Basal Ganglia and Parkinson's Disease Flashcards
What is the basal ganglia and what does it contain?
Basal ganglia is a very complex and poorly understood area of the brain
Basal ganglia are deep cerebral nuclei;
- Neostraitum (caudate nucleus & putamen)
- Paleostriatum (globus palldus)
- Subthalamic nucelus
Substantia nigra;
- filled with melanin
- Pars reticulate (GABAergic)
- Pars compacta (dopaminergic)
Substantia nigra is important fro producing dopamine as this feeds into this motor loop and allows for normal movement (issue in this is Parkinson’s)
What are the functions of Basal Ganglia?
- Smooth movement
- Switching behaviour
- Reward systems
- Closely linked to thalamus, cortex and limbic system
What is the pathway of the the basal ganglia ?
All pats of cerebral cortex project to corpus striatum, basal ganglia project to thalamus, thalamus projects to cerebral cortex (the motor loop)
Basal ganglia thought to generate basic pattens of movement (motor programs)
Cortical activation of putamen leads to excitation of supplementary motor area (SMA) by the ventrolateral nuclei (VLN) of thalamus
Direct pathway;
- cortical excitation of neostriatum leads to disinhibition of thalamic nuclei
- Movement follow activation of putamen by cortical areas
Indirect pathway;
- Cortical excitation of neostriatum leads to inhibition of inhibitory input to Subthalamus
- Activation of indirect pathway leads to inhibition of cortical areas
Activation of the dopamine pathway leads to activation of direct and inhibition of indirect pathways
What are clinical problems that are found in the basal ganglia ?
Parkinsons disease (substantial nigra pars compact deficit)
- hypo kinetic, bradykinesia, hypertonia
Huntington’s disease - chorea (caudate deficit)
- hyperkinetic, hypotonia
Hemiballism (sub thalamic deficit)
- hyperkinetic
- Violent, involuntary movements
Wilson’s disease (lenticular)
- Associated with copper deposition
- Involuntary movements
What are the clinical features of Parkinson’s disease?
- Tremor at rest
- Rigidity - cogwheel, limbs > axial
- Bradykinesia (slowness to initiate movement)
- Asymmetry
- Loss righting reflex
- 30% cognitive decline
- Hypomimia (lack of facial expression)
- Glabellar tap
- Quiet speech
- Micrographia
What is the pathophysiology of Basal Ganglia in Parkinsons Disease?
Bradykinesia, akinesia, rigidity
Degeneration of dopaminergic neurons of substantial nigra pars compacta (Loss of dopamine)
Inhibition of indirect pathway removed so stronger inhibition of thalamus and signal from thalamus to front cortex is reduced
See pathway attached
What are the features of Huntington’s disease (Chorea)?
- Autosomal dominant
- CAG triplet repeat disease (>40 repeats)
- Mutant huntingtin protein accumulates, toxic (causes wastage)
- Chorea, behavioural disorders, dementia
- Caudate nucelus wasting
What is the pathophysiology of the Basal Ganglia in Huntington’s disease ?
Hyperkinesia, dyskinesia (occurs briskly and quickly)
Characterised by inappropriate or repetitive execution of movement patterns
Degeneration of caudate, putamen & globes pallidus
Reduced outflow of inhibitory signal from globus pallidus and reduced inhibitory outflow
What are the features of Wilson’s disease?
- Rare autosomal recessive
- Abnormal Copper accumulation
- Hepato-lenticular degeneration (liver and brain)
- Dystonia, ataxia, subcortical dementia
- Copper transport protein abnormality
- Low serum copper and caeruloplasmin
- Kayser-fleischer rings (See pic)
- Treatment - low copper diet & Penicillamine (chelating agent)
What are the treatment options for Parkinson’s disease?
Treatments;
- Levodopa
- Dopamine Agonists
- Monoamine Oxidase (MAO) inhibitors
- Amantadine
- Acetylcholine antagonists
- Neural transplantation and brain stimulation
Targets;
- Dopa decarboxylase (DDC)
- Catechol-O-methyl transferase (COMT)
- Monoamine oxidase B (MAO-B)
- 3-methoxydopa (3-MDopa)
- 3-methoxytyrosine(3-MT)
- Dihydroxyphenylacetic acid (DOPAC)
We want to increase dopamine levels - cannot inject as its broken down very easily in body and cannot cross BBB hence we use levadopa a precursor which can cross the barrier hopefully help in Parkinson’s replace the dopamine we are lacking. Usually give with carbidopa or benserazide to help keep the level of levadopa in the periphery until it crosses the BBB - knocks out enzymes that would convert dopamine in the periphery.
What are the features of Levodopa?
First line treatment for Parkinson’s and combined with a dopa decarboxylase inhibitor (carbidopa or benserazide)
This combination lowers the dose needed and reduces peripheral system side effects 9e.g nausea, hypotension)
80% of patients show initial improvement in rigidity and hypokinesia
Limited in effectiveness with time as neurodegenration progresses
Overall no evidence that Levadopa slows or accelerates neurodegeneration
Long term side effects;
- Involuntary writing movements (dyskinesia) which may appear within 2 years. Affect and limbs mainly. Occurs at peak therapeutic effect
- Rapid fluctuations in clinical state. Hypokinesia and rigidity may suddenly worsen and then improve again. This on-off effect not seen in untreated PD patients or with other PD drugs. Reflects fluctuating receptor dynamics
What are the features of Dopamine Agonists ?
- Bromocriptine, cabergoline and pergolide (ergots) are orally active drugs that work on D1 and D2 receptors. they have limiting Sid effects - fibrotic reactions
- Pramipexole and ropinirole are D2/3 selective receptor agonists that are better tolerated. Short in half-life plasma (6-8 hrs) could be a problem
Rotigotine newer agent delivered by a transdermal patch
Apomorphine given by injection sometimes given to control the off-effect of levodopa
What are the features of the Monoamine Oxidase (MAO) inhibitors ?
Monoamine Oxidase (MAO) inhibitors;
- Selegiline & Rasagiline are a selective MAO-B which lacks the unwanted peripheral effects of non-selective MAO inhibitors
- Inhibition of MAO-B protects dopamine from extra neuronal degradation
- Combination with levodopa is more effective in relieving symptoms and prolonging life
Help to maintain level of dopamine in brain
What are the features of Amantadine?
Antiviral drug discovered to be beneficial in PD
Increased dopamine release is primarily responsible for its therapeutic effect
Less effective than levodopa or bromocriptine and action declines with time
What are the features of Acetylcholine Antagonists ?
Until discovery of levodopa, atropine and related drugs main form off treatment for PD
Muscarinic acetylcholine receptors exert an inhibitory effect on dopaminergic nerves suppression of which compensates for a lack of dopamine
Trihexyphenidyl (benzhexol), orphenadrine and procyclidine can all be used, with usual anti-cholinergic side effect
