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Sem 3 > case 7/ Parkinson's disease > Flashcards

case 7/ Parkinson's disease Flashcards

1
Q

What constitutes the striatum?

A

putamen and caudate nucleus

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2
Q

What constitutes the lentiform nucleus?

A

putamen and globus pallidus

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3
Q

What are the different neurone in the striatum?

A
  • medium spiny neurones: 96% striatal neurones, projects to other regions of the basal ganglia, are all GABAergic
  • interneurones: GABAergic and cholinergic: modulate activity of there neurones
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4
Q

What are the different pathways that input into the striatum?

A

-corticostriatal pathway:
glutamergic (excitatory)
input from cerebral cortex

-nigrostriatal pathway:
dopaminergic (modulates medium spiny neurones)
from substantial nigra pars compacta

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5
Q

How is input to the medium spiny neurones modulated?

A
  • glutamate activates spine causing excitation of neurones (driving neuronal activity)
  • dopamine receptors modulates amount of signal (level and eventual output)
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6
Q

What is the direct dopaminergic pathway in the basal ganglia?

A

facilitating of desired movements

  • D1 receptors (G protein coupled receptor)
  • activates GaS which increases adenylyl cyclase activity
  • catelyses cAMP from ATP:
  • phosphorilation/activation of intracellular substrates
  • -> turn up motor learning/synaptic plasticity
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7
Q

What is the indirect dopaminergic pathway in the basal ganglia?

A

inhibition of unwanted movements

  • D2 receptors (G protein coupled receptors)
  • activation of Gi/o which inhibits adenylyl cyclase activity:
  • no catalysis of cAMP from ATP:
  • decrease phosphorylation/activation of intracellular substrates
  • -> turns down motor learning/synaptic plasticity
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8
Q

What are the neuropeptides transmitters of the direct and indirect pathways?

A
  • direct pathway: dynorphin

- indirect pathway: enkephalin (opioid molecule)

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9
Q

what happens when there is no activity (background)

A

activation of indirect pathway:
-tonic dopamine release –> low synaptic and extra synaptic levels –> preferential D2R activation (high-affinity receptors) –> action inhibition “no-go” long term depression (lowering of synaptic strength)

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10
Q

What happens when doing a learned action?

A

activation of direct pathway:

-phasic dopamine release -> preferential D1R activation –> motor initiation, long term potentiation

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11
Q

What are the different functions of the basal ganglia and where are the loops placed?

A

limbic (behavioural, reward)
associative (executive: learning, memory, attention, motivation, emotion and volition: strong input from DLPFC)
sensory
motor
–> ventromedial to dorsolateral gradient (from limbic to motor)

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12
Q

What is chorea?

A

rapid, multifocal irregular movements

  • flitting between various muscle groups and body parts
  • motor impersistence (relative overactivity of direct pathway and relative under activity of indirect pathway)
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13
Q

What are examples of choreiform disorders?

A

Huntington’s disease

Levodopa-induced dyskinesia

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14
Q

What is dystonia?

A

abnormal twisting, distortion movements of the neck and limbs

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15
Q

What is the age of onset of Parkinson’s disease?

A

> 60 yo

young onset PD in 5% of people <40yo

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16
Q

What are the genes involved in Parkinson’s disease?

A 
parkin (recessive)
SNCA LRRK2 (dominant)
17
Q

What are the movement symptoms seen in PD?

A

-bradyskinesia
(increased inhibitory output to brainstem, thalamus and motor cortex + abnormal 20 Hz (beta band) oscillations in basal ganglia: increased activity at that frequency)
-resting tremor
(absent in approx 30% of people, less responsive to drugs, not just basal ganglia output: thalami-cortical-cerebellar loops and non dopaminergic pathways (5-HT))
-rigidity (cogwheel)
(increased muscle tone, more obvious during slow movements
–> peripheral: reduced inhibition from type 1b fibres and overactive type II fibres (connected to muscle spindles): muscle tense up
–> central: altered GABA an ACh interneurones: altered inhibition in indirect pathway: increased responsiveness of STN/GPi firing to peripheral stimulation)
-postural instability (late)

18
Q

What are the non-movement symptoms n PD?

A
  • anosmia (PD starts in olfactory bulb)
  • gut problems
  • REM sleep behaviour disorder
  • depression
  • prominant pain
19
Q

What is the Braak staging for PD?

A
  • Break stage 1 and 2: autonomic and olfactory disturbances
  • Braak 3 and 4: sleep and motor disturbances
  • Braak 5 and 6: emotional and cognitive disturbances
20
Q

What are the behavioural impairments in PD?

A
  • cognitive disturbances (executive planning: associative loops, thinking ability)
  • impulsive behaviour (dopaminergic deficit in limbic stratal areas)
  • depression anxiety (related to monoamine loss in brainstem)
21
Q

What are the risk factors for impulse control behaviours in PD?

A
  • dopamine agonist use> high dose levodopa
  • smoking, male
  • young onset Pd
  • depression
  • novelty seeking behaviour
  • family history of gambling, alcoholism
22
Q

What is the pathophysiology of PD?

A

-abnormal deposition of Lewy bodies causing death of the cells and loss of dopamine: alpha synuclei aggregate
-(caudal postal spread through the -brain)
(alpha synuclei is a protein that is involved in normal cellular functions such as synaptic functions)

--> reduced D1 and D2 stimulation: direct  pathway underactive and indirect pathways
is overactive (relative)

+ increased levels of proenkephalin: causing parkinson symptoms

23
Q

What do you need for a diagnosis of PD?

A
  1. -must have bradykinesia + one of the following
    - rigidity
    - resting tremor
    - postural instability
  2. unilateral onset and persistent asymmetry
  3. good levodopa response > 5 years
  4. levodopa induced chorea
24
Q

What are red flags for idiopathic PD diagnosis?

A
  • absent tremor, symmetrical onset
  • early gait abnormality and falls
  • pyramidal tract signs
  • poor levodopa response
  • supranuclear gaze palsy
  • dysautonomia, ataxia, stridor
  • apraxia, myoclonus, alien limb
  • early dementia
25
Q

What are the different treatment options for PD?

A
  1. dopaminergic therapies:
    - levadopa
    - dopamine receptor agonists (pramipexole, ropinirole)
    - peripheral COMT inhibitors (entacopone, opicapone)
    - monoxidase inhibitors (selegiline, rasagiline)
  2. NMDAR antagonists (amantadine)
  3. surgical therapies
    - GPm/STN deep brain stimulation
    - GPm lesion
26
Q

What are motor complications in the treatment of PD?

A

wearing off effect and motor fluctuations
–> L DOPA induced dyskinesia: (reduce therapeutic window: you spend time below response threshold and above dyskinesia threshold)
(occurs in 50% after 4-6 years of treatment. risk factors: young age ad disease severity, genetics)

27
Q

What are the mechanisms of motor complications? What can be done?

A
  • less able to handle the dopamine stimulation
  • abnormal handling of dopamine by 5-HT neurones
  • abnormal handling of synapse plasticity
  • dopamine receptor agonist treatment delays dyskinesia onset

what can be done:

  • continuous dopaminergic stimulation
  • amantapine (NMDA receptor antagonist, reduced dyskenesia by approx 40%)
  • surgical therapies
28
Q

Why should you not abruptly withdraw medication?

A

lead to neuroleptic malignant syndrome

29
Q

What is the aetiology of Hungtinton’s disease?

A
  • expanded CAG repeat (>40) in Huntington gene (on chromosome 4)
  • anticipation: as it goes down generation, it occurs at younger age
  • greater expansion in male transmission
30
Q

What is the pathophysiology of Huntington disease?

A

–> strial pathology (especially caudate):
-selective loss of D2 receptors (involuntary movements increase)
-later loss of D1 receptors (hypo kinetic movement disorder)
DIRECT PATHWAY RELATIVELY OVERACTIVE COMPARED TO INDIRECT)

  • -> cortical pathology
  • loss of neurones in layer 5 and 6
  • -> neuropsychiatric disturbances early on in the disease
  • anxiety, depression, impulsivity, apathy
31
Q

Wha is Tourette syndrome?

A

neuropsychiatric illness that is characterised by rapid, repetitive, stereotypes movements or vocalisation (tics: motor and vocal)
-onset <20 yo

32
Q

What is the pathophysiology of Tourette syndrome?

A
  • loss of cholinergic and GABAergic stratal interneurones: reduced basal ganglia inhibition
  • increased striatal dopamine D2 receptor binding in patients with TS compared to controls
33
Q

What is SPECT? What does it measure?

A

gamma emitting radioisotope

measures blood blow

34
Q

What is PET? What does it measure?

What are the different types of PET used in diagnosis of PD and Alzheimer’s?

A

positron emitting radioisotope
measures metabolic rate

  • 18F-DOPA PET (Parkinson)
  • FGD PET (radioactive glucose): shows which part of the brain is the most active (can be used in PD and Alzheimer’s disease
  • 18F-Florbetapir: presence of amyloid (for Alzheimers)
  • 11C-PK11195: for stroke: marker for inflammation (CRP)
35
Q

What can you miss with Nervous System imaging?

A

-raised intracranial pressure
-cerebral venous sinus thrombosis
(which both of the above can be seen through clinical assessment: papilledema in back of eye)
-stroke
-subarachnoid haemorrhage
-Guillain Barre syndrome
-myasthenia gravis
-anything to do with neuromuscular system

Sem 3 (20 decks)

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