exam
Reviewed
parkinsons
background
2nd most common age related neurodegen disorder, affecting 0.5% population and 2%
>80, with prevalence rising faster than any other neurological disorder
symptoms
motor = resting tremor (typically ~5Hz and often initially unilateral), postural stooping and
instability, bradykinesia delaying movement execution, and cogwheel rigidity manifesting
as stiff, jerky limb movements
non-motor (often prodromal) = disturbs sleep (REM sleep behaviour disorder, fatigue),
cognitive function (75% get dementia, anxiety/depression), autonomic NS (constipation,
orthostatic hypotension, sensory changes)
multimodal machine learning analysis can be useful to differentiate from other movement
disorders like multiple system atrophy, which have similar clinical presentations in early
stages but different prognoses
pathogenesis/pathology
pathology
two defining features:
1. degen of dopaminergic (DA) neurones in nigrostriatal tract, observable histologically as
loss of neuromelanin in Substantia Nigra pars compacta
= dec DA innervation of striatum, resulting in underactive direct (usually facilitates
movement via D1R activation) and overactive indirect (inhibits movement but usually
inhibited by D2R) pathway in BG, overall increasing thalamic inhibition and leading to motor
impairment symptoms (when 60-80% lost)
neuronal degen also disinhibits striatal ACh interneurones (tremor) and dysfunction in
amygdala, supraoptic etc
2. lewy bodies, intracerebral cytoplasmic proteinaceous inclusions of a-synuclein
a-syn exists under normal conditions (mainly random coil formation) in presynaptic
terminals, where it interacts with SNAREs to facilitate vesicle release > in PD, potentially
from elevated LRRK2 etc, is excessively phosphorylated, eg. ser129 phos is only present in
exam 1
, 4 healthy population but 90% PD + age-related presence of AGEs may also lead to
glycation, further stabilising = misfolding and aggregation into oligomers then fibrils (both
b-pleated sheet), forming lewy > accumulation compounded by dysfunction of the
proteasome/autophagy systems that would normally clear eg. GBA1
as well as contributing to degen, multiple direct effects: impaired SNARE assembly
impeding axonal transport/synaptic transmission, binds TOM20/22 in mitochondria (mt) to
inhibit import of proteins e.g Complex I increasing reactive oxygen species (ROS), inhibits
autophagy and proper protein folding leading to ER stress and enhancing
accumulation/sequesteration, may also affect glia by dec GDNF expression
healthy neurones grafted into PD develop a-syn pathology, demonstrating prion like
transmission of lewy bodies: deposition begins in defined sites and advances in
topographically predictable sequence, interestingly correlating with reverse order of
neocortical developmental myelination - clinical progression of pathology can therefore be
tracked using Braak staging:
pre clinical/presymptomatic (-10yrs) = dorsal motor nucleus of vagus and olfactory
bulb (sensory changes) > raphe nuclei and locus coeruleus (constipation, REM
disturbances)
first 5 yrs = SNc, amygdal, through to thalamus (classic motor symptoms) - projection
neurones with long/poorly myelinated axons particularly vulnerable which is why
mostly confined to motor regions
advanced (5-15yrs) = to neocortex (dykinesias, dysrthria, dementia, autonomic, sleep)
pathogenesis of degen is multifactorial (mnemonic -lemon)
1. loss of trophic support: a-syn may induce downregulation of RET receptor, decreasing
GDNF/BDNF etc in PD brain which disinhibits apoptosis
2. excitotoxicity: inc Subthalamic nucleus firing inc NMDAR activation into SNc - has low
calbindin levels and Cav1.3 pacemaker Ca channels, making it vulnerable to high Ca concs
= excitotoxicity and degen
3. mt/oxidative stress: as well as disruption of complex I import as above, evidence of
impairment antioxidants eg. glutathione in PD brain, with many PD mutations interlinked:
eg. PRKN is mutation to E3UL mitophagy activator, preventing proteasomal-ubiquitination
response, triggering apoptosis > dysfunction amplifies existing vulnerability of SN to ox
stress due to ROS bi-products of dopamine oxidation: causes cell damage, triggers
caspase activation/apoptosis and promotes a-syn toxicity/oligomer through formation of
4HNE (4hydroxy2nonenal from lipid perox)
4. neuroinflamm: neuromelanin release/a-syn aggregates activate microglia in SNc to pro-
inflamm M1 phenotype (innate), and may also trigger adaptive to activate T/B cells, all of
which release cytokines eg. TNFa contributing to degen which further perpetuates inflamm
- TNfa levels correlate with disease progression
exam 2
, aetiology
primarily presenting as sporadic/idiopathic, where aet is multifactorial and largely unclear,
though several factors implicated:
a. environment
observation that MPTP induces parkinsonism in animal models (kills DA neurones in SN)
suggests environment/toxins, eg. accumulation of agrochemicals, may play a role
b. may be mediated via gut microbiome, another factor with increasing evidence of
involvement
first from observation that lewy bodies are evident in ENS in prodromal phase <20yrs
before, suggesting pathology may start here then migrate via retrograde axonal transport
through vagus to brain
indeed some animal studies show a bidirectional spread of a-syn from gut to dorsal motor
nucleus of vagus and that truncal vagotomy may dec long term risk of diagnosis -
however, 2017 epidem study found no overall significant protection of vagotomy and lots of
confounders eg. vagus itself is anti-inflamm
appendix also theorised as a source/trigger site with pathological a-syn present in PD and
no-blood tissue barrier, but as before while some eg. swedish patient registry showed
delayed age of onset and dec incidence after appendectomy others no effect
microbiome itself seems to be important: changes seen in PD and studies showing
injection of these PD microbes into mice promotes a-syn agg/motor deficits, perhaps due
to inflamm, while mice with no microbiome showing attenuated motor deficits even with a-
syn agg
c. genetic
~10% cases not idiopathic but familial, often presenting w early onset = several genetic
links most commonly to PARK1-10 genes: linked to mt dysfunction, protein degradation, a-
synucleinopathy eg. PARK1 encodes a-synuclein so mutation =
overexpression/aggregation
other genes also linked to sporadic cases: GBA1 encoding glucocerebrosidase loss of
function (LOF) mutations seen in 33% cases and thought to inc risk by >5x due to
impairment of lysosomal autophagy to inc a-syn agg + LRRK2 (leucine rich repeat kinase)
gain OF mutations/inc activity also observed impairing
lysosomal/proteasomal/mitochondrial function/mitophagy and inc ox stress/inflamm
current treatments (pros/cons)
1. LDOPA
current gold standard, effective in 80%: natural DA precursor able to cross BBB via LAT1,
so can undergo conversion in remaining DA neurones to normalise basal ganglia activity,
significantly improving bradykinesia, cognition (if used early), other motor eg. speech
exam 3
, due to pharmacokinetics need combination therapy to allow central access: 90% would be
converted to DA by dopa decarboxylase in intestinal wall (further activated by vit b6) so
given with peripheral DDC inhibitor eg. carbidopa + 5% metabolised by plasma COMT so
inhibitor eg. entacapone (less hepatotoxic than tolcapone) also needed
despite efficacy, severe side effects (SEs):
acute: schizo symptoms from central effects and postural hypotension//nausea from
peripheral, though can be ameliorated with peripheral DR antag domperidone - also
risk of agranulocytosis
chronic more disabling: 2/3 develop ldopa induced dyskinesia (LID) within 5yrs =
hyperkinetic, involuntary choreic movements of the limbs/trunk + ‘on/off’ motor
fluctuations > potentially from fluctuating dopamine receptor stimulation, D1R
sensitisation, inc thalamocortical feedback, inc corticostriatal glutamate transmission,
some suggestion that may promote degen by inc ROS - once onset cannot be
reversed, so delay LDOPA as long as poss
to combat LID: only licensed adjunct drug is amantadine, NMDA antag which indirectly
augments DA release to reduce receptor stimulation fluctuations, though subcut
apomorphine may also be used in emergency ‘off’ + adenosine A2AR antag also recently
FDA approved as adjunct as prolongs LDOPA hl to enhance ‘on’ time without worsening
dyskinesia and may be neuroprotective - main focus currently on alternative
administrations to dec receptor stimulation fluctuations eg. duo dopa (intraduodenal
continuous infusion pump) or produodopa sc pump - such routes may also dec risk of
sudden withdrawal from pateint non compliance which risks potentially fatal neuroleptic
malignant syndrome
2. MAO-B inhibitors eg. rasagiline
block DA metabolism in striatum to dihydroxyphenylacetic acid > useful as monotherapy
early to boost remaining activity (and some evidence of neuroprotectivity eg safinamide by
blocking glu release) then adjunct later to lower LDOPA dose needed and so dec LID
3. long acting DR agonists
mainly activate D2R to inhibit indirect in basal ganglia - though share acute SE with LDOPA,
which will still be needed eventually, the long half life (esp if in patch form eg. rotigotine)
dec fluctuating activation so halves risk and delayed onset of LID > may also benefit other
symptoms eg. pain, depress (esp pramiprexole), so firstline after MAOBI
4. other approaches
historically mAChR antag eg. benzatropine were used - beneficial for tremor and to help
stop sialorrhoea but not effective for brady and cognitive/anti-muscarinic SE
many other drugs used to treat comorbid symptoms eg. SSRIs for depression, clonazepam
for REM disorder + non-pharm interventions eg. deep brain stimulation even showed better
efficacy than pharm in recent meta-analysis
exam 4
Reviewed
parkinsons
background
2nd most common age related neurodegen disorder, affecting 0.5% population and 2%
>80, with prevalence rising faster than any other neurological disorder
symptoms
motor = resting tremor (typically ~5Hz and often initially unilateral), postural stooping and
instability, bradykinesia delaying movement execution, and cogwheel rigidity manifesting
as stiff, jerky limb movements
non-motor (often prodromal) = disturbs sleep (REM sleep behaviour disorder, fatigue),
cognitive function (75% get dementia, anxiety/depression), autonomic NS (constipation,
orthostatic hypotension, sensory changes)
multimodal machine learning analysis can be useful to differentiate from other movement
disorders like multiple system atrophy, which have similar clinical presentations in early
stages but different prognoses
pathogenesis/pathology
pathology
two defining features:
1. degen of dopaminergic (DA) neurones in nigrostriatal tract, observable histologically as
loss of neuromelanin in Substantia Nigra pars compacta
= dec DA innervation of striatum, resulting in underactive direct (usually facilitates
movement via D1R activation) and overactive indirect (inhibits movement but usually
inhibited by D2R) pathway in BG, overall increasing thalamic inhibition and leading to motor
impairment symptoms (when 60-80% lost)
neuronal degen also disinhibits striatal ACh interneurones (tremor) and dysfunction in
amygdala, supraoptic etc
2. lewy bodies, intracerebral cytoplasmic proteinaceous inclusions of a-synuclein
a-syn exists under normal conditions (mainly random coil formation) in presynaptic
terminals, where it interacts with SNAREs to facilitate vesicle release > in PD, potentially
from elevated LRRK2 etc, is excessively phosphorylated, eg. ser129 phos is only present in
exam 1
, 4 healthy population but 90% PD + age-related presence of AGEs may also lead to
glycation, further stabilising = misfolding and aggregation into oligomers then fibrils (both
b-pleated sheet), forming lewy > accumulation compounded by dysfunction of the
proteasome/autophagy systems that would normally clear eg. GBA1
as well as contributing to degen, multiple direct effects: impaired SNARE assembly
impeding axonal transport/synaptic transmission, binds TOM20/22 in mitochondria (mt) to
inhibit import of proteins e.g Complex I increasing reactive oxygen species (ROS), inhibits
autophagy and proper protein folding leading to ER stress and enhancing
accumulation/sequesteration, may also affect glia by dec GDNF expression
healthy neurones grafted into PD develop a-syn pathology, demonstrating prion like
transmission of lewy bodies: deposition begins in defined sites and advances in
topographically predictable sequence, interestingly correlating with reverse order of
neocortical developmental myelination - clinical progression of pathology can therefore be
tracked using Braak staging:
pre clinical/presymptomatic (-10yrs) = dorsal motor nucleus of vagus and olfactory
bulb (sensory changes) > raphe nuclei and locus coeruleus (constipation, REM
disturbances)
first 5 yrs = SNc, amygdal, through to thalamus (classic motor symptoms) - projection
neurones with long/poorly myelinated axons particularly vulnerable which is why
mostly confined to motor regions
advanced (5-15yrs) = to neocortex (dykinesias, dysrthria, dementia, autonomic, sleep)
pathogenesis of degen is multifactorial (mnemonic -lemon)
1. loss of trophic support: a-syn may induce downregulation of RET receptor, decreasing
GDNF/BDNF etc in PD brain which disinhibits apoptosis
2. excitotoxicity: inc Subthalamic nucleus firing inc NMDAR activation into SNc - has low
calbindin levels and Cav1.3 pacemaker Ca channels, making it vulnerable to high Ca concs
= excitotoxicity and degen
3. mt/oxidative stress: as well as disruption of complex I import as above, evidence of
impairment antioxidants eg. glutathione in PD brain, with many PD mutations interlinked:
eg. PRKN is mutation to E3UL mitophagy activator, preventing proteasomal-ubiquitination
response, triggering apoptosis > dysfunction amplifies existing vulnerability of SN to ox
stress due to ROS bi-products of dopamine oxidation: causes cell damage, triggers
caspase activation/apoptosis and promotes a-syn toxicity/oligomer through formation of
4HNE (4hydroxy2nonenal from lipid perox)
4. neuroinflamm: neuromelanin release/a-syn aggregates activate microglia in SNc to pro-
inflamm M1 phenotype (innate), and may also trigger adaptive to activate T/B cells, all of
which release cytokines eg. TNFa contributing to degen which further perpetuates inflamm
- TNfa levels correlate with disease progression
exam 2
, aetiology
primarily presenting as sporadic/idiopathic, where aet is multifactorial and largely unclear,
though several factors implicated:
a. environment
observation that MPTP induces parkinsonism in animal models (kills DA neurones in SN)
suggests environment/toxins, eg. accumulation of agrochemicals, may play a role
b. may be mediated via gut microbiome, another factor with increasing evidence of
involvement
first from observation that lewy bodies are evident in ENS in prodromal phase <20yrs
before, suggesting pathology may start here then migrate via retrograde axonal transport
through vagus to brain
indeed some animal studies show a bidirectional spread of a-syn from gut to dorsal motor
nucleus of vagus and that truncal vagotomy may dec long term risk of diagnosis -
however, 2017 epidem study found no overall significant protection of vagotomy and lots of
confounders eg. vagus itself is anti-inflamm
appendix also theorised as a source/trigger site with pathological a-syn present in PD and
no-blood tissue barrier, but as before while some eg. swedish patient registry showed
delayed age of onset and dec incidence after appendectomy others no effect
microbiome itself seems to be important: changes seen in PD and studies showing
injection of these PD microbes into mice promotes a-syn agg/motor deficits, perhaps due
to inflamm, while mice with no microbiome showing attenuated motor deficits even with a-
syn agg
c. genetic
~10% cases not idiopathic but familial, often presenting w early onset = several genetic
links most commonly to PARK1-10 genes: linked to mt dysfunction, protein degradation, a-
synucleinopathy eg. PARK1 encodes a-synuclein so mutation =
overexpression/aggregation
other genes also linked to sporadic cases: GBA1 encoding glucocerebrosidase loss of
function (LOF) mutations seen in 33% cases and thought to inc risk by >5x due to
impairment of lysosomal autophagy to inc a-syn agg + LRRK2 (leucine rich repeat kinase)
gain OF mutations/inc activity also observed impairing
lysosomal/proteasomal/mitochondrial function/mitophagy and inc ox stress/inflamm
current treatments (pros/cons)
1. LDOPA
current gold standard, effective in 80%: natural DA precursor able to cross BBB via LAT1,
so can undergo conversion in remaining DA neurones to normalise basal ganglia activity,
significantly improving bradykinesia, cognition (if used early), other motor eg. speech
exam 3
, due to pharmacokinetics need combination therapy to allow central access: 90% would be
converted to DA by dopa decarboxylase in intestinal wall (further activated by vit b6) so
given with peripheral DDC inhibitor eg. carbidopa + 5% metabolised by plasma COMT so
inhibitor eg. entacapone (less hepatotoxic than tolcapone) also needed
despite efficacy, severe side effects (SEs):
acute: schizo symptoms from central effects and postural hypotension//nausea from
peripheral, though can be ameliorated with peripheral DR antag domperidone - also
risk of agranulocytosis
chronic more disabling: 2/3 develop ldopa induced dyskinesia (LID) within 5yrs =
hyperkinetic, involuntary choreic movements of the limbs/trunk + ‘on/off’ motor
fluctuations > potentially from fluctuating dopamine receptor stimulation, D1R
sensitisation, inc thalamocortical feedback, inc corticostriatal glutamate transmission,
some suggestion that may promote degen by inc ROS - once onset cannot be
reversed, so delay LDOPA as long as poss
to combat LID: only licensed adjunct drug is amantadine, NMDA antag which indirectly
augments DA release to reduce receptor stimulation fluctuations, though subcut
apomorphine may also be used in emergency ‘off’ + adenosine A2AR antag also recently
FDA approved as adjunct as prolongs LDOPA hl to enhance ‘on’ time without worsening
dyskinesia and may be neuroprotective - main focus currently on alternative
administrations to dec receptor stimulation fluctuations eg. duo dopa (intraduodenal
continuous infusion pump) or produodopa sc pump - such routes may also dec risk of
sudden withdrawal from pateint non compliance which risks potentially fatal neuroleptic
malignant syndrome
2. MAO-B inhibitors eg. rasagiline
block DA metabolism in striatum to dihydroxyphenylacetic acid > useful as monotherapy
early to boost remaining activity (and some evidence of neuroprotectivity eg safinamide by
blocking glu release) then adjunct later to lower LDOPA dose needed and so dec LID
3. long acting DR agonists
mainly activate D2R to inhibit indirect in basal ganglia - though share acute SE with LDOPA,
which will still be needed eventually, the long half life (esp if in patch form eg. rotigotine)
dec fluctuating activation so halves risk and delayed onset of LID > may also benefit other
symptoms eg. pain, depress (esp pramiprexole), so firstline after MAOBI
4. other approaches
historically mAChR antag eg. benzatropine were used - beneficial for tremor and to help
stop sialorrhoea but not effective for brady and cognitive/anti-muscarinic SE
many other drugs used to treat comorbid symptoms eg. SSRIs for depression, clonazepam
for REM disorder + non-pharm interventions eg. deep brain stimulation even showed better
efficacy than pharm in recent meta-analysis
exam 4
