PD I

Question 1

What is Parkinson’s disease

Answer 1

Age related neurodegenerative disorder which affects all ages. Age is a risk factor

Question 2

Key motor symptoms of PD

Answer 2

Rigidity
Loss of facial expressions
Resting tremor
Stopped posture
Flexed arm, hips, knees
Shuffling

Question 3

Non motor symptoms of PD

Answer 3

Sleep: restless legs, REM sleep behaviour disorder, daytime sleepiness (hypersomnia)

Autonomic: bladder, sweating, low BP, dribbling, swallowing, constipation

Psychiatric: anxiety and depression, apathy, attention, memory loss, confusion, panic

Sensory: pain, tickling, smell, visual problems

Other: fatigue, sexual dysfunction

Question 4

PD aetiology

Answer 4

Mostly sporadic, late onset, no known cause

Question 5

Environmental aetiology

Answer 5

MPTP (heroin derivative)
Agrochemicals (herbicide and pesticide)
Gut microbiome (endogenous)

Question 6

Genetic aetiology

Answer 6

10% familial cases
Park1-10 gene mutants cause dysfunction in mitochondria, a-syn, protein degradation

PARK1: SNCA encodes a-syn. Point mutation causes folding and aggregation
GBA1: encodes glucocerebrosidase (GCase enzyme) loss of function mutant ion in AD. OR of 5.5 high,impaired lysosomal autophagy
LRRK2: encodes leucine rich repeat kinase 2, gain of function mutation impairs lysosomal/proteasomal/mitochondrial function and causes oxidative stress

Question 7

PD pathology

Answer 7

DA cell loss in SNc
Contain neuromelanin (oxidised DA)
DA neurons project to striatum
Striatal dopaminergic denervation [18F] PET scan

Question 8

Lewy Body

Answer 8

Pathological hallmark of PD, damaged proteins are trapped in the lewy bodies
Stains for a-syn, ubiquitin (protein which is tagged)

Question 9

Braak staging based on Lewy Body deposition

Answer 9

Preclinical (10 yrs) LB in DMNV, Olfactory bulb, Raphe nucleus, LC

Early treated PD (stable) motor symptoms emerge SN, amygdala, hippocampus, N basalis of Meynert

Advanced PD (10-15 yrs) neocortex, prefrontal cortex, somatosensory

Question 10

Role of a-synuclein

Answer 10

In presynaptic terminals
Role in vesicle trafficking (neurotransmission)

Question 11

Mutant a-syn

Answer 11

90% phosphorylation causes misfolded proteins
Beta pleated sheet oligomers
Amyloid fibrils
A-syn jumps onto different cells
Causes oxidative stress, protein sequestration, disruption of axonal transport, synaptic dysfunction, inhibits UPS, mitochondrial dysfunction

Question 12

PD parallels with AD

Answer 12

Phosphorylation (GBA1 and LRRK2 vs Tau hyperphosphorylation)

A-syn vs amyloid beta plaques

Question 13

Prion hypothesis

Answer 13

A-syn passes cell-cell causing Lewy body spread
Cell injury and leaking
Transmembrane
Endo and exocytosis
Exosome release
Nanotube
Transynaptic

A-syn accumulation in the gut prior to reaching DMNV via gut brain axis

Question 14

Microbiome

Answer 14

PD causes changes in bacterial populations of the gut causing leaky blood and inflammation

A-syn and motor deficits in mouse PD models

Appendix contains a-syn. Appendicetomy reduces PD risk

Infection/ intestinal inflammation induce GIT a-syn expression

Phospho a-syn in GIT in prodromal phase (iRBD)

Vagotomy reduces PD risk

A-syn bidirectional spread from gut to DMNV and SN

Cell-cell transmission of a-syn confirmed

Question 15

What forms the striatum

Answer 15

Caudate and putamen

Question 16

Direct pathway PD

Answer 16

Under active

Cortex - striatum (D1 Gs metabotropic) - GPi/SNr (less GABA) - thalamus (increased GABA)

Reduced thalamocortical feedback/firing

Question 17

Indirect pathway in PD

Answer 17

Overactive

Cortex - striatum (D2 Gi/Go) - GPe (more GABA) - STN (less GABA) - GPi/SNr

Projections to STN are disinhibited

Question 18

Issue with current PD drugs

Answer 18

Only symptomatic

Question 19

Current PD drugs

Answer 19

DA precursor: L-DOPA (can cause dystonia and psychosis
DOPA decarboxylase inhibitors: carbidopa/benserazide
MAO-B inhibitors: sekagiline/sasagiline
COMT inhibitor: entacapone
DA agonists: pergolide D1/d2, ropinirole, Lisuride, bromocriptine
Muscarinic antagonists: benzhexol (elevated ACh in striatum causes tremors)

Question 20

What is L-DOPA induced dyskinesia

Answer 20

Hyperkinetic involuntary movements (choreic/dystonic)
Mainly affects limbs and trunk
Occurs 5 yrs after L-DOPA

Question 21

LID cause

Answer 21

DA receptor stimulation
Continuous DA receptor stimulation (long acting DA agonists) causes less dyskinesia

Cannot be reversed maladaptive neuroplasticity in striatum

Mechanism not fully understood thought to be enhanced glutamate stimulation across corticostriatal synapse

Question 22

LID drug

Answer 22

Amantadine (NMDAR antagonist)
Can cause cognitive impairment

Question 23

Drugs to reduce dyskinesia

Answer 23

Long acting DA 2 receptor agonist: Ropinirole 1st line treatment

Irreversible MAO-B inhibitor: reduces L-DOPA dose (L-DOPA sparing) - rasagiline

Duodopa pump: intraduodenal infusion of L-DOPA minimises fluctuations no patch is successfully absorbed

Question 24

Depression drug

Answer 24

Sertraline (SSRI)

Question 25

Anxiety drug

Answer 25

Deep brain stimulation (electrical stimulation)

Question 26

Cognition drug

Answer 26

L-DOPA and DA agonists

Question 27

Insomnia drug

Answer 27

L-DOPA if due to akinesia

Question 28

Restless legs drug

Answer 28

Dopamine agonists

Question 29

iRBD drug

Answer 29

Clonazepam (sedative)

Question 30

Pain drug

Answer 30

Dopamine agonists or opioids

Poorly managed

Question 31

Unmet medical needs

Answer 31

Stop neurodegeneration
Stop dyskinesia and keep having L-DOPA
Current drugs are only symptomatic no disease modifying drugs exist
Parkinson’s is progressive so drugs need to slow the course
PD AIS not diagnosed until 50% cells are lost so drugs are needed to repair existing damage