Epidemiology of PD: - ❌ year mean age of onset - 50% more likely to affect ❌ - 90% ❌, 10% hereditary
Primary motor symptoms: - ❌ affects 70% - ❌ (slow movement) affects everyone - ❌ affects 90%
Psychiatric disturbances ❌ post diagnosis. Dementia affects ❌% of patients ❌ after diagnosis.
Former smokers have 20% decreased risk of getting PD while current smokers have a 50% decreased risk.
Reminder: The basal ganglia. ❌ matter structures - ❌. Connections to ❌, subthalamic nuclei, substantia nigra. Important in coordinating motor function.
Neurochemistry of PD: Dopamine (DA) deficient because of a greater than ❌% loss of DA neurons in ❌, and degeneration of ❌ in the striatum. ❌ bodies cause functional changes.
Basal ganglia-thalamo-cortical loop is the ❌ in the brain where choices about planned movements are made. 4 linked parts: motor cortex, striatum, basal ganglia, thalamus. The motor ❌ sends information about all planned movement to the ❌. The signals then move to the ❌, and then to the ❌ completing the selection process. The signals contain information about which moves to make and which moves to block.
Degeneration of dopaminergic neurons in the ❌ results in reduced stimulation of ❌ receptors in the striatum. The consequence is overactive ❌ inhibition of the thalamus, and reduced ❌ excitation/activation of cortical systems. At the same time, ❌ in the glutamate pathways that connect the cortex to the ❌ reinforce the ❌ 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 ❌ 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 ❌ (DA cannot cross BBB) • Extensive ❌ (periphery) • SEs: nausea, vomiting, ❌ • 1% oral dose reaches brain • t1/2 ❌ (1h) Modified release preps: more continuous supply .. so we add DDC inhibitors e.g. carbedopa, benserazide. DCC inhibitors ❌ peripheral conversion: - decreases L-dopa ❌ required - decreases ❌ effects Carbidopa + levodopa = ❌ Benserazide + levodopa = Madopar .. can also add ❌ inhibitors e.g. entacapone, tolcapone • Prevent breakdown in periphery/CNS (30%) • ❌ half life
Usually around 3-4 hours after a dose of levodopa, the medication ❌ off and symptoms re-emerge or worsen. Symptoms then typically improve 15-45 ❌ after the next dose is taken. This phenomenon is called ‘wearing off’.
Motor fluctuations (e.g. ❌ 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 ❌ 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 ❌, which in turn relies on your most recent dose of medication. ‘On’ time is when levodopa is ❌ well and symptoms are controlled. ‘Off’ time is when levodopa is no longer working well and symptoms such as ❌ movement re-emerge. As PD progresses they become less dose-❌ related.
DA agonists - ❌ derivatives: e.g. Bromocriptine, cabergoline, (pergolide*) L-DOPA adjunct: • Dose reduction • Exacerbates L-DOPA motor ❌
Monotherapy: Longer ❌ , delay L-DOPA (L-DOPA sparing) • increases SEs especially ❌ • N&V, orthostatic hypotension, • Serious ❌ fibrosis
