Lec 18- Parkinsons Flashcards
1
Q
Motor disorders of the basal ganglia
A
- Parkinson’s
- Hypokinetic disorder (Akinesia and rigidity) often associated with tremor
- Huntington’s disease- Hyperkinetic disorder- chorea
- Ballism/Hemiballism
- Hyperkinetic disorder
- Basal ganglia= collection of 6 nuclei that controls our voluntary movement
2
Q
Parkinsons I
A
- 1817 James Parkinson- shaking palsy
- Progressive disorder
- Muscle rigidity
- Akinesia- difficulty in initiating movement
- Resting involuntary tremor- simulates pill rolling
- Slow shuffling gait
- Dementia
3
Q
Parkinsons II
A
- 0.1% of population, disease of the elderly
- >50yrs- 1% of population
- Mean survival time after diagnosis- 10yrs
- Drug therapy improves clinical symptoms but does not alter disease progression
4
Q
Parkinson’s Disease III
A
- Specific loss of DA cells in the substantia nigra pars compacta
- Loss of dopaminergic nigrostriatal pathway- idiopathic stroke, viral infection
- Parkinsonism- drug-induced, amphetamines, neuroleptics
5
Q
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
A
- Irreversible selective destruction of nigro-strial neurones
- Frozen adddict syndrome
- Converted to MPP+ by MAO B and uptake by specific DA transporter system
- Inhibits mitochondrial oxidation reaction- oxidative stress
- Useful experimental tool
6
Q
Pathology
A
- In early-onset Parkinson’s- there is a specific gene mutation
- Leads to the presence of Lewy bodies- aggregates of proteins that build up inside nerves, contribute to dementia
- Contain a-synuclein
- Parkin, ubiquitin, LRRK2, PINK
- Defective disposal of these proteins may render cells susceptible to oxidative stress
7
Q
The Basal Ganglia
A
- Six interconnected nuclei
- The striatum, GPe, GPi, STN-only glutamatergic nuclei, site of deep brain stimulation, SNr, SNc
- Integrates motor and sensory information from the cortex before relaying it back to the cortex via the thalamus
- Many parallel loop circuits, not all strictly ‘motor’ (also sensory even emotional (limbic) loops)= Parallel processing hypothesis
- The output from the BG is controlled by two parallel but opposing pathways which are modulated by DA
8
Q
Dopaminergic modulation of basal ganglia output- (DIRECT PATHWAY)
A
- Cerebral cortex- Both paths start this way (DIRECT PATHWAY)
- Sends excitatory glutaminergic paths to basal ganglia
- Striatum (input stations) receives excitatory signal
- Striatum neurones are GABAergic (inhibitory) reduce excitation to Substania nigra, GPi (these are the output stations)
- SNr/GPi (also GABAergic) send inhibitory signals to the thalamus
- SNr/GPi (Output stations) inhibit thalamocortical motor loop
- SNc (substania nigra compacta) releases DA, acts on D-1 project to output stations, postsynaptic receptors causes excitatory action (increases Adenylate cyclase and cAMP)
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9
Q
Dopaminergic modulation of basal ganglia output (INDIRECT)
A
- Cerebral cortex excites the Striatum
- Striatum inhibits GPe cells
- GPe inhibits STN (subthalamic Nucleus)
- STN excitatory (glutaminergic) neurones stimulate SNr/GPi
- There is an excitatory feedback loop between SNr/GPi and GPe
- SNc releases DA in the (striatum) onto D2-receptors (inhibitory), the cells containing D2 project to GPe
10
Q
The BG and motor dysfunction
A
- Arises through an imbalance between the direct and indirect pathways => motor dysfunction
- Hypokinetic disorders: Parkinson’s disease
- Hyperkinetic movement disorders e.g. Huntingtons, ballism
11
Q
Parkinson’s
A
- Primary pathology is the loss of nigrostriatal dopaminergic pathway
- => excessive inhibition of the thalamocortical pathway
- We lose excitation of the direct pathway
- May explain (to an extent)
- Akinesia (the absence or reduction of movement
- Bradykinesia (slowness of movement)
- Rigidity (resistance to passive movement)
12
Q
In Parkinson’s- Dopaminergic modulation of basal ganglia- Direct pathway
A
- For direct pathway
- We lose DA, so no released by SNc
- No excitation of the striatum (so no adenylate cyclase => cAMP => No AP, Ca influx and Ca-dependent exocytosis) so reduced GABA release
- SNr/GPi then get excited (no GABA released onto them), these cells then release EXCESS GABA onto the thalamocortical motor loop
- Excessive inhibition of thalamocortical loop gives symptoms of Parkinson’s (Reduced Voluntary movement)
13
Q
Dopaminergic modulation of basal ganglia output- INDIRECT
A
- SNc has reduced DA released so less D2 neuronal stimulation
- Less inhibition of striatum which increases GABA release= Increased inhibition of GPe
- GPe is inhibited so less GABA is released onto STN (excited)
- Increased activity of STN neurones, STN are glutaminergic which excites output stations (SNr/GPi)
- Excessive stimulation of SNr/GPi causes increased release of GABA
- Excess release of GABA causes increased inhibition of thalamocortical motor loop
14
Q
Current research- neuronal synchronisation is the key
A
- The rate and pattern of neuronal firing encodes information in the BG
- DA depletion induces bursting firing and synchronisation of BG neuronal firing
- Neuronal Oscillations at the beta frequency (20Hz) correlate with bradykinesia
- Oscillatory activity in the cortex and the STN-GP network has been implicated in pathological disorders
15
Q
Surgical treatments
A
- Pallidotomy or subthalamotomy
- Thalamotomy- excessive bradykinesia
-
Deep brain stimulation of subthalamic nucleus (STN) @130Hz
- Gets rid of pathological oscillations
- Direct non-invasive stimulation of the motor cortex
21
Q
The mechanism for L-DOPA induce dyskinesia
A
- Short acting t1/2
- Dosage
- Age of PD onset
- Severity of PD
