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.

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