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Stage 3 Case 2 > Pathophysiology of dementia > Flashcards

Pathophysiology of dementia Flashcards

1
Q

What is dementia?

A

A term for changes in cognitive function typically (though not always) associated with age.

Umbrella term for memory loss and other thinking abilities to interfere with daily life.

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2
Q

Types of dementia

A
  1. Alzheimer’s
  2. Lewy body dementia
  3. Vascular dementia
  4. FTD
  5. Other (Parkinson’s and Huntington’s)
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3
Q

Dementia characteristics

A
  • Accumulation of proteins in the brain
  • These induce dysfunction and degeneration of neurones
  • Dysfunction and loss of neurones and/or synapses causes symptoms
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4
Q

Risk factors of Alzheimer’s (4)

A

Low SES

Diabetes

High BP

Obesity

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5
Q

Symptoms of Alzheimer’s

A

Apathy, confusion, wandering and disorientation, delusions and suspiciousness, mood changes and hallucinations.

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6
Q

What can Alzheimer’s progress to?

A

Double incontinence, profound weight loss, minimal responsiveness , death typically due to aspiration pneumonia.

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7
Q

What are some atypical presentations of Alzheimer’s?

A

Visual or speech problems

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8
Q

What is amyloid Beta?

A

A peptide cleaved from amyloid precursor protein.

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9
Q

What does amyloid Beta do?

A

Forms extracellular plaques and often accumulates around blood vessels (CAA).

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10
Q

What is associated with familial Alzheimer’s?

A

Mutations in the APP.

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11
Q

What are the two splice variants of amyloid beta?

A

40 amino acids

42 amino acids

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12
Q

Which splice variant of amyloid beta is thought to splice more easily?

A

42 amino acids

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13
Q

What is Tau?

A
  • A microtubule associated protein that is thought to stabilize microtubules in the cell.
  • Phosphorylated under disease conditions which is thought to reduce microtubes interactions.
  • Forms tangles once dissociated, destabilised of microtubule network.
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14
Q

What can a lot of tau in the brain indicate?

A

Cognitive impairment.

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15
Q

Two things that are present in Alzheimer’s disease? (brain)

A

Plaques and tangles (relationship unclear though and present during ageing)

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16
Q

Are plaques or tangles more associated with cognitive impairment?

A

Tangles

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17
Q

Neuritic plaques

A

Formed via a combination of amyloid beta and tau. (amyloid beta middle and surrounded by tau)

Necessary for Alzheimer’s diagnosis post-mortem.

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18
Q

What is the hypothesis that drugs treatment for Alzheimer’s is based on?

A

The amyloid cascade hypothesis.

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19
Q

The amyloid cascade hypothesis

A
  1. Accumulation of amyloid beta (due to mutation)
  2. Tau phosphorylating
  3. Cell death and inflammation
  4. Dematian with plaques and tangles
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20
Q

How is Lewy body dementia characterised?

A

Accumulation of alpha synuclein into Lewy bodies (also found in Parkinson’s)

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21
Q

What symptom is Lewy body NOT characterised by?

A

Amnestic changes (memory loss)

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22
Q

What symptom is Lewy body characterised by?

A

Fluctuating cognitive status

Neuropsychiatric features (visual hallucinations)

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23
Q

How does Vascular dementia occur?

A

Altered cerebral blood flow (e.g. after stroke of due to small vessels disease)

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24
Q

What are some symptoms of vascular dementia?

A

Planning difficulties, mood changes and problems concentrating.

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25
Q

What does neuronal loss relate to?

A

Cognitive impairment

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26
Q

Which type of dementia has more brain weight loss?

A

Alzheimer’s

27
Q

What is Acetylcholine?

A

A neurotransmitter in the brain that is vital for memory and attention.

28
Q

What is acetylcholine’s synthesis catalysed by?

A

Choline acetyl transferase (ChAT)

29
Q

What two things make acetylcholine?

A

Acetyl-CoA and Choline

30
Q

How is ACh transported?

A

Via Vesicular Acetyl choline transporter (VAChT) in the synaptic vesicles.

31
Q

How is ACh released in the synaptic cleft?

A

Membrane depolarisation

32
Q

How is ACh hydrolysed?

A

Acetylcholinesterase (AChE)

33
Q

What is produced after hydrolysis of ACh?

A

Choline and acetate (acetic acid)

34
Q

What happens to choline from the hydrolysis of ACh?

A

Transported back via Choline transporter (ChT) for synthesis of ACh.

35
Q

What are the two major nuclei in the Cholinergic system?

A

The basal forebrain and pedunculopontine nucleus

36
Q

The two Cholinergic receptors

A

Nicotinic and muscarinic receptors

37
Q

What is nicotinic receptor?

A

Inotropic; directly coupled to ion channel

38
Q

What is muscarinic receptor?

A

Metabotropic; indirectly linked to ion channels

39
Q

5 subtypes of muscarinic receptor?

A

M1 and M3 (post synaptic), M2 and M4 (pre-synaptic), (M5 (possibly both)

40
Q

Subtypes of Nicotinic

A

Pentamers (5 monomers) formed from a combinations of alpha, beta, gamma and epsilon.

In CNS typically pre-synaptic and thought to have modulatory role in synaptic transmission

41
Q

Which parts of the fore brain are one of the first to affected by tangles?

A

Nucleus basalis of Myenert

42
Q

What is the cholinergic hypothesis?

A
  • ChAT selectively impaired in some regions
  • Particular loss of nicotinic and muscarinic subtypes in CNS
  • Suggests that cholinergic drugs may be effective in Alzheimer’s disease by augmenting cholinergic activity.
43
Q

How do dementia therapeutics typically work?

A

AChE inhibitors, increasing cholinergic (ACh) activity at the synapse.

44
Q

Examples of AChE inhibitors

A

Donepezil (Aricept)

Rivastigmine (Exelon)

Galantamine (Razadyne)

45
Q

What does increase of cholinergic activity at the synapse do?

A

Some extent improve cholinergic input

46
Q

Donepezil half life

A

70 hours (long)

47
Q

Risks with Donepezil

A

Neuroleptic malignant syndrome, particularly in those taking anti-psychotics

48
Q

What is Donepezil licensed for?

A

Alzheimer’s and Lewy body

49
Q

Donepezil effects on cognitive decline

50
Q

Rivastigmine half life

51
Q

Risks with Rivastigmine

A

Atrial fibrillation, depression and aggression

52
Q

What is Rivastigmine licensed for?

A

Alzheimer’s and Lewy body

53
Q

Rivastigmine effects on cognitive decline

A

Modest (comparable to Donepezil)

54
Q

Why is helpful that Rivastigmine can be taken transdermally?

A

To help reduce some GI side effects that can limit drug compliance.

55
Q

Galantamine half life

56
Q

Galantamine contraindications

A

Significant hepatic or renal dysfunction

57
Q

Galantamine effects on cognitive decline

58
Q

Disadvangates of AChE inhibitors

A

Not disease modifying

Small cognitive benefit

Dose limiting side effects

AChE inhibited in other parts of the body also

ACh is not the only issue with Alzheimer’s

59
Q

Side effects of AChE inhibitors

A

Nausea

Vomiting

Diarrhoea

Anorexia and weight loss

Fatigue

Bradycardia

Sleep disturbance

60
Q

Alternative to AChE inhibitors

61
Q

How does Memantine work?

A

NMDA receptor antagonist thought to inhibit excitotoxic glutamatergic signalling and reduce neurodegeneration

62
Q

Why may memantine be good to use?

A

Less cardiac effects than AChEIs but also significant GI effects

May be especially effective when combined with AChEIs

63
Q

Aducanumab (Aduhelm©)

A
  • Antibody therapy that aims to bind and clear amyloid-βto inhibit and clear plaques
  • Huge cost and unclear evidence of benefit, potentially fatal side effects with amyloid-related imaging abnormalities (ARIA)
64
Q

Future research for Alzheimer’s

A
  • Antibodies for tau due it being better correlated to cognitive status
  • Inflammation is also associated with Alzheimer’s disease, including risk genes and amyloid plaque formation mechanisms, specific inhibitors are under investigation

Stage 3 Case 2 (7 decks)

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