IDT - Parkinsons, Ishmael Flashcards
What is the pathophysiology of Parkinson’s Disease?
It is a Striatal Dopamine deficiency resulting from degeneration of DA-containing neurons.
What is the average age of onset for Parkinson’s disease?
55-60 years of age
Less than 10% of diagnosis are less than 40yo
At what percentage of loss of striatal dopamine do mild Parkinson’s symptoms occur?
Mild symptoms occur at 70-80% striatal dopamine loss.
What percentage of loss of striatal dopamine do advanced Parkinson’s patients have?
greater than 85% loss of striatal dopamine.
Is Parkinson’s disease considered a Hyperkinetic or Hypokinetic movement disorder?
Hypokinetic - movement is slowed or absent, and the tremors occur at rest.
What is a Hyperkinetic movement Disorder?
A problem that involves increased movement.
Where do the majority of movement disorders originate?
In the brain
Involuntary muscle spasms that lead to awkward, sustained often painful postures.
Dystonia
An involuntary Dance-like flowing movement of arms/legs/whole body
Chorea (Dyskinesia)
What are the two major Pathophysiological characteristics of PD?
- Degeneration of Nigrostriatal Pathway
2. Appearance of Intra-cytoplasmic inclusions
What is a Lewy Body?
An intra-cytoplasmic inclusion that radiates from center of remaining dopaminergic neurons of SNc.
What is the major component of Lew Bodies?
Alpha-synuclein
How might Sporadic parkinsonism be onset through Environmental Factors??
Drug Induced (Antipsychotics) Toxins (Rotenone, paraquat) Ageing
When/Where do Intracellular inclusions containing alpha-SYN occur?
Multiple System Atrophy (oligodendrocytes)
Dementia w/ Lewy Bodies (neurons)
Parkinson’s Disease (neurons)
Where is Alpha-SYN normally expresse?
Presynaptic Terminal, in vesicular membranes
What is the role of Alpha-SYN
Maintenance of synaptic vesicles
What might be the effect of mutations in Alpha-SYN?
Accumulation of cytoplasmic DA by “Leaky Vesicles”, caused by misfolding of Alpha-SYN
What are the clinical Manifestations of PD?
- Tremors at rest
- Bradykinesia
- Rigidity
- diminished sense of smell
- Mask Like Face
- Excessive Salivation
- Swallowing Difficulties
- Depression
- Sleep Disturbances
- Anxiety
- Dementia
What is the relationship between Decreased F-DOPA uptake and progession of Bradykinesia to Akinesia?
Increase in Bradykinesia progressing to AKinesia is related to decreased F-DOPA uptake.
(Dec uptake = more likely Akinesia)
What is Bradykinesia/Akinesia?
Difficulty initiating movement, especially fine motor skills.
what is characteristic feature of PD tremors at rest?
rhythmic oscillating tremors, when muscles are at rest (3 cycles per second)
When Dopaminergic cell death occurs due to non-traditional causes/Timeline
Idiopathic Parkinson’s Disease
What are the Key symptoms of Idiopathic PD?
Shows bilateral symmetry
Considerably less resting tremor
No response to L-DOPA therapy
How should Parkinsons and Depression be treated?
as separate comorbidities
Which Genes are associated with PD?
Ubiquitin –> Alpha-SYN
PARK2
PINK1
LRRK2
Describe the process of tagging a protein with Ubiquitin.
- E1 enzyme ACTIVATES ubiquitin in a rxn requiring ATP
- Ubiquitin is TRANSFERRED to an E2 carrier protein.
- E3 complex recruits substrate and transfers Ubiquitin to target protein (requires a enzyme specific protein)
How are unfolded ubiquitin proteins degraded?
20S proteasome cylinder
What is the 26S proteasome comprised of?
One 20S cylinder and two 19S cap proteins
How does 26S proteasome recognize polyubiquitinated proteins?
Cap recognizes and facilitates the unfolding and release of Ub chain.
What enzyme degrades the chain to free Ub?
Ubiquitin Carboxy-terminal hydrolase (UCH-L1)
What is the problem with Alpha-SYN and ubiquitin-proteasome system?
Alpha-SYN aggregates cannot be unfolded and might interfere with normal functions of 26S proteasome.
Kinase that has been linked with PD in Familial, Sporadic/Idiopathic instances.
LRRK2 - Kinase, greatest known genetic contributor to PD
What is the Pesticide Hypothesis?
Pesticide Toxins may cause/produce PD-like symptoms
Group of San Francisco Young Heroin Addicts who posses neurological symptoms of PD
“Frozen Addicts”
What is MPTP?
Toxin that produces PD-like symptoms in non-human primates
How is MPTP a pro-toxin?
Lipophilic (Crosses BBB), is converted to MPP by MAO-B, which then enters Neuron via DAT and binds to neuromelanin. It is gradually released causing damage to neurons of the Substantia Nigra
How does MPP cause Cell death?
It concentrates in the Mitochondria of cells, inhibiting oxidative phosphorylation, depleting mitochondrial ATP, causing cell death.
What is distinct about MPTP induced PD?
It produces acute and irreversible symptoms, but does not produce Lewy Bodies
What Nuclei compose the Basal Ganglia?
Caudate; Putamen; Globus Pallidus; Subthalamic; Substantia Nigra
What Nuclei compose the Striatum?
Caudate and Putamen
What Type of DA Receptor is found on the Presynaptic Neuron leading to Striatum?
D2 Autoreceptor
What Type of DA receptor is found on the Postsynaptic Cell of the Striatum?
D1/D2 family receptors
What are the pathways from BG to Motor Cortex?
Direct
Indirect
What is the Direct Pathway?
Substantia Nigra –> Striatum –> Substantia Nigra –> Thalamus –> Cortex
Which Neurons of the Direct Pathway are inhibitory?
GABA neurons
- Striatum –> Sub Nig
- Sub Nig –> Thalamus
What is the Indirect Pathway?
Sub Nig –> Striatum –> Globus Pallidus –> Lateral Thalamic Nucleus –> Sub Nig –> Thalamus –> Cortex
How are drugs to treat Parkinson’s disease currently designed?
Drugs Treat Symptoms, do not alter progression of disease.
What do Next Generation PD drugs target?
LRRK2; Alpha-SYN,
Neuroprotective, and halt progression
What are the present strategies to treat PD?
Replace DA
Mimic DA action
Inhibit breakdown of DA
Anti-Muscarinics –> modulate GABA
What is the mainstay of PD treatment?
L-DOPA
Is an inert drug in which only 1-3% is absorbed into the CNS
L-DOPA
Why is L-DOPA therapy often delayed?
sometimes delayed for Window of Usefulness, and Unfavorable Side effects
What drug is often given alongside L-DOPA?
A peripherally acting aromatic amino acid decarboxylase inhibitor (Carbidopa)
What are some common L-DOPA forumlations?
Carbidopa/Levodopa (1:10 or 1:4) (brand name Sinemet)
Sinemet-CR, increased half life can help end of dose reactions and effects
Parcopa - Orally Disintegrating Tablet (swallowing difficulty)
What are the traditional wearing off or End of Dose reactions of L-DOPA therapy?
Akinesia, symptoms come back between doses
Advanced patients –> reaction to drug is less predictable
Hos long do the positive beneficial treatments of L-DOPA therapy last?
5-8 years
What symptoms show greatest improvement during L-DOPA therapy?
BradyKinesia (most improvement)
Rigidity
Tremor (less improvement)
What are the adverse effects associated with L-DOPA therapy?
- Gastrointestinal Problems (Nausea/Vomitting)
- Cardiovascular Problems (Vasodilation)
- Secondary Dystonia (involuntary, painful, prolonged contractions beginning in one body region)
- Choreoathetosis (Dyskinesia, involuntary writhing movements of face, neck, tongue, hands, limbs) Drug induced
- ON/OFF Phenomenon (hours of freezing akinetic (off) and alternative dyskinesia (on))
- Behavioral Effects (Depression, anxiety, insominia, psychotic-like-reactions)
What 2nd generation oral DA receptor agonists are widely used for PD?
Ropinirole (Requip)
Pramipexole (Mirapex)
What is a 2nd generation transdermal DA receptor agonist widely used for PD?
Rotigotine
What is the selective affinity for 2nd generation DA receptor agonists?
Great affinty for D2 class of DA receptors (indirect pathway) D3>D2>D1
What other condition are DA receptor agonists often used for?
Restless Legs Syndrome
