistance in the patient's limbs
- "Imbalanced" rigidity- affecting the flexor muscles more than the extensors
- May lead to postural abnormalities: especially of the fingers and the arms; also stooped posture, speech problems, shuffling gait
- Fatigue

Front 10

bradykinesia

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a general slowness in initiating voluntary movements such as standing up from a chair or eating

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hypokinesia

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an abnormally low amount of movement
pt sits very still, with a blank, mask-like expression, and little eye-blinking

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akinesia

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occurs in more advanced state
complete freezing as the patient attempts to initiate the first movements of a complex motor task

Front 13

Movement characteristics

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- lots of dependance of visual feedback
- when a movement is underway, the pace may become more rapid and the patient may have difficulty stopping the movement
- symptoms tends to show an "on" "off" quality and to be esp. severe in the early morning or during times of stress
- Fine motor coordination is often well preserved

Front 14

Tremor

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- Often the first complaint
- Early, prodromal symptom
- Tremor may even disappear
- Found mainly in the hand, forearm, and foot

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"Resting" tremor

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less pronounced or disappears when pt. makes a purposeful movement

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Asymmetrical tremor

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more on one side of the body

Front 17

Postural instability (ataxia)

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problems with balance

Front 18

Intellectual and personality changes

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- intellectual or memory impairment (20-60%) of PD pts.
- correlated with akinesia and with age
- Depression is quite common (30-50%); once thought to be a secondary consequence of the pts. illness but now looked upon as, at least partly, an inherent feature of PD itself

Front 19

Pathology: Where is the damage?

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pars compacta of the substantia nigra contains cell bodies of melanin-containing dopaminergic neurons whose axons extend to the corpus striatum: nigro-striatal pathway

Front 20

Nigrostriatal pathway

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- Substantia nigra to the corpus striatum
- contains 80% of the brains dopaminergic axons

Front 21

How can you cause parkinsonism symptoms? What drugs?

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by administering large doses of dopamine antagonists drugs (such as chlorpromazine and haloperidol)
-parkinsonism is a common side effect when these drugs are given to a schizophrenic

Front 22

Post-mortem studies show:

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- reduced levels of dopamine and homovanillic acid in the corpus striatum
- These reductions are correlated with the extent of cell loss in the pars compacta and with the severity of clinical symptoms (akinesia,etc.) before the pts. death.

Front 23

PET used to do what?

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visualize dopamine in the corpus striatum of living patients.

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CSF shows...

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lower levels of homovanillic acid

Front 25

The nigro-striatal pathway exerts inhibitory control over __________ ?

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cholinergic activity in the corpus striatum.

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_____-_____% of cells may have to be lost in the nigro-striatal pathway for PD symptoms appear

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70-80

Front 27

Are drugs able to stop the degeneration of the nigro-striatal pathway?

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Pharmacologic interventions do little or nothing to stop the degeneration- therefore, prove to be ineffective at providing symptom relief

Front 28

Loss of dopaminergic cells in other areas?

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ventral tegmental area that projects to the nucleus accumbens
other limbic structures
frontal cortex

Front 29

Surviving cells are characteristic by what?

Back 29

intracytoplasmic inclusions called Lewy bodies

Front 30

First successful drug treatments

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the use of anticholinergic (anti-muscarinic) drugs, such as scopolamine, with no understanding as to why these drugs seemed to work.
Anticholinergics are still used to treat tremor in some elderly pts.

Front 31

L-dopa

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can pass beyond BBB and was readily converted to dapamine with dopaminergic neurons; its effect on PD symptoms was dramatic- far more effective than the anticholinergic drugs in use

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Adverse Peripheral side effects of L-dopa

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nausea and vomiting, cardiac irregularities
w/ large doses of l-dopa

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Can the adverse peripheral side effects of l-dopa be eliminated? If so, how?

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Yes, if the peripheral conversion of l-dopa into dopamine is prevented.
- Need a decarboxylase inhibitor that is unable to pass through the bbb.
- Now, l-dopa is combined with carbidopa (Synemed)
- Dosage levels could be cut by 75-80%
- clinical response began within one week
- peripheral side effects were markedly reduced

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Do the central side effects of l-dopa still remain?

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Yes:
1. psychotic and depressive symptoms, dsykineisas ("wreathing")
To get rid of- must lower the dosage level

Front 35

L Dopa + L Dopa Decarboxylase
why?

Back 35

To avoid symptoms

Front 36

Is tyrosine affective in increasing dopamine levels?

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No, on the wrong side of the rate-limiting step

Front 37

Can dopamine get through the bbb?

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No

Front 38

The on-off phenomenon

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Patients response to l-dopa is rapid, but relatively brief

Front 39

How can you make l-dopa last longer?

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The use of selegiine (deprenyl) as a Type B MAO inhibitor
- May allow dopamine to act longer following its synthesis and release

Front 40

What happens after a few years of l-dopa therapy?

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The patient's clinical response becomes variable and unstable. PD is a progressive disease and nothing slows the rate of progress in the degeneration of the nigro-strial pathway. In addition, new evidence suggests that l-dopa itself may be neurotoxic

Front 41

Other than anticholinergic drugs and l-dopa, what other drugs can be used to treat PD? (3)

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Dopamine agonists (bromocriptine, Parlodel)
COMT- inhibitors
Surgical interventions
Tissue grafts
Embryonic stem cells
Hurdles

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Tissue Graft

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Chromaffin cells from the adrenal gland
Fetal tissue implant (dopamine producing cells)
- monkey experiments with fetal tissue implants
- Transplant with the "frozen addicts"

Front 43

Embryonic stem cells

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cultured to become dopaminergic neurons and then grafted into the corpus striatum

Front 44

MPPP

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a synthetic opiate, similar to demerol

Front 45

MPTP

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a by-product when one attempts to make MPPP

Front 46

MPTP converted to what?

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MPTP converted to MPP+ by MAO in the neurons of the substantia nigra

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MPP+

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destroys the cell bodies of melanin-containing neurons of the substantia nigra

Front 48

Neuromelanin and age

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The amount of neuromelanin increases with age; this may account for the later age of onset of PD

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Type B MAO-Inibitors

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1. Selegeline (Deprenyl) in a prophylactic treatment of PD
2. Rasagiline- potent selective Type B MAO-I being developed specifically for neuroprotection

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Is there evidence suggesting that PD is caused by an environmental toxin?

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Yes, before 1800- no recorded observation of PD; could it be a product of the industrial revolution?
- family clustering
- 50% increase in PD in younger people
- paraquat
- pesticides

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Family clustering of disease

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-the onset seems to come at the same time
- one family all developed within a four year spread (ages were 68, 58, and 37)
- this clustering occurs in about 50% of families which have multiple members affected with PD

Front 52

paraquat

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MPPP--> MPTP--->MPP+--> "cyperquat"

"paraquat"- Nixon administration sprayed on marijuana plans in northern Mexico

Front 53

Genes identified with familial and sporadic cases of PD:

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1. Parkin gene- chromosome 6, especially in early onset (< 40)
2. alpha- synuclein gene- chromosome 4; most abundant protein found in Lewy bodies

Front 54

PD vs HD (location)

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PD: degeneration of the substantia nigra and nigro-striatal pathway
HD: degeneration of the corpus striatum and the gabanergic striatal-nigral pathway

Front 55

Balance Model

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akinetic symptoms result from ACh > DA in corpus striatum

dyskinetic symptoms result DA > ACh in the corpus striatum
- occurs in HD bc of the degeneration of the striatal-nigral pathway and thus the loss of the inhibitory influence normally afforded by the gabanergic neurons making up this pathway

Front 56

Anticholinergic (anti-muscarinic drugs) treat what disease?

Back 56

PD

Front 57

Dopaminergic antagonists and l-dopa treat what disease?

Back 57

PD

Front 58

Challenge Test- for what disease?

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HD

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Antipsychotic drugs result in Parkinsonian symptoms and worsen PD; have some usefulness in treating symptoms of what?

Back 59

HD