NE4 Parkinson's disease

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.

Former smokers have 20% decreased risk of getting PD while current smokers have a 50% decreased risk.

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.

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.

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

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

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.

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