Parkinson's disease 26/03

Question 1

What are 6 key mechanisms of pathogenesis in PD?

Answer 1

(not necessarily in this order)

1. Neuroinflammation
2. NMDA mediated excitotoxicity
3. Altered Ca2+ homeostasis due to calcium channel overexpression
4. Mitochondrial dsyfunction, oxidative stress and apoptotic cell death
5. Alpha-synuclein misfolding
6. Increased LRRK2 activity

Question 2

What are the preclinical symptoms of PD and how do they relate to lewy body deposition?

Answer 2

Symptoms begin around 10 years before clinical diagnosis

• Autonomic dysfunction such as constipation, hypotension - Loss of sense of smell - Anxiety and depression
• Rapid eye movement disorder (RBD) i.e., uncontrollable movements in sleep

Early alpha synuclein deposition and lewy body formation spreads upwards through the vagus nerve to dorsal vagus nucleus, involing both parasympthatic and sympathetic nervous systems -> Constipation, hypotension. Hypotension arises from cardiac sympathetic denervation and often begins prodromally but may not become ‘clincal’ under later disease stages.
Progression to the brainstem -> RBD
Progression to olfactory bulb -> hyposmia
Progression to the raphe nucleus (5HT) and the locus coeruleus (NA) which may relate to affective symptoms

Question 3

What are the early clinical symptoms of PD and how do they relate to lewy body deposition?

Answer 3

Early clinical stage lasts around 5 years

-Bradykinesia -Resting tremor -Rigidity

Lewy body pathology spreads to the substantia nigra. Loss of dopaminergic neurons results in loss of motor function. Loss of 60% of dopamine neurons occurs before motor symptoms appear. Symptoms are initially quite treatable using dopaminergic therapies.

Question 4

5 Braak stages of lewy body deposition

Answer 4

• *Preclinical:**
  1. ) Dorsal motor nucleus of vaugus, olfactory bulb
  2. ) Raphe nuceli and locus coeruleus
• *Clinical:**
  3. ) Substantia nigra, amygdala, hippocampus
  4. ) mesocortex and thalamus
  5. ) Neocortex

Question 5

What are the advanced symptoms of PD?

Answer 5

Occurring around 10yrs after diagnosis in stage 4, 5 and 6 of lewy body deposition

Motor:
Wearing off; dyskinetic drug effects
Gate
Postural instability
Difficulty in swallowing and speaking

Non-motor:
Cognitive decline: PD dementia.
Psychosis
Autonomic dysfunction

Non-dopaminergic motor & non-motor features dominate the disease in late stages.

Question 6

Direct pathway of motor control

Answer 6

Stimulation of direct motor pathway facilitates movement

1. ) Substantia nigra releases dopamine onto excitatory D1 receptors in striatum.
2. ) Striatum send GABAergic inhibition to GPi
3. ) GPi GABAergic projections to thalamus are inhibited, causing excitation of thalamus
4. ) thalamus sends excitatory projections to motor cortex to initiate movement

Question 7

Indirect pathway of motor control

Answer 7

Stimulation of indirect motor pathway inhibits movement

1. ) Substantia nigra releases dopamine onto inhibitory D2 receptors in striatum.
2. ) Striatum send less GABAergic inhibition to GPe (GPe activated)
3. ) GPe GABAergic projections to STN are excited, causing inhibition of STN
4. ) STN sends less excitatory innervation to the GPi
5. ) GPi sends less GABA inhibition to thalamus
6. ) Thalamus sends glutamatergic excitation to motor cortex, inhibiting movement

Question 8

How does loss of dopaminergic SNc neurons caused reduced motor activity in parkinsons?

Answer 8

Less dopaminergic innervation of striatum causes underactivation of direct pathway and overactivation of indirect pathway. Ultimately this reduces thalamic output to motor cortex resulting in movement disorders (bradykinesia, tremor, rigidity, instability)

Question 9

Which drugs are currently in use for Parkinsons?

Answer 9

1. Dopamine precursors. Levadopa

2. Dopa decarboxylase inhibitors. (Carbidopa) - Given alongside Levadopa. Prevents the L-DOPA being used to synthesise dopamine in the periphery, as dopamine cannot cross BBB.

3. MAO-B inhibitors. Inhibits breakdown of dopamine in the neuron.

4. COMT inhibitors. Prevents breakdown of dopamine in extracellular space.

5. Muscarinic antagonists

6. NMDA antagonists. These are used to reduce dyskinesias.

Question 10

What are the side effects if L-DOPA

Answer 10

Levodopa induced dyskinesia caused by excessive thalamocortical feedback (uncontrollable hyperkinetic movements)

Occurs with chronic use of L-dopa and is associated with the pulsatile stimulation of dopamine receptors caused by wearing off of L-dopa between doses.

Once triggered, it cannot be undone. This suggests maladaptive neuroplasticity in striatum.

Question 11

Dementia in parkinson’s disease.

Answer 11

1. Post-mortem findings that correlate with P.D. dementia are severe pathologies in the monoaminergic and cholingeric nuclei, termed ‘subcortical’ dementia - in particular the basal cholingergic forebrain system. However, response to cholinergic substates is modest, suggesting it is not the primary substrate for P.D. dementia.
2. The density of cortical bodies correlates with the severity of P.D. dementia.
3. There is correlatory evidence for synergy between amyloid and alpha-synuclein pathologies.

Question 12

non-motor features of P.D.

Answer 12

Non-motor features of P.D. may occur many years before emergence of motor stages, and dominate the disease in later stages. Some appear to have a dopaminergic basis, whereas others do not (such as dementia which may have cholingergic basis). They include:

• Cognition
• Mood disorders
• Emotional disturbance such as impluse control disorders
• Autonomic dysfunction
• Hyposmia
• Pain