Questão 1
Questão
Epidemiology of PD:
- [blank_start]65[blank_end] year mean age of onset
- 50% more likely to affect [blank_start]men[blank_end]
- 90% [blank_start]idopathic[blank_end], 10% hereditary
Primary motor symptoms:
- [blank_start]Tremor[blank_end] affects 70%
- [blank_start]Bradykinesia[blank_end] (slow movement) affects everyone
- [blank_start]Rigidity[blank_end] affects 90%
Psychiatric disturbances [blank_start]5-10 years[blank_end] post diagnosis.
Dementia affects [blank_start]80[blank_end]% of patients [blank_start]20 years[blank_end] after diagnosis.
Responda
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65
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men
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idopathic
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Tremor
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Bradykinesia
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Rigidity
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5-10 years
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20 years
-
80
Questão 2
Questão
Former smokers have 20% decreased risk of getting PD while current smokers have a 50% decreased risk.
Questão 3
Questão
Reminder: The basal ganglia. [blank_start]Grey[blank_end] matter structures - [blank_start]striatum, globus pallidus[blank_end]. Connections to [blank_start]thalamus[blank_end], subthalamic nuclei, substantia nigra. Important in coordinating motor function.
Neurochemistry of PD: Dopamine (DA) deficient because of a greater than [blank_start]50[blank_end]% loss of DA neurons in [blank_start]substantia nigra[blank_end], and degeneration of [blank_start]terminals[blank_end] in the striatum. [blank_start]Lewy[blank_end] bodies cause functional changes.
Questão 4
Questão
Basal ganglia-thalamo-cortical loop is the [blank_start]motor loop[blank_end] in the brain where choices about planned movements are made. 4 linked parts: motor cortex, striatum, basal ganglia, thalamus.
The motor [blank_start]cortex[blank_end] sends information about all planned movement to the [blank_start]striatum[blank_end]. The signals then move to the [blank_start]basal ganglia[blank_end], and then to the [blank_start]thalamus[blank_end] completing the selection process. The signals contain information about which moves to make and which moves to block.
Responda
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motor loop
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cortex
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striatum
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basal ganglia
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thalamus
Questão 5
Questão
Degeneration of dopaminergic neurons in the [blank_start]substantia nigra[blank_end] results in reduced stimulation of [blank_start]D1 and D2[blank_end] receptors in the striatum.
The consequence is overactive [blank_start]GABA[blank_end] inhibition of the thalamus, and reduced [blank_start]glutamate[blank_end] excitation/activation of cortical systems. At the same time, [blank_start]hyperactivity[blank_end] in the glutamate pathways that connect the cortex to the [blank_start]striatum[blank_end] reinforce the [blank_start]inhibitory[blank_end] influence that basal ganglia has on movement.
The symptom most clearly related to this dopamine deficiency is hypokinesia.
Rigidity and tremor more complex and involve disturbances in [blank_start]Ach, NA, 5HT[blank_end] and GABA.
> what ?
- old dopamine neurons not making enough dopamine = too much gaba going to thalamus. not enough glutamate going to cortex and too much glutamate coming from it = no movey movey
Responda
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substantia nigra
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D1 and D2
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GABA
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glutamate
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hyperactivity
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striatum
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inhibitory
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Ach, NA, 5HT
Questão 6
Questão
Drug that enhance dopaminergic activity
1. Levodopa
• Dopamine [blank_start]precursor[blank_end] (DA cannot cross BBB)
• Extensive [blank_start]decarboxylation[blank_end] (periphery)
• SEs: nausea, vomiting, [blank_start]arrhythmias, vasodilation[blank_end]
• 1% oral dose reaches brain
• t1/2 [blank_start]short[blank_end] (1h)
Modified release preps: more continuous supply
.. so we add DDC inhibitors e.g. carbedopa, benserazide. DCC inhibitors [blank_start]prevent[blank_end] peripheral conversion:
- decreases L-dopa [blank_start]dose[blank_end] required
- decreases [blank_start]side[blank_end] effects
Carbidopa + levodopa = [blank_start]Sinemet[blank_end]
Benserazide + levodopa = Madopar
.. can also add [blank_start]COMT[blank_end] inhibitors e.g. entacapone, tolcapone
• Prevent breakdown in periphery/CNS (30%)
• [blank_start]Double[blank_end] half life
Questão 7
Questão
Usually around 3-4 hours after a dose of levodopa, the medication [blank_start]wears[blank_end] off and symptoms re-emerge or worsen. Symptoms then typically improve 15-45 [blank_start]minutes[blank_end] after the next dose is taken. This phenomenon is called ‘wearing off’.
Motor fluctuations (e.g. [blank_start]on/off[blank_end] phenomenon) are the changes in motor performance associated generally with taking levodopa but also with dopamine agonists in some cases. It is caused by a [blank_start]gradual[blank_end] loss of DA producing cells over time. This means that the level of dopamine in your brain is increasingly dependent on the availability of levodopa in the [blank_start]blood[blank_end], which in turn relies on your most recent dose of medication. ‘On’ time is when levodopa is [blank_start]working[blank_end] well and symptoms are controlled. ‘Off’ time is when levodopa is no longer working well and symptoms such as [blank_start]tremor, rigidity and slow[blank_end] movement re-emerge. As PD progresses they become less dose-[blank_start]timing[blank_end] related.
Questão 8
Questão
DA agonists - [blank_start]Ergot[blank_end] derivatives: e.g. Bromocriptine, cabergoline, (pergolide*)
L-DOPA adjunct:
• Dose reduction
• Exacerbates L-DOPA motor [blank_start]complications[blank_end]
Monotherapy:
Longer [blank_start]t1/2[blank_end] , delay L-DOPA (L-DOPA sparing)
• increases SEs especially [blank_start]psychiatric[blank_end]
• N&V, orthostatic hypotension,
• Serious [blank_start]pulmonary, peritoneal and pericardial[blank_end] fibrosis