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Ageing block > Pathophysiology of PD > Flashcards

Pathophysiology of PD Flashcards

1
Q

Outline the aetiology of PD

A

-Age-related neurodegenerative disorder
-Most cases are sporadic with late onset and no known cause
Possible causes=
-Genetics ( mutations in genes encoding alpha-synuclein, LRRK2, DJ-1,PINK1)
-Environmental toxins (MPTP; agrochemicals eg pesticides-persistent accumulations)

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2
Q

Outline the neuropathology of PD

A
  • Dopaminergic nigrostriatal tract degeneration
  • Loss of pigmented cell bodies in substantia nigra pars compacta
  • The dopamine cells in the midbrain SNc contain neuromelanin which is why the SNG appears as black lines
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3
Q

where does the neuromelanin come from

A

-breakdown/oxidation of dopamine

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4
Q

What are the characteristics of the LEWY BODY

A
  • pathological hallmark of PD-not exclusive; DLB,PDD
  • contain alpha-synuclein which form large aggregates in lewy bodies
  • Lewy bodies are inclusions that form in the neurones in PD
  • Abs for ubiquitin & caspase (apoptosis marker) co-stain Lewy bodies
  • Lewy bodies are found in many remaining dopaminergic neurones in SNc in PD
  • Stain for many proteins including alpha-synuclein, ubiquitin
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5
Q

What is the function of ubiquitin

A

-Tags damaged proteins and signals their transport to the ubiquitin proteosome system for breakdown

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6
Q

How can the progressive clinical path of PD be divided ?

A
  1. ) Preclinical PD~10yrs
  2. )Early treated PD (stable) ~5yrs
  3. ) advanced PD~10yrs
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7
Q

Outline the preclinical stage of PD

A
  • olfactory loss
  • RBD
  • constipation
  • anxiety
  • depression
  • Impaired colour vision
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8
Q

Outline the early treated PD (Stable) stage of PD

A

-Bradykinesia
-Rigidity
-Resting tremor
+/- non-motor symptoms

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9
Q

Outline the advanced PD stage

A

Motor complications:

  • weaning off/dyskinesias
  • gait& balance problems
  • Axial deformities
  • Dysarthria/dysphagia

Non-motor complications:

  • Cognitive decline/dementia
  • depression
  • psychosis
  • autonomic dysfunction
  • sleep-awake dysfunction
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10
Q

what distinguishes preclinical PD from early treated PD

A

-the onset of motor symptoms

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11
Q

What is the role of activated microglia in the pathogenesis of PD

A
  • microlglia are cells of the immune system in the brain
  • In PD there’s an infiltration of microglia into the substantia nigra that can lead to the release of inflammatory mediators
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12
Q

What is the role of glutamate in the pathogenesis of PD?

A
  • There’s increased transmission of glutamate at the NMDA receptor
  • There is a pacemaker channel which is very dense and active in the SN, so you get an increase of intracellilar calcium in substantia nigra as a result of excess glutamate
  • The increased calcium activates excitotoxic pathways which cause neuronal dysfunction & death
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13
Q

What is possible the role of neurotrophic factors in pathogenesis of PD?

A
  • These are important for maintaining neural survival

- May not be functioning efficiently in PD

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14
Q

What is the role of increased ROS (reactive oxygen species) in pathophysiology of PD?

A
  • leads to increased oxidative stress

- Leads to alpha-syn misfolding and thus accumulation of alpha synuclein

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15
Q

What is responsible for accumulation of alpha-synuclein?

A

-May be linked to oxidative stress or may be due to genetic malfunctions

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16
Q

What factors contribute to oxidative stress in PD?

A
  1. ) The SNc has high basal free radical production from:
    - autooxidation of dopamine to form neuromelanin
    - dopamine metabolism by MAO
    - Both these reactions lead to production of hydrogen peroxide which is broken down in the presence of iron to form hydroxyl radicals in the fenton reaction
  2. ) elevated levels of iron in SNc help drive the fenton reaction
  3. ) reduced anti-oxidant capcity
    - Reduced glutathione(GSH) a major anti-oxidant enzyme system clearing
17
Q

Outline the genes that may be responsible for build up of alpha synuclein

A
  • Parkin(loss-of-function)
  • LRRK2( Gain of function)
  • DJ-1(loss of function)
  • PINK1 ( loss of function)
18
Q

What percentage reduction of striatal DA does symptoms appear

A
  • When striatal DA reduced by 60-80%
  • This can be shown by a fluoride-dopa PET scan which will show a reduced number of DA nerve terminals in PD pt striatum
  • This label gets taken up by the dopamine neural terminals via the DA transporters. These can take up DA as well as 18F-dopa which looks similar
  • It then stays in the nerve terminal and emits positrons so when you put the pt in the PET scanner, you’ll see glowing in the area where the nerve terminals are
  • A PD pt will show reduced uptake of this label
19
Q

Outline the indirect pathway of the basal ganglia

A

(see lecture)

-Dopamine allows for inhibition of the indirect pathway which facilitates movement (as it overide glutamate)

20
Q

Outline the direct pathway of the basal ganglia

A

(see lecture)

  • activated by glutamate bevause it has AMPA receptors on it
  • Very little thalamocortical feedback
21
Q

Which receptors does dopamine act on? How does DA facilitate movement

A

D1 dopamine receptors

  • these are G coupled
  • DA in the striatum on the direct pathway will act on these receptors
  • They are Gs coupled so you get an excitation
  • You excite the pathway so it basically has the same effect as glutamate, GABA will be released so will inhibit the pathway, less GABA released si disinhibition of the thalamocortical pathway which means movement is facilitated
22
Q

What happens when we activate the thalamocortical pathway

A
  • facilitates movement

- So activation of direct pathway by glutamate or DA facilitates movement

23
Q

What is the function of dopamine in the basal ganglia pathways

A
  • Overides the glutamate so in it’s presence you’ll always be able to move
  • Dopamine activates the direct pathway and inhibits the indirect pathway so facilitates movement
  • Inhibition of the indirect pathway by DA facilitates movement
  • DA is needed cos otherwise you’d have conflicting signals
24
Q

Outline the pathophsiological changes in basal ganglia circuitry in PD

A
  • Direct pathway= underactive
  • Indirect pathway=overactive
  • Thalamocortical feedback is reduced, evoking motor deficits
  • Pathway’s lost
25
Q

Outline the reason for an increase in ach seen in PD patients

A
  • Cholinergic interneurone pop. present in the striatum
  • They have D2 cell receptors on their cell body
  • DA will actviate these receptors if we have sufficient DA
  • The D2 receptors are Gi coupled so activation of these receptors causes inhibition of firing of the cholinergic interneurons
  • In PD pts, there is insufficient DA so the D2 receptors on the cholinergic interneurones are no longer activated, this results in the disinhibition of the cholinergic interneurones, they increase their firing rate, so you get an increase in ach within the striatum
  • This is why when DA levels are down, ach levels are up in the striatum (idea of a see saw)
  • This increase in ach has an unknown effect

Ageing block (16 decks)

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