29-09-23 - Basal Ganglia and Parkinson's Disease Flashcards
Learning outcomes
- Understand the anatomical location of the basal ganglia, and the way in which other stuctures connect with them
- Describe the proposed functions of the basal ganglia and the role of dopamine
- Be aware that malfunctions of the basal ganglia are implicated in other clinical conditions
- Be familiar with the clinical presentation of Parkinson’s disease and extrapyramidal syndromes
- Be aware of the various treatment options for Parkinson’s disease
Orientation of The Basal Ganglia Structures
What are basal ganglia?
What does the corpus striatum consist of?
What are the 4 different basal ganglia?
How do all of these structures interact?
- The basal ganglia are a cluster of subcortical nuclei deep to cerebral hemispheres.
- Basal ganglia are deep cerebral nuclei
- The corpus striatum includes the neostriatum (caudate nucleus and putamen, together commonly referred to as the striatum), and paleostriatum or GP
- The corpus striatum is the largest component of the basal ganglia
- 4 different basal ganglia:
1) Neostriatum (consists of caudate nucleus & putamen)
2) Paleostriatum (globus pallidus)
* Globus pallidus medial (internal)
* Globus pallidus lateral (external)
* The lenticular nuclei subdivide into the putamen and globus pallidus, which further divides into an external (GPe) and internal (GPi) segments.
3) Subthalamic nucleus
4) Substantia nigra
* Filled with melanin
* Pars reticulata (GABAergic) - The pars reticulata is a portion of the substantia nigra and is located lateral to the pars compacta. Most of the neurons that project out of the pars reticulata are inhibitory GABAergic neurons
* Pars compacta (dopaminergic) - There are 400–500 thousand dopaminergic cells within each side of the human substantia nigra pars compacta (SNpc) making them a minuscule portion of total brain mass
- These structures intricately synapse onto one another to promote or antagonize movement.
What are 4 functions of the basal ganglia?
- These structures intricately synapse onto one another to promote or antagonize movement:
1) Smooth movement
2) Switching behaviour
3) Reward systems
4) Closely linked to thalamus, cortex and limbic system
Describe the motor loop. What are basal ganglia thought to generate?
What does cortical activation of the putamen lead to?
What are basal ganglia thought to generate and process?
- The motor loop: All parts of cerebral cortex project to corpus striatum, basal ganglia project to thalamus, thalamus projects to cerebral cortex (in picture)
- Cortical activation of putamen (in neostriatum) leads to excitation of supplementary motor area (SMA) by the ventrolateral nuclei (VLN) of thalamus
- Basal ganglia thought to generate basic patterns of movement (motor programs), they are
- Also thought to process sensory information to regulate motor function
Describe the direct and indirect motor loop pathway.
What dictates whether the direct or indirect pathway is stimulated?
1) Direct motor loop pathway:
* Cortical excitation of neostriatum leads to disinhibition of thalamic nuclei
* Movement follows activation of putamen (in neostriatum) by cortical areas
2) Indirect motor loop pathway:
* Cortical excitation of neostriatum leads to inhibition of inhibitory input to Subthalamus
* Activation of indirect pathway leads to inhibition of cortical areas
- The substancia nigra (SN) releases dopamine that acts on D1 or D2 receptors on striatal neurons in the neostriatum
- Stimulation of D1 receptors will excite the striatal neurons, resulting in the stimulation of the direct pathway, leading to excitation of supplementary motor area (SMA) by the ventrolateral nuclei (VLN) of thalamus and movement
- Stimulation of D2 receptors will result in the excitation of the Globus pallidus medial (interal – GPm) via the subthalamus (Sth), which will inhibit the supplementary motor area (SMA) by the ventrolateral nuclei (VLN) of thalamus, leading to an inhibition of movement
Direct and indirect motor loop pathway together diagram (in picture)
What are 4 clinical problems associated with the basal ganglia?
What are signs associated with each?
- 4 clinical problems associated with the basal ganglia:
1) Parkinson’s disease (substantia nigra pars compacta deficit)
* Hypokinetic - Abnormally diminished motor activity
* Bradykinesia - slowness of movement and speed (or progressive hesitations/halts) as movements are continued
* Hypertonia - a condition in which there is too much muscle tone. For instance, arms or legs are stiff and hard to move
* Akinesia - the inability to voluntarily move one’s muscles and limbs
2) Huntington’s disease – chorea (caudate deficit)
* Hyperkinetic
* Hypotonia
* Dyskinesia - involuntary, erratic, writhing movements of the face, arms, legs or trunk.
3) Hemiballism (subthalamic deficit)
* Hemiballism (subthalamic deficit)
4) Wilson’s disease (lenticular)
* Associated with copper deposition
* Involuntary movements
What are 10 clinical features of Parkinson’s disease?
- 10 clinical features of Parkinson’s disease:
1) Tremor at rest
2) Rigidity – cogwheel, limbs>axial
* a type of rigidity that typically affects the limbs, causing them to move in small increments, similar to how gears move
3) Bradykinesia
4) Asymmetry
5) Loss righting reflex
6) 30% cognitive decline
7) Hypomimia (lack facial expression)
8) Glabellar tap
9) Quiet Speech
10) Micrographia
Pathophysiology of the Basal Ganglia in Parkinson’s Disease.
How is the motor loop affected in Parkinsons?
- Pathophysiology of the Basal Ganglia in Parkinson’s Disease
- In Parkinsons, there is degeneration of dopaminergic neurons of substantia nigra pars compacta in the motor loop
What kind of condition is Huntington’s disease (Chorea)?
How is gene programming affected?
What substance begins to accumulate?
What are 3 clinical signs of Huntington’s?
How is the caudate nucleus affected?
- Huntington’s disease (Chorea) is an autosomal dominant condition
- In Huntington’s, there is a CAG (glutamine amino acid) triplet repeat (>40 repeats)
- Mutant huntingtin protein accumulates, which is toxic
- 3 clinical signs of Huntington’s:
1) Chorea
* A movement disorder that causes sudden, unintended, and uncontrollable jerky movements of the arms, legs, and facial muscles
2)Behavioural disorders
3) Dementia
* The caudate nucleus in the neostriatum wastes away
Pathophysiology of the Basal Ganglia in Huntington’s Disease.
Describe 3 clinical signs of Huntington’s disease.
What is Huntington’s characterised by?
How are the caudate and putamen of the neostriatum affected?
How does this affect the motor loop?
What is Huntington’s disease treatment the opposite of?
What are 2 potential treatments for Huntington’s disease?
What is the aim of this treatment?
- Pathophysiology of the Basal Ganglia in Huntington’s Disease
- Huntington’s disease – chorea (caudate deficit):
1) Hyperkinetic
2) Hypotonia
3) Dyskinesia - involuntary, erratic, writhing movements of the face, arms, legs or trunk. - There is degeneration of the caudate and putamen of the neostriatum in Huntington’s
- In the motor loop, the direct pathway is unaffected, while the indirect pathway is completely inhibited
- Huntington’s disease is the opposite of Parkinson’s disease
- 2 potential treatments for Huntington’s disease:
1) Dopamine antagonist effective in reducing involuntary movement
* Chlorpromazine & haloperidol
2) Tetrabenazine (monoamine transporter inhibitor) decreases dopamine storage
- The aim of this treatment is to dampen the direct pathway
What type of condition is Wilson’s disease?
What is it caused by?
What are 6 signs/symptoms of Wilson’s disease?
What are 2 parts of the treatment of Wilson’s disease?
- Wilson’s disease is a rare autosomal recessive condition
- It is caused by a deficit in the lenticular nuclei (putamen and globus pallidus), which causes a copper transport protein abnormality, leading to abnormal copper accumulation
- 6 Signs/symptoms of Wilson’s disease:
1) Hepato-lenticular degeneration (liver & brain)
2) Dystonia
* a neurological movement disorder characterized by involuntary (unintended) muscle contractions that cause slow repetitive movements or abnormal postures that can sometimes be painful.
3) Ataxia
* A term for a group of disorders that affect co-ordination, balance and speech
4) Subcortical dementia
5) Low serum copper and caeruloplasmin
6) Kayser-Fleischer rings (see arrow)
- 2 parts of the treatment of Wilson’s disease:
1) Low copper diet
2) Penicillamine (chelating agent)
What are Pakinson’s disease treatment options?
- Pakinson’s disease treatment options:
1) Levodopa
* (in combination with carbidopa or benserazide)
2) Dopamine agonists
* (e.g. pramipexole, ropinirole and bromocriptine)
3) Monoamine Oxidase (MAO) Inhibitors
* (e.g. selegiline and rasagiline).
4) Amantadine
* releases dopamine
What is the first line treatment for Parkinson’s disease?
Why is this combination of drugs effective?
What do patients show improvement in?
When is there limited effectiveness of levodopa?
What are 3 long term side-effects of levodopa?
- Levodopa is the First line treatment for PD and combined with a dopa decarboxylase inhibitor (carbidopa or benserazide).
- This combination lowers the dose needed and reduces peripheral system side effects (e.g. nausea, hypotension).
- 80% of patients show initial improvement in rigidity and hypokinesia (Abnormally diminished motor activity)
- Limited in effectiveness with time as the neurodegeneration progresses.
- Overall, no evidence that Levodopa slows or accelerates neurodegeneration
- 3 long term side-effects of levodopa:
1) Involuntary writhing movements (dyskinesia)
* May appear within 2 years.
* Affect face and limbs mainly.
* Occurs at peak therapeutic effect.
2) 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
3) Nausea & anorexia
* Results from the effects of dopamine formed peripherally.
* Domperidone (dopamine antagonist) can be used to mitigate these effects
What are 4 different types of Dopamine Agonists used to treat Parkinson’s?
What is an example of each?
- 4 different types of Dopamine Agonists used to treat Parkinson’s?
1) Ergots
* Bromocriptine, cabergoline and pergolide (ergots) are orally active drugs that work on D1 and D2 receptors.
* They have limiting side effects – can cause fibrosis in the CVS and lungs
2) D2/3 selective receptor agonists
* Pramipexole and ropinirole are D2/3 selective receptor agonists that are better tolerated.
* Short half-life in plasma (6-8hrs) could be a problem
3) Rotigotine
* Newer agent delivered by a transdermal patch
2) Apomorphine
* Given by injection sometimes given to control the ‘off-effect’ of levodopa.
What are 2 examples of Monoamine Oxidase (MAO) Inhibitors?
How do their side-effects compare with other drugs?
How do these drugs work? What are they combined with?
- 2 examples of Monoamine Oxidase (MAO) Inhibitors:
1) Selegiline
* Metabolised to amphetamine, so can cause excitement, anxiety & insomnia
2) Rasagiline
- These drugs are a selective MAO-B which lacks the unwanted peripheral effects of non-selective MAO inhibitors.
- Inhibition of MAO-B protects dopamine from extraneuronal degradation.
- Combination with levodopa is more effective in relieving symptoms and prolonging life.
What is the role of some transplants in the treatment of PD?
What is unknown about this technique?
What is a new area of technology being studied for the treatment of PD?
How is Electrical stimulation used in the treatment of PD?
- Some transplants have been shown to survive and establish functional dopaminergic connections and clinical benefit in PD
- It is not known yet if the transplanted cells will be prone to the neurodegeneration already going on
- Stem cell technology is the great hope.
- Electrical stimulation of the subthalamic or GPi (Globus pallidus medial (internal))nuclei by inserted electrodes (DBS) is used in severe cases.
- This can improve motor dysfunction by stimulating the indirect pathway
