memory disorder Flashcards
dementia
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
Alzheimer’s disease
most common cause of dementia
- accounts for about 70% of cases of dementia
- about 30% of the population aged over 85.
biology (pathophysiology) of AD
- 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
AB
- 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
AB formation
- 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
AB detection in vivo- amyloid PET
CSF- presumed inverse relationship between CSF AB and CNS AB
- reduced CSF AB a positive biomaker result for AD
Tau
- 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
neurofibrally tangles formation
- neuron
- tau stabilizes microtubules
- tau hyperphosphorylation causes microtubule depolymerisation (Alzheimer’s disease)
- Tau oligomers aggregation
- formation of paired helical filament
- formation of NT causing neural death and release of Tau oligomers
to extracellular environment - activation of microglia and progressive neuronal damage
Neurofibrillary tangles
Stage 1-2: Entorhinal stage
stage 3-4: Limbic stages
Stage 5-6: Neocortical stages
Tau detection in Vivo
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.
Neuronal loss
- 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.
pathological sequence of Alzheimer’s disease
AB and tau –> synaptic dysfunction –> cell loss –> cognitive and functional decline (dementia)
- precise mechanisms are poorly understood
temporal sequence of AB accumulation in AD
- 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
AD related cognitive changes
- 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
clinical diagnosis of AD
- 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
implication- why does timely clinical diagnosis matter
- 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
prevention of AD
- modifiable risk factors
- probably modify rate of disease protgression, symptom onset rather than pathology
- ## mechanisms sometimes unclear (eg. deafness)
treatments of AD (1)
- 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
treatment of AD (2)
- 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
