Parkinson's Flashcards
Projection pathway of corticobulbar tract
Motor neurons project to the brainstem nuclei via internal capsule
What does the corticobulbar tract control?
movement of the face, tongue, and pharyngeal muscles
Projection pathway of the corticospinal tract
Motor neurons project via the posterior internal capsule to the cerebral peduncle. From here it divides into three distinct tracts.
1. Lateral corticospinal tract (80%): decussate at the medulla
2. Ventral/anterior corticospinal tract (10%): decussate at terminal spinal cord
3. Corticospinal tract (10%): remain ipsilateral
What does the corticospinal tract control?
skilled voluntary movement involving the neck and limbs
What is the role/participants of the extrapyramidal pathway
The Extra-pyramidal pathways provide additional information and modulation to optimise the motor programme.
- Premotor cortex: early motor programme development
- Cerebellum: controls the timing of muscle contractions within the motor programme
- Basal Ganglia: selection of appropriate motor programme
- (motor) Thalamus: integrates information from BG and cerebellum
Describe the circuitry of the basal ganglia
The VTA/SNpc send dopaminergic projections to the striatum, where dopamine acts on two distinct groups of spiny projection neurons/MSNs. The direct group contains Substance P, and expresses the D1 type dopamine receptor. The indirect group contains enkephalin, and expresses the D2 type receptor. The direct pathway sends GABAergic projections to the GPi/SNpr, which are the major output nuclei of the basal ganglia. The indirect pathway sends inhibitory projections to the GPe, which has inhibitory projections to STN. The STN projects excitatory glutamate onto the output nuclei. The output nuclei SNpr/GPi send GABAergic projections to the thalamus.
What occurs in the BG when there is a phasic spike of DA?
In the direct pathway, DA binds to D1 receptors, causing an increase in cAMP and increased cellular activation, therefore release of GABA and inhibition of GPi/SNpr.
In the indirect pathway DA binding to D2 receptors leads to a decreased firing rate. Thus there is less GABA released onto the GPe. This causes an inhibition of the STN, and thus less excitation of the output nuclei.
Less GABA released from GPi/SNpr onto thalamus = disinhibition of the thalamus
List the symptoms of PD
Motor: Bradykinesia (Slow Movement), Dyskinesia, Rigidity, Postural instability, Resting tremor, akinesia (inability to initiate movement)
Non motor: Cognitive impairments, sleep disorders, depression, memory deficits
What is the hallmark pathology of PD?
Death of dopaminergic cells in the substantia nigra pars compacta and VTA. Formation of Lewy bodies in dopaminergic cells, which occur due to accumulation of the alpha-synuclein protein in the cytoplasm.
At what stage in the parkinson’s pathology do symptoms appear?
After death of ≥65% of the dopaminergic cells in the SNpc/VTA.
What are the available treatments for parkinsons?
- Physical therapy/exercise
- environmental adjustments
- L-DOPA
- Surgery for deep brain stimulation
What is the net affect to the basal ganglia in parkinsons?
Decreased dopamine release leads to an increased inhibition of the thalamus AND abnormal, prolonged synchronous firing
What should a good animal model of PD possess?
progressive death of dopaminergic cells in the SNpc/VTA, and formation of lewy bodies. Should show motor deficits including akinesia, bradykinesia, rigidity, postural instability, and resting tremor. Should respond to treatment with levodopa/DBS.
What does the 6OHDA animal model involve?
Injection of 6-OH DA into the SNpc/medial forebrain bundle (SNpc/VTA projection fibres)/striatum into a single hemisphere.
6OHDA taken up by dopaminergic and noradrenergic cells (if you want dopaminergic specificity, also inject a noradrenaline uptake blocker). Within the cells, the 6OHDA interferes with mitochondrial metabolism causing production of radical oxygen species which promote cell death.
Data compared to un-lesioned hemisphere, or a sham lesion.
What does the MPTP model involve
Injection of MPTP (i.v ,.i.m.) into the bloodstream, from which it will travel to the brain. The injection can be given to any mammal expressing the MAO B enzyme (not rats), but is mainly given to primates. Injection must occur repetitively over days/weeks to ensure no behavioural recovery.
MPTP is metabolised by MAO B into MPP+, which is selectively taken up by dopamine cells resulting in mitochondrial dysfunction and production of free radicals.
Data is collected from a control animal, or with primates, prior to injection for comparison as primates are a limited (and thus expensive) resource.
How is dopamine antagonism used to model PD?
An acute model of PD that can be used in all models, but does not model the pathology. Antagonist can be D1/D2 selective or generalised, and acts to temporarily block the effects of dopamine.
A caveat is that this treatment affects all dopamine cells (not just SNpc/VTA), and does not reflect clinical features such as response to treatment.
Data is compared to the same animal with saline injection.
How is animal model pathology assessed?
Pathology can be assessed qualitatively using the step test, apomorphine test, cylinder test, open field test or rotarod or quantitatively through immunohistochemistry or high performance liquid chromotography
Step Test
animals (must be trained) are dragged 1m across surface at a specific angle, direction, and speed. Number of ‘steps’ in measured. Less steps = less DA.
Apomorphine test
apomorphine is a dopamine agonist, and is injected systemically into animals that are parkinsonian in one hemisphere. Because the Parkinsonian side adapts to low dopaminergic input, there is a significantly greater number of DA receptors in the striatum. When agonist is added this stimulation far outweighs the normal side, causing the rat to spin around
cylinder test
the rat is placed in a tube, and assessed on number of paw touches to the wall of cylinder. Relatively low placements on side contralateral to lesion indicates DA loss.
rotarod
a general motor behaviour test, where rats ability to learn to stay on a rotating rod is assessed. PD animals tend to lack learning ability, thus will continue to fall off across multiple trials.
