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
16
Q
Assessment of symptoms
A
- UPDRS III- unified Parkinson’s disease rating scale (5 sections including self and clinical rated evaluation)
- Cared Assessment
- ADL- activities of daily living (self-reported)
17
Q
Drug therapy
A
- UK Guidelines Parkinson’s disease consensus working group 1998
- Loss of DA upsets balance of excitation provided by DA and ACh systems
- Most therapies aimed at replacing or replenishing dopaminergic neurotransmission or reducing ACh action at muscarinic receptors
- Secondary changes in 5-HT, GABA, peptides (enkephalin) in the nigra and GPe
- Choice of therapy depends on age, symptoms, cognitive impairment, other illnesses
18
Q
Anti-muscarinics
A
- Early (mild) stage
- Help in tremor (not hypokinesia or ridigity )
- Useful in secondary Parkinsonism (neuroleptic-induced)- cant use L-DOPA= psychosis and schizophrenia
- Benztropine, biperiden
- Troublesome side effects, best avoided in elderly patients
19
Q
L-DOPA (Di-hydroxy phenylalanine)
A
- First line treatment- oral administration (crosses BBB) 250mg-8g DD 1.5 hr half-life (TDS)
- Usually given in combination with peripheral dopa decarboxylase inhibitor carbidopa 500mg-1g BD or TDS (SINEMET or SINEMET CR)
- L-DOPA and benserazide (MADOPAR)
- Initially 80% of patients show improvement 20% become normal
20
Q
L-DOPA side effects
A
- Dyskinesia- Unpredictable motor complications (extrapyramidal)
- Wearing off effects- Effectiveness declines with time
- Progressive On-Off (swinging)- On periods complicated by dyskinesias and off periods severely akinetic
- Neuropsychiatric side effects- Schizo-like syndrome e.g. hallucinations
- Nausea and vomiting, anorexia, hypotension
- symptoms of therapy or disease progression?
- Accelerate degenerative process- oxidative stress
- Does reducing L-DOPA exposure really reduce disease progression
21
Q
The mechanism for L-DOPA induce dyskinesia
A
- Short acting t1/2
- Dosage
- Age of PD onset
- Severity of PD
22
Q
Combined therapies
A
- L-dopa sparing strategy- aimed at reducing the effective dose of L-dopa
- +Dopa-decarboxylase inhibitors- carbidopa, benserazide
- +DA agonists- Bromocriptine, pramipexole
- +COMT inhibitor- entacapone
- +MAO-B inhibitors- Selegiline
- +DA releasers- Amantadine
- +ACh antagonists- Benztropine
23
Q
Dopamine agonist
A
- Not as effective as L-DOPA initially
- Evidence for less on/off fluctuation
- Monotherapy (bromocryptine PARLODEL x3 or barbegoline x1) Also in connection with L-DOPA (Pramipexole x3, Ropinirole x3)
- Alternative to L-DOPA in younger patients?- Less side effects
- Expensive
24
Q
Apomorphine
A
- DA agonist
- Administered by injection
- Rescue treatment for sudden on/off periods
- Works within 5-15 minutes
- Often used as a rescue treatment
25
Q
COMT Inhibitor
A
- The catechol-o-methyl-transferase enzyme involved in the metabolism of DA i.e. allows more L-DOPA to enter the brain
- Used as adjunct therapy- prolong L-DOPA half-life
- Reduces [plasma] fluctuations
- Entacapone (COMTAN 200mg tab taken with L-DOPA dosage) May require 10-30% L-Dopa dose reduction
- Additional side effects- diarrhoea discoloured urine
- Tolcapone (TASMAR) withdrawn due to fatal liver damage
26
Q
MAO-B inhibitors and DA releasers
A
- MAO-B inhibitors - selegiline (only neuroprotective treatment) (ELDEPRYL)
- 5mg tablets < 10mg per day
- Neuroprotective?? but little evidence
- Side effects hallucinations and confusion
- FATAL INTERACTION with opioids
- Mild antidepressant - avoid with TCAs & SSRIs
- DA releasers - amantadine (SYMMETREL)
- Gelatin capsule or syrup
- enhance release, block uptake
- anticholinergic effect
- NMDA antagonism- LTP (reduced cognitive ability)
- useful in early treatment for rigidity and end-stage dyskinesia
- Side effects confusion, lightheadedness, red spiders web mottling of legs
27
Q
Alternative treatments
A
- Fetal-nigral (striatal) transplantation
- Green tea, smoking, cannabis, ecstasy (?? roles in oxidative stress)
- Use of stem cells
- The embryonic stem cell that matures into a DA neurone
- Ethical issues of embryonic research
- Adult stem cells- New neurones
- Gene therapy
28
Q
Gene Therapy
A
- Insertion of genes into an individual’s cells and tissues
- Extra, correct copies of genes are provided to complement the loss of function
- Viruses bind to their hosts and introduce their genetic material into the host cell as part of their replication cycle
- In PD- A neuroprotective strategy
29
Q
A
- AAV-hAADC-2 (Genzyme)
- L-DOPA to DA, no side effects, Phase I trial
- AAV-GAD (Neurologix)
- Intrasubthalamic, Phase I results positive, Phase II recruiting
- TH, AADC, GTP cyclohydroxylase (Prosavin)
- Lentivirus, 3 genes, converts cells to DA producing
- no side effects
- GDNF (Cere120, Neurturin)
- AAAV Lentiviral vector into BG gene expression without toxicity.
- Neurotrophic factors for dopamine cells
