memory disorder

Question 1

dementia

Answer 1

cognitive or behavioral symptoms that interfere with function, represent decline, are not due to delirium or psychiatric illness, are associated with cognitive impairment
- umbrella term for a symptom of underlying disease, many underlying

Question 2

Alzheimer’s disease

Answer 2

most common cause of dementia
- accounts for about 70% of cases of dementia
- about 30% of the population aged over 85.

Question 3

biology (pathophysiology) of AD

Answer 3

• Proteinopathy
• Aetiology: sporatoc, late onset: failure of clearance of AB
• carrying ‘APOE e4’ only recognised genetic risk factor
• familial: (Rare): over production of AB
• caused by known mutation in APP, presenilian-1, or presenililin- 2 genes.
• autosomal dominant, penetrance approaching 100%
• environmental factors moderate

Question 4

AB

Answer 4

• chain of 40-42 amino acids peptides
• cleaved from amyloid pre-curser protein (APP) by B and Y-secretase enzymes
• AB oligomers aggregate to form insoluble plaques on the surface of neurons
• triggers a cascade of events which ultimately cause neurodegeneration

Question 5

AB formation

Answer 5

• two-step process dependent on the action of two cleaving enzymes on AP, if APP is cleaved by B-secretase and then Y-secretase, product is AB
• oligomers are then released into the extracellular. AB oligomers are chemically ‘sticky’. they aggreagte to form plaques on the cell surface

Question 6

AB detection in vivo- amyloid PET

Answer 6

CSF- presumed inverse relationship between CSF AB and CNS AB
- reduced CSF AB a positive biomaker result for AD

Question 7

Tau

Answer 7

• a protein involved in stabalising microtubules of axons
• 6 different varitents
• Tau can be phosphorylated at a number of sites on the protein, which decreases its ability to bind microtubules
• pathological tau becomes hyperphosphoryleted and aggregates neurofibrially tangles.
• implicated in many different neurodegenerative diseases

Question 8

neurofibrally tangles formation

Answer 8

1. neuron
2. tau stabilizes microtubules
3. tau hyperphosphorylation causes microtubule depolymerisation (Alzheimer’s disease)
4. Tau oligomers aggregation
5. formation of paired helical filament
6. formation of NT causing neural death and release of Tau oligomers
   to extracellular environment
7. activation of microglia and progressive neuronal damage

Question 9

Neurofibrillary tangles

Answer 9

Stage 1-2: Entorhinal stage
stage 3-4: Limbic stages
Stage 5-6: Neocortical stages

Question 10

Tau detection in Vivo

Answer 10

tau PET:
- tracer has to cross cell membrane, in addition to blood-brain barrier
- tau tracer has to bind to the right of tau
CSF analysis:
- quantification of levels of total and p-tau (specific to AD)
Blood tests to measure tau in plasma undergoing validation:
- aus a world leader in undertaking these studies.

Question 11

Neuronal loss

Answer 11

• presence of AB and tau tangles causes activation of microglia (an immune response to inflammation) and ultimately apoptosis
• precise interaction between ab and tau is unknown
• ## cell depth follows the pattern of tau disposition; begins in medical temporal lobes.

Question 12

pathological sequence of Alzheimer’s disease

Answer 12

AB and tau –> synaptic dysfunction –> cell loss –> cognitive and functional decline (dementia)
- precise mechanisms are poorly understood

Question 13

temporal sequence of AB accumulation in AD

Answer 13

• it takes 30 years to go from no amyloid levels to the ones seen in AD
• it takes 12 years to go from no amyloid to ‘at risk’ levels
• it takes 19 years to go from at risk to levels seen in AD

Question 14

AD related cognitive changes

Answer 14

• memory impairment: insidious onset, recent memory difficulties, a failure to learn and remember new information
• navigation/ orientational difficulties: getting lost, unable to keep track of time and place
  language decline:
• Anomia
• circumlocution

Question 15

clinical diagnosis of AD

Answer 15

• decline in cognition or behaviour causing cognitive impairment
• we estimate patients cognition against patient’s baseline
• assess performance on multiple tasks measuring all domains of cognition
• compare performances to established normative data sets to determine impairment vs normal ageing

Question 16

implication- why does timely clinical diagnosis matter

Answer 16

• dementia is progressive and permits future planning —> one day this will include advanced decision making such as threshold for assisted suicide
• considerations around fitness to drive—> mandatory reporting requirements to VicRoads.
• ## assessment of decision-making capacity: protection of the vulnerable preservation of anatomy

Question 17

prevention of AD

Answer 17

• modifiable risk factors
• probably modify rate of disease protgression, symptom onset rather than pathology
• ## mechanisms sometimes unclear (eg. deafness)

Question 18

treatments of AD (1)

Answer 18

• symptomatic relief: not disease modifying
• anti-amyloid:
  1. antibodies (facilitate clearance)
  2. BACE omhibitors/moderators –> liver toxicity
  Anti-Tau
  1. antibodies
  2. antisense oligonucleotide (ASO: inhibitors trnaslation of tau mRNa’s)
  Downstream:
• promote BDNF/ synaptic generation –> some positive impact
• remove ion, reduce oxidative stress –> not looking good
• anti inflammatory

Question 19

treatment of AD (2)

Answer 19

• the solution will be in rational combination therapy
• early inhibition of production ( avoids toxic overdosing) using B- and/ or Y-secretese inhibitors/moderators
• facilitation of clearance of AB in those at risk
• adjunct therapy to promote brain health