Basal Ganglia Flashcards
(40 cards)
Identify the main components of:
- Striatum
- Dorsal Striatum
- Ventral Striatum
- Lentiform
- Striatum = Dorsal striatum and Ventral striatum
- Dorsal striatum = caudate and lentiform
- Ventral striatum = nucleus accumbens and olfactory tubercle
- Lentiform or lenticular = Putamen (outside) and globus pallidus (underneath)
Identify the main components of basal ganglia.
-Striatum; both dorsal striatum (caudate nucleus and putamen) and ventral striatum (nucleus accumbens and olfactory tubercle)
-Globus pallidus (internal, and external)
-Ventral pallidum
-Substantia nigra
-Subthalamic nucleus
(Amygdala not part of basal ganglia )
Identify the functions of the basal ganglia.
- Smooth movement (refines corticospinal motor pathway)
- Switching behaviour
- Reward systems
- Closely linked to thalamus, cortex and limbic system
Identify and describe the main pathways of the basal ganglia.
DIRECT PATHWAY
- Signal from cortex to striatum (excitatory signal, excitatory synapse)
- Signal from Striatum to internal GP (inhibitory synapse)
- Signal from internal GP to thalamus (inhibitory synapse)
- Signal from thalamus to motor cortex
Overall effect is excitatory (increases amount of activity going to motor cortex, so turns up motor activity)
Increases excitation going through thalamus
INDIRECT PATHWAY
- Signal from cortex to striatum (excitatory signal, excitatory synapse)
- Signal from Striatum to external GP (inhibitory synapse)
- Signal from external GP to subthalamic nucleus (inhibitory nucleus)
- Signal from subthalamic nucleus back to internal GP (exctitatory synapse)
- Signal from internal GP to thalamus (inhibitory synapse)
- Signal from thalamus to motor cortex
Overall effect is inhibitory (decreases amount of activity going to motor cortex, so turns down motor activity)
Decreases excitatory thalamic input to cortex
Identify a NT which excites basal ganglia, and one which inhibits basal ganglia.
Inhibition with GABA, Excitation with Glutamate
Describe the way the Substantia Nigra, and Striatal interneurons systems work in the basal ganglia.
Substantia Nigra (Dopaminergic system): turns up direct pathway + turns down indirect pathway + increased VA/VL drive to cortex OVERALL MORE MOTOR ACTIVITY
Striatal Interneurons (Cholinergic system): turns down direct pathway + turns up indirect pathway + decreased VA/VL drive to cortex OVERALL LESS MOTOR ACTIVITY
Identify clinical problems in the basal ganglia.
- Parkinson’s disease (substantia nigra)
- Huntington’s disease (caudate)
- Wilson’s disease (lenticular)
- Hemiballismus (subthalamic)
Describe the main features of Huntington’s disease.
- Autosomal dominant
- Progressive
- CAG triplet repeat disease (>40 repeats)
- Mutant huntingtin (protein) accumulates, toxic (to nerves, esp. to nerves in caudate nucleus)
- Chorea (fidgety movements), behavioural disorders, dementia
- Caudate nucleus wasting
- No treatment (can target chorea with pills for symptomatic relief)
Describe the main features of Wilson’s disease.
- Autosomal recessive
- Abnormal copper accumulation
- Hepato-lenticular degeneration (liver & brain)
- Dystonia, ataxia, subcortical dementia
- Copper transport protein abnormality
- Low serum copper and caeruloplasmin (can do blood test for the latter)
- Kayser-Fleisher rings (accumulation of copper around pupil)
- Treatment: Penicillamine Rx (drug, absorbs copper)
Identify neurodegenerative diseases.
- Parkinson’s disease
- Alzheimer’s disease
- Huntington’s disease
- Motorneurone diseases (Amyotrophic lateral sclerosis, ALS)
- Spinocerebellar degenerations
- Spongiform encephalopathies
- FTD, other dementias
- Others
Define the following in the context of PD: • Extrapyramidal • Akinetic-rigid syndromes • Parkinsonism • Parkinson’s plus • Multiple system atrophy (MSA)- a-syn • Progressive Supranuclear Palsy (Steele-Richardson Olszewski) - tau • Cortical Lewy body disease - a-syn • Drug-induced Parkinsonism • Corticobasal degeneration - tau
- Extrapyramidal “any of a group of clinical disorders marked by abnormal involuntary movements, alterations in muscle tone, and postural disturbances”
- Akinetic-rigid syndromes: increased rigidity, less movements
- Parkinsonism: any disorder manifesting the symptoms of parkinson’s disease or any such symptom complex occurring secondarily to another disorder, such as encephalitis, or to drugs.
- Parkinson’s plus
- Multiple system atrophy (MSA)- a-syn: combination of Parkinsonism (reduced amount of movement) but with cerebellar features (past pointing or other forms of tremor), and autonomic features
• Progressive Supranuclear Palsy (Steele-Richardson Olszewski)- tau: disease due to abnormal accumulation of tau, which includes features of Parkinsonism but with abnormal eye movements (lose vertical gaze) + mostly axial rather than in the limbs
• Cortical Lewy body disease - a-syn: disease due to abnormal accumulation of alpha synuclein, resulting in
Parkinsonism + dementia
- Drug-induced Parkinsonism
- Corticobasal degeneration - tau: often includes alien limb syndrome
Describe the histopathology behind PD.
Accumulation of alpha synuclein in Lewy bodies (possible that abnormal alpha synuclein changes normal alpha synuclein, to cause it to accumulate)
In PD, lose SN dopamine cell (treatment is to replace and modulate dopaminergic system).
If lose dopaminergic input, reduce excitation going to cortex, and allow indirect, cholinergic system to take over (since reduce lost dopamine inhibition), which also reduces amount of excitation going to motor cortex through the thalamus.
Overall effect, less motor activity
What are the genes associated with PD called ?
PARK genes (Parkinson disease associated genes)
Identify the main features of PD.
- Tremor at rest
- Rigidity – cogwheel, limbs>axial
- Bradykinesia (slowness of movement)
- Asymmetry
- Loss righting reflex (if push someone with PD backward, lose reflex to go back not to fall)
- 30% cognitive decline
- Hypomimia (lack facial expression)
- Glabellar tap (tap glabella, you will blink two or three or four times, then stop blinking, while in PD keep tapping and blinking keeps going )
- Quiet Speech
- Micrographia
Which kind of tremor would be one while holding a cup of tea ?
Benign essential tremor
How is PD diagnosed ?
Clinical diagnosis (based on symptoms)
To what extent is the abnormal alpha synuclei protein present prior to PD symptoms actually developing ?
If go back up to 10 years before PD diagnosis, can find abnormal alpha synuclein pathology in the gut of people who then developed PD
Identify the main causes of neurodegeneration.
Immune attack Toxins Protein handling disorders Lack of growth factors Oxidative stress Excitatory Ionic dysequilibrium Mitochondrial dysfunction Activation of cell death pathways
What is the main aim in PD drug treatment ?
Main strategy is to counteract the deficiency in dopamine in the basal ganglia
Identify the main classes of drug treatments for PD. Provide examples for each.
- Levodopa (in combination with carbidopa or benserazide)
- Dopamine agonists (e.g. pramipexole, ropinirole and bromocriptine)
- Monoamine oxidase B (MAO-B) inhibitors (e.g. selegiline and rasagiline).
- Amantadine- releases dopamine
- Muscarinic Ach Antagonsist (benzhexol)
Explain the process of Levadopa metabolism and absorption.
if take dopamine orally, to increase dopamine in body (e.g. Parkinson’s disease), gets degraded very rapidly in stomach.
Hence, Levadopa (pro-drug):
-Rapidly taken up from stomach and small intestine into large neutral amino acid transport carriers (LNAA)
(normally, DOPA decarboxylase present in gastric mucosa would convert it into Dopamine, which gets degraded and isn’t taken up in systemic circulation.)
-Another drug, Carbidopa (peripheral decarboxylase inhibitor), is given. It will inhibit DOPA decarboxylase in stomach, to allow Levadopa to be taken up into body via LNAA, which gets into systemic circulation and conversion into dopamine occurs in neurons that express DOPA decarboxylase and allow replenishment of NT stores (hence Carbidopa increases bioavailability of Levadopa).
Describe the main features of Levadopa as a treatment for PD.
- 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 effects.
- Increases L-DOPA levels
- Limited ineffectiveness with time as the neurodegeneration progresses.
- Overall no evidence that L-Dopa slows or accelerates neurodegeneration
What proportion of patients show initial improvement in rigidity and hypokinesia with Levadopa ?
• 80% of patients show initial improvement in rigidity and hypokinesia
Identify side effects of Levadopa.
- Involuntary writhing movements (dyskinesia) which may appear within 2 years. Affect face 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.
