PD I Flashcards
What is Parkinson’s disease
Age related neurodegenerative disorder which affects all ages. Age is a risk factor
Key motor symptoms of PD
Rigidity
Loss of facial expressions
Resting tremor
Stopped posture
Flexed arm, hips, knees
Shuffling
Non motor symptoms of PD
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
PD aetiology
Mostly sporadic, late onset, no known cause
Environmental aetiology
MPTP (heroin derivative)
Agrochemicals (herbicide and pesticide)
Gut microbiome (endogenous)
Genetic aetiology
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
PD pathology
DA cell loss in SNc
Contain neuromelanin (oxidised DA)
DA neurons project to striatum
Striatal dopaminergic denervation [18F] PET scan
Lewy Body
Pathological hallmark of PD, damaged proteins are trapped in the lewy bodies
Stains for a-syn, ubiquitin (protein which is tagged)
Braak staging based on Lewy Body deposition
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
Role of a-synuclein
In presynaptic terminals
Role in vesicle trafficking (neurotransmission)
Mutant a-syn
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
PD parallels with AD
Phosphorylation (GBA1 and LRRK2 vs Tau hyperphosphorylation)
A-syn vs amyloid beta plaques
Prion hypothesis
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
Microbiome
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
What forms the striatum
Caudate and putamen
Direct pathway PD
Under active
Cortex - striatum (D1 Gs metabotropic) - GPi/SNr (less GABA) - thalamus (increased GABA)
Reduced thalamocortical feedback/firing
Indirect pathway in PD
Overactive
Cortex - striatum (D2 Gi/Go) - GPe (more GABA) - STN (less GABA) - GPi/SNr
Projections to STN are disinhibited
Issue with current PD drugs
Only symptomatic
Current PD drugs
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)
What is L-DOPA induced dyskinesia
Hyperkinetic involuntary movements (choreic/dystonic)
Mainly affects limbs and trunk
Occurs 5 yrs after L-DOPA
LID cause
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
LID drug
Amantadine (NMDAR antagonist)
Can cause cognitive impairment
Drugs to reduce dyskinesia
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
Depression drug
Sertraline (SSRI)
Anxiety drug
Deep brain stimulation (electrical stimulation)
Cognition drug
L-DOPA and DA agonists
Insomnia drug
L-DOPA if due to akinesia
Restless legs drug
Dopamine agonists
iRBD drug
Clonazepam (sedative)
Pain drug
Dopamine agonists or opioids
Poorly managed
Unmet medical needs
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
