Parkinson's Disease Flashcards
Who does Parkinson’s Disease effect? When is onset?
- Affects everyone of every background.
- Onset around 60 years of age (most people start noticing motor problems (shaking, stiffness, troubles with balance) around this age.
What are early motor symptoms of Parkinson’s?
- Tremors/Posture
- Balance problems
Can Psychosis develop during Parkinsons?
- Psychosis can develop (from the progression of Parkinson’s itself, or side effects of medications (dopamine-based treatments)).
- This results in cognitive decline. (mild cognitive decline 80% of patients)
-> Dementia - as the disease progresses, dementia (severe cognitive decline) becomes common.
What are non-motor symptom’s associated with Parkinson’s?
- Constipation (often early, before motor symptoms) - possibly due to dysfunction in the autonomic nervous system (which controls digestion).
- REM sleep behaviour disorder - people act out their dreams physically (eg., kicking or punching) because the usual muscle paralysis during REM sleep is lost.
RBD increases the chances of developing Parkinson’s by around 80%.
Dreams often intense, involving themes of fear or escape.
Substantia Nigra
- located in the midbrain
- contains dopamine-producing neurons
- these neurons contain neuromelanin (gives substantia nigra its dark color)
- In parkinsons, these dopamine neurons degenerate, causing the dark band of substantia nigra to disappear.
Corpus Striatum
- Dopamine neurons from the substantia nigra project to the striatum via long axons.
- Striatum is part of the basal ganglia (involved in movement control)
- Dopamine modulates the striatum (it is the target region - where the action is)
Tyrosine Hydroxylase
- Enzyme involved in dopamine production
- Found in the axons of dopamine-producing neurons in the striatum
- By the time of symptom onset, many nigral neurons have already died, and within a year, the axons lose tyrosine hydroxylase → leads to functional loss, not just neuron death.
Reward Prediction Error
- Dopamine neurons fire when there’s a difference between expected and actual outcomes (e.g., expecting a reward but not getting it).
- Dopamine loss in Parkinson’s disrupts this reward-based learning and motor control system.
What is the dopamine pathway that is influencing motor activity?
- Substantia nigra (in midbrain) → sends dopamine to → striatum (in basal ganglia)
- Striatum → influences motor activity and learning via circuits with the cortex
The cortex acts as the decision-maker or “actor” in response to signals from the basal ganglia
What is the role of the basal ganglia (BG) direct and indirect pathways in movement control?
- Direct Pathway → Excites thalamus & cortex → GO (promotes movement)
- Indirect Pathway → Inhibits thalamus & cortex → STOP (inhibits movement)
- Striatum (critic) – Largest BG nucleus, processes info about past experience
- Basal Ganglia – Acts like a trusted advisor for movement decisions
Basal Ganglia
group of nuclei located below the cortex. they help in selecting and initiating voluntary movement.
describe the flow of information about movement in the brain
- Input -> From cortex (CTX)
- The cortex sends information about movement plans to the corpus striatum (which includes the caudate nucleus and putamen). - Processing in BG.
- Striatum evaluates the information, deciding whether to promote or inhibit movement.
- If movement is approved, direct pathway excited thalamus, if movement if rejected, indirect pathway inhibits thalamus. - Output -> To Pallidum
- Processed signal from striatum is sent to pallidum (includes globus pallidus)
- Regulates signals going to the thalamus and superior colliculus (for eye and head movements). - Final Output -> To Thalamus and Cortex.
- sends instructions back to cortex to initiate or stop movement. - Eye and Head Movement -> Superior Colliculus.
- Midbrain receives signals form pallidum and striatum to control eye and head movements.
What is the flow of information for Limb Movement?
CTX → Striatum → Pallidum → Thalamus → CTX → Movement
What is the flow of information for eye and head Movement?
Striatum → Substantia Nigra (pars reticulata) → Superior Colliculus → Eye and head movement
Many areas are involved in movement, what are they?
- motor cortex
- somatosensory cortex
- auditory association areas
- visual cortex (extra-striate)
- multimodal association cortices and frontal motor areas (eye movement)
What cells mostly take up the striatum?
- 90% of the cells are medium size spiny projection neurons.
- they are plastic.
- around 3 million MSNs
- 75 billion glutamate synapses (1 or 2/axon)
BG neurons
- Dopaminergic neuron
- Cortical pyramidal neurons
- Medium Spiny Neurons
- Globus pallidus or substantia nigra pars reticulata neuron (MSNs target lots of cells a bit, and one A LOT)
Tonic Inhibition of Movement
- substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi) are tonically active.
-> constantly firing at rest. - continiously inhibiting their target structures, which prevents movement from happening unless that inhibition is reduced.
Effect of the Direct Pathway
- releases inhibition to allow movement.
- when the caudate and putamen (striatum) -> become active -> send inhibitory signals to SNr and GPi,
- reduces tonic activity of SNr and GPi, releases inhibition on their targets, allows for movements to occur.
What are the targets of SNr and GPi?
- SNr inhibits superior colliculus -> controlling eye movement.
- GPi inhibits the VA/VL complex of the thalamus -> sends excitatory signals to frontal cortex -> drives movement. If GPi inhibited, VA/VL complex becomes more active, increasing cortical activity and allowing movement.
What is an example of ‘Functional Disinhibition’?
- Functional disinhibition = inhibition of an inhibitory signal, which results in increased activity or movement.
- Direct pathway of the basal ganglia is a prime example of this mechanism
How are saccadic eye movements controlled?
- tonic inhibition by SNr.
- The substantia nigra pars reticulata (SNr) is constantly active.
- SNr inhibits the superior colliculus (SC) to prevent random eye movements.
What is an example of motor action selection through the BG using functional disinhibition?
- present target at animal -> striatum (caudate + putamen) is activated.
- striatum sends inhibitor signals to SNr.
- SNr inhibition decreases -> SC becomes more active.
- SC generates a saccade toward target.
(direct pathway) - With repeated training, the striatum becomes better at recognizing the target.
- Faster and more accurate saccadic response over time.
- The animal learns to associate the target with a saccade.
What is the difference between Direct Pathway and Indirect Pathway in BG?
- Direct -> Facilitates movement
- Striatum (caudate + putamen) inhibits the SNr and GPi (which are tonically active)
- Reduces inhibition on the thalamus (VA/VL complex).
- Thalamus more active -> increases cortical activity -> movement. - Indirect Pathway -> Inhibits Movement.
- Striatum inhibits the GPe (external segment of the globus pallidus).
- Reduces inhibition on the sub-thalamic nucleus (STN). (extra inhibitory step)
- STN excites GPi and SNr, increasing their activity.
- Stronger inhibition on the thalamus -> decreased cortical activity -> movement suppressed.
BG output & Dopamine Modulation
- DA is released by the substantia nigra pars compacta (SNc).
- DA acts on 2 receptors in striatum.
- D1 -> Direct pathway (on dSPNs - direct pathway striatal projection neurons)
Activation of D1 receptors leads to increase in excitability of dSPNs, direct pathway more active promoting movement.
D2 -> Indirect pathway (on iSPNs - indirect pathway striatal projection neurons)
D2 receptors lead to decrease in excitability of iSPNs - indirect pathway less active, reduces inhibition on thalamus, allowing for movement.
- both pathways ENHANCE movement.
What theory challenged the GO/STOP Model?
- using opto-reporting, see what happens during unstimulated behaviour (w/o external light activation).
- both direct & indirect pathways were active BEFORE movement, and less active after movement.
- contradicts GO/STOP model - if indirect was only a STOP signal, it should not be active before movement.
-Both pathways seem to be involved in movement preparation and action selection — not just starting or stopping.
Instead of simple “on/off” switch:
basal ganglia likely:
1. Direct pathway = Promotes specific movement
- Indirect pathway = Refines or regulates movement to prevent unwanted motions
What is the result of a lesion to the Basal Ganglia (motor symptoms)?
- Huntington’s Disease
- Chorea
- Dystonia
- Impaired gait / posture
- Speech / swallowing difficulty
- Death 15-20y - Parkinson’s Disease
- Tremor
- Bradykinesia
- Face mask
- Postural Instability
- Gait abnormality
- Time from motor diagnosis
to death 18y (2-37y)
What are the non-motor symptoms when there is a lesion in the BG?
- Sleep disturbances
- Depression, Irritability,
- Apathy
- Executive (dys)function
- Impulse control difficulty
- Cognitive slowing
- Sleep, bowel disturbances
- Depression in most new
- Executive (dys)function
- Impulse control difficulty
- MCI in 20-25% of new cases
- Dementia in 10% of new cases
- Dementia in 83% within 20y
- Not deficits in declarative memory
what are the dopamine terminals that can be targeted to produce psychotic symptoms?
- Increase of synthesis (L-DOPA).
-> Targets pathway from Tyrosine -> DOPA. - Stimulation of release of DA at nerve terminal (amphetamine, tyramide)
- Inhibition of breakdown (pargyline) (targets MAO breaking dopamine down)
- Inhibition of re-uptake of dopamine to dopamine transporter.
What are dopamine terminals that can be targeted as an antipsychotic?
- Inhibition of synthesis of dopamine (a-methyltyrosine)
-> targets tyrosine pathway to DOPA -> dopamine. - Interference with vesicular storage (reserpine, tetrabenazine) (inhibits)
- Blocking of DA receptors and autoreceptors (antipsychotics: perphenazine, haloperidol)
What is the gold standard for PD treatments? What is the caveat?
- gold standardL L-DOPA (dopamine precursor that crosses blood-brain barrier and increases DA levels in brain)
-> this restores activity in the direct and indirect pathways, improving motor function. - almost magical effect on motor symptoms for many BUT
-> L-LOPA can have short-term benefits & tragic side effects (dyskinesia around 50% at 5y)
- no benefit for non-motor symptoms; makes many worse (mood and cognitive alterations)
- no disease modifying action.
What are treatments for PD?
- L-DOPA (dopamine precursor)
- Surgical lesion (GPi or STM)
- DBS (deep brain stimulation GPi or STN)
- Electrical stimulation reduces the excessive inhibitory output from the basal ganglia, which improves motor function.
Problem:
- You can’t stimulate neurons continuously because they may adapt and stop responding (habituation).
- Backpropagation: The stimulation also affects axons projecting to the targeted neurons, which can have widespread, unintended effects on other parts of the brain.
Still no disease modifying therapy.
Can we replace DA cells as a PD treatment?
- Grafts of fetal cells / hiPSC neurons to make DA in striatum?
Idea to create induced pluripotent stem cells (iPSCs), differentiate them into DA neurons, and graft them into the striatum.
Why it could work:
-> The brain is plastic and can adapt to new dopaminergic input.
-> Some patients who received grafts showed functional improvement.
Problem:
- Post-mortem analysis of these grafts showed that the transplanted cells developed Parkinson’s pathology (like Lewy bodies).
- This suggests that the disease environment (e.g., toxic protein accumulation, inflammation) spreads to the grafted neurons, causing them to degenerate as well.
SO what should we do to treat PD?
- Increasing DA availability - Good but not enough to stop disease.
- Hacking the circuits - also good but not enough either.
- Replaced DA neurons, they also get sick.
All these great ideas mitigate disease symptoms, but DO NOT stop progression.
We should focus on causes of PD, not reversing the end result -> Provide Neuroprotection.
Neuroprotection
- Understanding cause of disease.
- AGE
- DA declines in normal ageing. - Environment
- Age
- Infection
- Head injury
- MTPT
- Paraquat
-PCBs - Genes
- Parkin
- PINKI
- DJ-I
- SNCA (alpha-synuclein)
- LRRK2
- VPS35
- RME-8
etc.
Allele frequency vs effect size.
which genes diminished the substantia nigra as seen in PD?
aSyn
- Key protein involved in PD.
- Mutations in the SNCA gene or too much alpha-synuclein (due to duplications or triplications) can cause: Late-onset PD, aggressive disease progression.
What happens if you knock out (KO) the gene for alpha-synuclein?
- If you remove just the aSyn gene → no obvious problems (likely because beta and gamma-synucleins can compensate).
- If you remove all three synuclein genes (alpha, beta, gamma) → the mice get very sick.
What happens if there is a mutation in aSyn?
- toxic gain of function
- hard to design targeted therapies
- Gene silencing (turning off the SNCA gene) is being tested in clinical trials.
- aSyn refers to the protein encoded by the SNCA gene.
- misfolded Asyn can:
1. Trigger pathology (forming toxic aggregates)
2. Replicated pathology (spreads to other cells, causing them to also misfold)
3. Transmission - spreads through brain networks like “prion” (infectious protein).
Goal of treatments -> stop the spread of misfolding aSyn.
LRRK2
- mutations can cause PD by increasing its kinase activity
- causes dopamine and glutamate release & affects receptor trafficking
- if we knock it out in mice, they are fine, it is not essential for survival, makes it promising drug target.
- potential treatments:
1. gene silencing
2. kinase inhibitors
all being tested.
PFF-Induced Alpha-Synuclein Pathology
- PFF = Pre-formed fibrils of alpha-synuclein → these fibrils can trigger toxic misfolding of normal alpha-synuclein.
- If LRRK2 is knocked out (LKO) → protected from PFF-induced toxicity.
- If LRRK2 is mutated and hyperactive (LKI) → more vulnerable to PFF-induced toxicity.
