PDA III Parkinson's Disease

PD general features

-Progressive neurodegenerative disease

-3 in 1000 overall, about 1% in people over age 60

-Major symptoms are movement disorders

-Primary neuropathology: death of neurons in the substantia nigra

Major symptoms of PD

-Resting tremor (pill-rolling tremor, looks like they're holding a pill)

-Cog-wheel rigidity

-Bradykinesia: moves around less (aka akinesia, paucity of movement, inertia of movement)

-Postural disturbances, shuffling gait

-Absence of facial expression

-Dementia, esp. in later stages

Substantia nigra

-Population of dopamine neurons in the midbrain

-Neurons send their axons to neurons in the forebrain that make up the striatum

-Neurons are black: full of melanin

Sub. nigra in PD

-Neurons in the sub. nigra die in PD, neurons can't make it to the striatum

-Death of nigrostriatal pathway

-Significant loss of visible black (loss of neurons)

S. nigra NT

-Dopamine

-Dopamanergic at the striatum

Dopamine in PD

-Loss of dopamine activity in the striatum

PET scan of the striatum

-Pic is of the two striata

-We have 2 striata on each side of the brain: disease is usually worse on one side than the other

-The PET ligand is binding to the presynaptic dopamine transporter on S. Nigra (we are tracking the disappearance of S. Nigra)

Tracking activity in neural circuits

-Remember glutamate is excitatory and GABA is inhibitory

Normal neuroanatomy of the tremor

-Striatal neuron is an interneuron: cell body and axon terminal in one place (striatum)

-Striatal neuron is cholinergic (uses ACh)

-S.N. releases DA, DA releases and is accepted on striatal neurons (Gi coupled D2 receptors on the striatum)

-DA decreases the amount of ACh releasing on GABAergic neurons (Gq coupled muscarinic receptors)

-Decreased ACh means less body movement

Neuroanatomy of the tremor in PD

-S.N. dies

-S.N. releases less DA

-More ACh is released

-Results in more inhibition SN via GABA

-Look at this more

Healthy movement

-Direct pathway and indirect pathway to the globus pallidus

-DA stimulates D1 (stimulatory, direct) and D2 (inhibitory, indirect): both cause excitation in the cerebral/motor cortex

-Excitation in the cerebral cortex causes healthy movement

PD bradykinesia

-Slow movement

-Purple: loss of activity

-Red: gain of activity

-Decrease in DA decreases stimulatory D1 and inhibitory D2

-Results in decreased cerebral/motor cortex stimulation

-Less cerebral/motor cortex activity leads to bradykinesia in PD

PD etiology

-Idiopathic: cause is unknown

-Genetic: small minority of cases, tend to have earlier onset

-Drug-induced: drugs block DA, so symptoms look like PD, but there is no S.N. death (parkinsonism, pseudoparkinsonism)

-Toxin-induced (MPTP)

Synthesis of catecholamine NTs

-Tyr comes from our diet

-TH: tyrosine hydroxylase

-TH converts Tyr to Dopa

-Aadc: aromatic amino acid decarboxylase

-Aadc converts dopa to dopamine

Dopamine storage

-VMAT2: vesicular monoamine transporter

-VMAT2 brings dopamine into vesicles for later release

Dopamine release

-Works on D1/D2 receptors on postsynaptic striatal neurons

Dopamine autoreceptors

-Gi coupled D2 receptors

Enzymes that metabolize dopamine

-COMT

-MAO

Drugs for PD

-L-DOPA

-Carbidopa

-DA agonists

-Enzyme inhibitors

-Amantadine

-Anticholinergics

L-DOPA

-Amino acid precursor to dopamine

-AADC: Aromatic amino acid decarboxylase

-AADC converts L-DOPA to dopamine (sometimes prematurely in the peripheral tissues)

-L-DOPA is carried across BBB by a transporter, carried into DA neuron by another transporter

-Only 1-5% reaches the brain

L-DOPA acute ADEs

-N/V

-Hypotension

-Arrhythmias

-These are DA-mediated and peripheral

L-DOPA chronic ADEs

-Abnormal, involuntary movement (dyskinesias)

-Nightmares, hallucinations

-These are central in origin: due to L-DOPA being converted to dopamine in the brain

On-off phenomenon

-In regards to L-DOPA treatment

-On: when pt has control of their symptoms

-Off: when pt doesn't have control

-First 1-2 years pt has smooth, day long control of symptoms

-At 2-5 years: peak dose dyskinesia, symptoms return at low plasma conc but before it's time for the next dose

-Reason: therapeutic plasma conc narrows as more and more neurons die

L-DOPA self-limitation

-At some point, there won't be enough dopamine neurons to convert L-DOPA into dopamine

-Destined to fail

Carbidopa

-AADC inhibitor that can't cross the BBB

-Would inhibit L-DOPA changing to dopamine in the peripheral tissues (blocks wasted dopamine)

-3-10 fold more L-DOPA makes it into the brain

-SINEMET (L-DOPA/carbidopa combo product)

DA Agonists

-Apomorphine (APOKYN)

-Pramipexole

-Ropinirole

-Rotigotine

DA agonist efficacy

-Not a perfect treatment strategy

-There are dopamine systems in the brain outside the striatum (ADEs)

-Dopamine can act in peripheral tissues (ADEs)

-Loss of negative feedback of dopamine via circuits (no regulation)

-Normally, dopamine works phasically (brain releases it when we need it), so putting the same amount of an agonist in the body all the time isn't a perfect approach

Apomorphine (APOKYN)

-Dopamine agonist for PD

-Used in off periods of L-DOPA

Pramipexole, ropinirole, and rotigotine advantages

-Long DOA for less on/off phenomenon

-May be used early in course of the disease to delay L-DOPA therapy

-Oral or transdermal

Pramipexole, ropinirole, and rotigotine disadvantages

-N/V

-Hallucinations

-Hypotension

-Somnolence

-Compulsive behavior: gambling and punding (compulsive organization)

Enzyme inhibitor classes

-Carechol-O-Methyl Transferase (COMT) inhibitors

-MAOis

COMT inhibitor MOA

-COMT metabolizes L-DOPA and DA

-COMT inhibitors inhibit the metabolism

-Typically as adjuncts to reduce the off symptoms

COMT inhibitor drugs

-Tolcapone

-Entacapone

-Opicapone

Tolcapone

-Acts in periphery and CNS

-Giver q2-3days

-Hepatotoxic: requires liver function monitoring

-Reserved for refractory pts

Entacapone

-Acts only in periphery

-Given with each L-DOPA dose

Opicapone

-Acts only in periphery

-Given with each L-DOPA dose

MAOi MOA

-INhibition of MAO-A is associated with antidepressant activity

-Inhibition of MAO-B is helpful in PD

-Purpose is to decrease DA metabolism and decrease free-radical formation

MAOI drugs

-Selegiline

-Rasagline

MAOI pros/cons

-Therapeutic dose does not cause HTN crisis (no effect on MAO-A)

-Loses selectivity at high doses

-May interact with meperidine, TCAs, SSRIs, and tyramine

Amantadine MOA

-Block NMDA glutamate receptors

-Stimulates the release of DA and inhibits DA reuptake

-Used in mild cases or as L-DOPA adjunct

-Loses efficacy over a few months

Anticholinergics

-Specifically antimuscarinic (on GABAergic neurons)

-Used as adjuncts to address the DA/ACh imbalance in the striatum

-Most effective at reducing tremor, not as effective at reducing rigidity or bradykinesia

Anticholinergic drugs

-Benztropine

-Trihexyphenidyl

PD treatment summary figure

-Figure will be on exam

PD treatment algorithm