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MD4001 > Basal Ganglia > Flashcards

Basal Ganglia Flashcards

1
Q

Identify the main components of:

  • Striatum
  • Dorsal Striatum
  • Ventral Striatum
  • Lentiform
A
  • 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)
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2
Q

Identify the main components of basal ganglia.

A

-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 )

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3
Q

Identify the functions of the basal ganglia.

A
  • Smooth movement (refines corticospinal motor pathway)
  • Switching behaviour
  • Reward systems
  • Closely linked to thalamus, cortex and limbic system
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4
Q

Identify and describe the main pathways of the basal ganglia.

A

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

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5
Q

Identify a NT which excites basal ganglia, and one which inhibits basal ganglia.

A

Inhibition with GABA, Excitation with Glutamate

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6
Q

Describe the way the Substantia Nigra, and Striatal interneurons systems work in the basal ganglia.

A

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

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7
Q

Identify clinical problems in the basal ganglia.

A
  • Parkinson’s disease (substantia nigra)
  • Huntington’s disease (caudate)
  • Wilson’s disease (lenticular)
  • Hemiballismus (subthalamic)
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8
Q

Describe the main features of Huntington’s disease.

A
  • 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)
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9
Q

Describe the main features of Wilson’s disease.

A
  • 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)
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10
Q

Identify neurodegenerative diseases.

A
  • Parkinson’s disease
  • Alzheimer’s disease
  • Huntington’s disease
  • Motorneurone diseases (Amyotrophic lateral sclerosis, ALS)
  • Spinocerebellar degenerations
  • Spongiform encephalopathies
  • FTD, other dementias
  • Others
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11
Q 
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
A
  • 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
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12
Q

Describe the histopathology behind PD.

A

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

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13
Q

What are the genes associated with PD called ?

A

PARK genes (Parkinson disease associated genes)

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14
Q

Identify the main features of PD.

A
  • 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
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15
Q

Which kind of tremor would be one while holding a cup of tea ?

A

Benign essential tremor

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16
Q

How is PD diagnosed ?

A

Clinical diagnosis (based on symptoms)

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17
Q

To what extent is the abnormal alpha synuclei protein present prior to PD symptoms actually developing ?

A

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

18
Q

Identify the main causes of neurodegeneration.

A 
Immune attack
Toxins
Protein handling disorders
Lack of growth factors
Oxidative stress
Excitatory 
Ionic dysequilibrium
Mitochondrial dysfunction
Activation of cell death pathways
19
Q

What is the main aim in PD drug treatment ?

A

Main strategy is to counteract the deficiency in dopamine in the basal ganglia

20
Q

Identify the main classes of drug treatments for PD. Provide examples for each.

A
  • 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)
21
Q

Explain the process of Levadopa metabolism and absorption.

A

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).

22
Q

Describe the main features of Levadopa as a treatment for PD.

A
  • 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
23
Q

What proportion of patients show initial improvement in rigidity and hypokinesia with Levadopa ?

A

• 80% of patients show initial improvement in rigidity and hypokinesia

24
Q

Identify side effects of Levadopa.

A
  • 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.
25
Q

Would you prescribe Levadopa with a young person affected with PD ? Why or why not ?

A

Don’t want to go straight with LDOPA if going to get side effects within a few years, so might wanna try other strategies first (e.g. Dopamine agonists). Someone who is 70, give LDOPA straight away .

26
Q

Identify examples of Dopamine agonists. What is their mechanism of action, and route of administration ?

A
  • Bromocriptine, cabergoline, and pergolide (ergots) are orally active drugs that work on D1 and D2 receptors. They have limiting side effects – fibrotic reactions.
  • Pramipexole and roprinole are D2/3 selective receptor agonists that are better tolerated. Short half-life in plasma 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.
27
Q

Identify treatment of choice if someone has fragile Parkinson’s disease for some time and other
drugs don’t work so well.

A

Dopamine agonists

28
Q

Identify a main side effect of all dopamine agonists.

A

Dopamine dysregulation syndrome
• Sudden onset sleep
• Impulse control disorders – gambling, binge
eating, hypersexuality
• Hypotension
• Neuroleptic malignant syndrome if stopped abruptly

29
Q

Identify examples of MAO inhibitors. What is the main difference between these two ?

A

Selegiline (in combination with levadopa, more effective in relieving symptoms (not disease modifying) and prolonging life)

Rasagiline (alternative and may retard the disease progression)

30
Q

Describe mechanism of action of Selegiline (MAO inhibitor).

A
  • Selegiline is a selective MAO-B which lacks the unwanted peripheral effects of non- selective MAO inhibitors.
  • Inhibition of MAO-B protects dopamine from extraneuronal degradation.
31
Q

What are the main enzyme systems which breakdown dopamine ?

A

MAO
COMT
Therefore, inhibit those two to increase amount of endogenous dopamine

32
Q

Describe mechanism of action of Amantadine in PD.

A

• Antiviral drug, increased dopamine release is primarily responsible for its therapeutic effect (+ inhibits re-uptake)

33
Q

How effective is Amantadine in PD relative to the other drugs used for it ?

A

Less effective than levodopa or bromocriptine and action declines with time.

34
Q

Identify examples of Muscarinic Acetylcholine anatagonists. What are their side effects ?

A

Benzhexol, Orphenadrine and procyclidine

Usual anti-cholinergic side effects (possible cognitive impairment + urinary retention)

35
Q

What is the mechanism of action of Muscarinic Acetylcholine antagonists ?

A

Muscarinic acetylcholine receptors exert an inhibitory effect on dopaminergic nerves suppression of which compensates for a lack of dopamine
Muscarininc ACh antagonists block actions of ACh in striatum

36
Q

Identify non-pharmacological treatments of PD.

A

Neural Transplantation and Brain Stimulation

37
Q

Describe Neural Transplantation for PD.

A
  • Various transplantation approaches havebeen tried. Some transplants have been shown to survive and establish functional dopaminergic connections and clinical benefit
  • Not known yet if the transplanted cells will be prone to the neurodegeneration already going on
  • Stem cell technology is the great hope
38
Q

When is brain stimulation used in PD ?

A

Electrical stimulation of the subthalamic or Gpi nuclei by inserted electrodes (DBS) is used in severe cases (esp. when drugs don’t work). Can improve motor dysfunction.

39
Q

Distinguish between the following:

  • Placebo
  • Symptomatic effect
  • Disease modifying

Graph these (clinical outcome over time)

A
  • Placebo: get a little better, then back to normal
  • Symptomatic effect: get better but back to normal when stop treatment
  • Disease modifying: better over time

Refer to slide 39 for graphs

40
Q

Identify examples of COMT inhibitors. How do these work ?

A

Entacapone

Inhibit COMT, which blocks degradation of Dopamine

MD4001 (74 decks)

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