Term
| What cardinal clinical signs define PD? |
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Definition
1-3 are most responsive to treatment
1) Bradykinesia (slow gait, reduced blink frequency)
2) Resting Tremor (Unilateral usually in hans/arms)
3) Rigidity (Unilateral-Cog-wheel at
onset....appendicular>axial)
4) Postural instability (late onset and poorly responsive) |
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Term
| What risk/protective factors are associated with PD? |
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Definition
1) Age, Pesticide Exposure, Drinking well water, Occupation (Physician, Teacher, Clergy) and Male Gender are positively correlated
2) Smoking, NSAID, History of Exercise and Caffeine intake decrease risk. |
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Term
| What basic pathological features define PD? |
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Definition
1) SNpc neurons degenerate eliminating DA input to the Striatum
**Raphe nuclei, Locus ceruleus and autonomic degeneration also seen**
2) Lewy bodies (alpha synnuclein and ubiquitin) found in degenerating neurons.
3) Inflammation (microglia activation)
4) Iron deposition from Ox- stress (fenton reaction) |
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Term
| How does alpha synuclein relate to PD? |
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Definition
1) Protein found in Lewy bodies, which is also substrate for E3 ligase (Parkin)
2) Too much normal OR mutated form associated with PD |
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Term
| What is the MPTP story of PD? |
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Definition
MPTP was taken in by IV drug users and found to cause PD through Mitochondrial dysfunction.
1) Converted to MPP+ in Astrocytes in brain
2) MPP+ taken up by DAT in DA neurons
3) Complex 1 inhibitor in Mitochondria of DA neurons |
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Term
| What is the evidence for involvement of proteosomal machinery in PD pathogenesis? |
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Definition
1) Parkin (E3 ligase) and UCHL1 (polyubiquitin recycling) associated with PD onset
2) Lewy Bodies contain proteosomal transcription factors and alpha synuclein. |
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Term
| How are Proteosomal processing and Mitochondrial abnormalities linked in PD? |
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Definition
1) Parkin (E3 ligase) disruption leads to mitochondrial abnormalities.
2) PINK (mitochondrial autophagy), DJ1 (oxidative stress in mitochondria) and OM1 |
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Term
| What is the evidence for Mitochondrial impairment in PD? |
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Definition
1) MPTP as complex 1 inhibitor
2) Rotenone (complex 1 inhibitor) model
3) Parkin, JD-1 and OM-1 mutations |
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Term
| What is the evidence for oxidative stress in PD? |
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Definition
1) Oxidative damage and glutathione (GSH) loss in postmortem tissue
2) Oxidative stress causes alpha-synuclein aggregation and oxidation in Lewy bodies
3) DJ-1 mutation (oxidative response in mitochondria)
4) Iron accumulation in PD
5) Mitochondrial impairment increases free radical generation. |
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Term
| Why is inflammation often seen in PD? |
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Definition
Microglia activation in SNc
**NSAID use is protective** |
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Term
| What is Ubiquinone (CoQ10) and what is its relevance? |
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Definition
In clinical trials to treat PD, acting as a free radical scavenger.
- Idea is to reduce oxidative stress from mitochondrial generation of free-radicals. |
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Term
| How does dopamine replacement work to treat PD? |
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Definition
D2>D1
1) D2 receptor agonists increase inhibitory stimulation of Striatum, increasing activity of "indirect" pathway and leading to increased cortical stimulation. |
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Term
| How might you treat only the tremors of PD? |
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Definition
| Amantadine, Rimantadine and/or anticholinergic agents. |
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Term
| How do Dopamine Agonists compare therapeutically to Levopoda (L-DOPA)? |
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Definition
D2 agonists (Ergotamine and Non-ergotamine/lower side effects)
1) LESS effective for symptomatic therapy against cardinal features (Bradykinesia, Tremor, Rigidity)
2) LESS likely to produce dyskinesia
3) MORE likely to cause DA side effects (SLEEP ATTACK, compulsive behavior, neuropsychiatric, dyspnea, leg edema, hypotension)
**Possible "protective" role against development of dyskinesia** |
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Term
| What drugs produce "Sleep attacks"? |
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Definition
| DA receptor agonists sometimes cause these rapid bouts of "intense sleepiness." |
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Term
| What is the difference between "Ergotamine" and "Non-ergotamine" DA receptor agonists used to treat PD? |
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Definition
1) Ergotamine (Pergolide & Bromocriptine) RARELY USED
- D3>D2>>D1, D4 and D5
- 5-HT1/2 receptors
- Alpha 1/2 NA receptors
- Cause Raynaud's, serious fibrosis, pericardiis, cardiac valvulopathy
- Hepatic metabolism
2) Non-Ergotamine (Pramipexole, Ropinirole, Rotigotine)
- D3>D2 and D4, NOT D1 or D5
- No NA and 5-HT action
- Mild anti-depressent effects, but sleep issues
- Renal metabolism |
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Term
| How is Levodopa used to treat PD? |
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Definition
DA does not cross BBB, but L-DOPA does, and can be converted to DA via L-AADC in nigrostriatal nerve terminals.
-Gold standard, but since AADC is found everywhere, 99% of oral dose in converted prior to passing BBB and can increase onset of hyperkinetic dyskinesia
-L-DOPA does not work from postural instability, freezing and balance problems |
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Term
| How does Carbidopa contribute to Levodopa treatment of PD? |
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Definition
Carbidopa is an AADC inhibitor that does not cross BBB.
- Given to reduce peripheral conversion of L-DOPA, prior to crossing BBB, diminishing need for such high doses and avoiding vomiting/nausea |
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Term
| Why might a physician advocate for starting a PD patient with mild symptoms on a long half-life DA agonist monotherapy instead of Levodopa? |
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Definition
| The pulsatile nature of DA exposure with Levodopa may disrupt post-snpatic DA receptor signaling mechanisms, leading to "motor fluctuations" (medication-responsive and unresponsive periods) and "dyskinesias" |
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Term
| How do Monoamine Oxidase B (MAOB) inhibitors such as Selegiline, Zydis Selegiline and Rasagiline treat PD? |
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Definition
- Reduce DA catabolism at DA and NE stages, by selectively inhibiting B form of MAO
- Don't act on A form of MAO, which causes "cheese effect" of life-threatening hyper-activation of autonomic pathways causing hypertension, hyperpyrexia and seizures when eating tyramine-containing food |
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Term
| How do Catechol-O-methyl transferase (COMT) inhibitors such as Entacapone (MAIN) and Tolcapone (liver toxicity) work to treat PD? |
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Definition
Entacapone is a reversible, peripheral COMT inhibitor (causes orange urine and diarrhea)
- Reduce DA catabolism at L-DOPA and Epinephrine stages, increasing striatal availability and prolonging half-life of Levopoda
- Increase "on time" and reduce "off time."
- DA side effects (may also need to lower Levopoda) |
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Term
| What surgical interventions are available for PD patients? |
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Definition
DBS of STN or GPi (reduce/normalize)
- Often require less medication |
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