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BMS3052 > 38. Alzheimer's Disease > Flashcards

38. Alzheimer's Disease Flashcards

1
Q

Define

Vascular dementia

A

dementia (as multi-infarct dementia) of abrupt or gradual onset that is caused by cerebrovascular disease

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2
Q

Define

Frontotemporal dementia

A

any of several degenerative brain diseases that are caused by progressive atrophic changes in the frontal or temporal lobes, that usually start in late middle age, that result in changes to behavior and personality (such as impulsiveness, social impropriety, and apathy) and typically impaired language function, and that lead in advanced cases to a profound decline in cognitive and language functioning

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3
Q

Define

Lewy body dementia

A

a dementia with an onset typically after the age of 60 that is marked by the presence of Lewy bodies in the cytoplasm of cortical neurons and is characterized chiefly by a progressive decline in cognitive functioning, fluctuations in attention and alertness, recurrent visual hallucinations, and parkinsonian symptoms (such as tremor and muscle rigidity)

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4
Q

Define

Tau protein

A

a protein that binds to and regulates the assembly and stability of neuronal microtubules and that is found in an abnormal form as the major component of neurofibrillary tangles

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5
Q

Define

AB1-40

A

major form of AB that is secreted, lower tendency to aggregate, thought to have neurotrophic tendency

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6
Q

Define

AB1-42

A

form of AB produced in low quantities, more prone to form oligomers, protofibrils and fibrils, main form in amyloid plaques

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7
Q

Define

Neurofibrillary tangles

A

a pathological accumulation of paired helical filaments composed of abnormally formed tau protein that is found chiefly in the cytoplasm of neurons of the brain and especially the cerebral cortex and hippocampus and that occurs typically in Alzheimer’s disease

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8
Q

Define

Alzheimer’s disease (AD)

A

a degenerative brain disease of unknown cause that is the most common form of dementia, that usually starts in late middle age or in old age, that results in progressive memory loss, impaired thinking, disorientation, and changes in personality and mood, and that is marked histologically by the degeneration of brain neurons especially in the cerebral cortex and by the presence of neurofibrillary tangles and plaques containing beta-amyloid

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9
Q

Definition

dementia (as multi-infarct dementia) of abrupt or gradual onset that is caused by cerebrovascular disease

A

Vascular dementia

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10
Q

Definition

any of several degenerative brain diseases that are caused by progressive atrophic changes in the frontal or temporal lobes, that usually start in late middle age, that result in changes to behavior and personality (such as impulsiveness, social impropriety, and apathy) and typically impaired language function, and that lead in advanced cases to a profound decline in cognitive and language functioning

A

Frontotemporal dementia

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11
Q

Definition

a dementia with an onset typically after the age of 60 that is marked by the presence of Lewy bodies in the cytoplasm of cortical neurons and is characterized chiefly by a progressive decline in cognitive functioning, fluctuations in attention and alertness, recurrent visual hallucinations, and parkinsonian symptoms (such as tremor and muscle rigidity)

A

Lewy body dementia

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12
Q

Definition

a protein that binds to and regulates the assembly and stability of neuronal microtubules and that is found in an abnormal form as the major component of neurofibrillary tangles

A

Tau protein

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13
Q

Definition

major form of AB that is secreted, lower tendency to aggregate, thought to have neurotrophic tendency

A

AB1-40

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14
Q

Definition

form of AB produced in low quantities, more prone to form oligomers, protofibrils and fibrils, main form in amyloid plaques

A

AB1-42

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15
Q

Definition

a pathological accumulation of paired helical filaments composed of abnormally formed tau protein that is found chiefly in the cytoplasm of neurons of the brain and especially the cerebral cortex and hippocampus and that occurs typically in Alzheimer’s disease

A

Neurofibrillary tangles

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16
Q

Definition

a degenerative brain disease of unknown cause that is the most common form of dementia, that usually starts in late middle age or in old age, that results in progressive memory loss, impaired thinking, disorientation, and changes in personality and mood, and that is marked histologically by the degeneration of brain neurons especially in the cerebral cortex and by the presence of neurofibrillary tangles and plaques containing beta-amyloid

A

Alzheimer’s disease (AD)

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17
Q

What is mild cognitive impairment?

A

significant memory loss without the loss of other cognitive functions

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18
Q

What is the prevalence of dementia?

A

An estimated 459,000 Australians currently live with dementia with 10% of individuals over 65 and 30% over 85 affected

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19
Q

What are the gender difference in dementia prevalence?

A

females are particularly vulnerable contributing to 65% of all dementia-related deaths

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20
Q

What is the most common form of dementia?

A

Alzheimer’s disease

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21
Q

What are three other forms of dementia that aren’t AD?

A

Vascular dementia

Frontotemporal dementia

Lewy body dementia

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22
Q

What is the second most common form of dementia?

A

Vascular dementia

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23
Q

What is the leading type of early onset dementia (under 65 y)?

A

Frontotemporal dementia

24
Q

What causes vascular dementia?

A

Lacunes and infarcts caused by atherosclerosis, cardioembolic and small vessel diseases

25
Q

What causes frontotemporal dementia?

A

Pathologies caused by abnormal aggregation of tau, TAR DNA binding protein 43 or fused in sarcoma protein

26
Q

What are the two types of Alzheimer’s disease?

A

Familial AD (FAD)

Late-onset AD (LOAD)

27
Q

What is the prevalence of Familial AD?

A

5% of AD cases

28
Q

What is the cause of Familial AD?

A

associated with mutations in the amyloid precursor protein APP as well as the processing enzymes presenilin 1 and 2,

29
Q

What ages does familial AD affect people?

A

very aggressive form of the disease affecting individuals in their 40s and 50s

30
Q

What is the prevalence of late onset AD?

A

>95% of all cases of AD

31
Q

What is the cause of late onset AD?

A
  • Age related; no strong links to any mutations of the amyloid processing pathway
  • genome wide association studies reveal genes, ApoE, CLU, PICALM associated with increased risk of AD
32
Q

What is the typical presentation of AD?

A
  • Memory impairment – working memory, recently learnt information
  • Executive dysfunction – challenges with planning and problem solving
  • Confusion and agitation – difficulty completing familiar tasks, confusion with time/place
  • Mood and personality changes – withdrawal from social activities, suspicious, depressed, fearful and anxious
33
Q

What is the atypical presentation of AD?

A
  • Language impairment – problems with speaking/writing
  • Visual problems – trouble understanding visual images/spatial relationships
  • Motor dysfunction
34
Q

What is the typical pathology of AD?

A

Aggregation of amyloid protein (plaques) – extracellular

Hyperphosphorylation of tau protein (NFT) – intracellular

Synaptic dysfunction and cell death

Hippocampal atrophy and memory deficits

35
Q

What are the two pathways of amyloid processing?

A
36
Q

True or False:

Intracellular Aβ is always bad

A

False

Intracellular Ab found in normal human brain, highest in young

37
Q

How do neurofibrillary tangles form?

A

Hyperphosphorylation of Tau in microtubules cause them to detach and aggregate with other soluble tau forming a neurofibrillary tangles

38
Q

Are amyloid plaques a cause or consequence of AD?

A

Unknown

Accumulation of amyloid plaques does not correlate with cognitive impairment

BUT mutations in amyloid precursor protein and in presenilin 1 and 2, which are essential in generating Ab, cause familial, early onset AD

39
Q

Are neurofibillary tangles a cause or consequence of AD?

A

Unknown

Neurofibrillary tangles do correlate strongly with synaptic/neuronal loss and cognitive decline

BUT mutations in tau cause frontotemporal dementia and not AD

40
Q

True or False:

Mutations in tau cause AD

A

False

Mutations in tau cause frontotemporal dementia and not AD

41
Q

What are the genetic links in familial AD?

A
42
Q

What are the genetic links in late onset AD?

A
  • Cholesterol metabolism - APOE risk allele ε4, clusterin, ABCA7 (ATP-binding cassette transporter)
  • Immune response – complement receptor 1, CD33, TREM2 (receptor on microglia that stimulates phagocytosis)
  • Endocytosis - BIN1, PICALM (PI binding clathrin assembly protein), CD2AP (scaffold protein), EPHA1 (ephrin tyrosine kinase), SORL1 (sortilin-related receptor)
  • Rare variants of APP, presenilin 1 and 2
43
Q

What is the role of tau?

A

to promote assembly of tubulin into microtubules and stabilise their structure

44
Q

What are the theories of AD?

A

Amyloid Cascade Hypothesis

Tau Hypothesis

Current debate - role of Ab in AD

45
Q

What does the Amyloid Cascade Hypothesis explain about AD?

A
  • Build up of Ab and tau drives AD pathogenesis?
  • In FAD – overproduction of Ab42, altered propensity to aggregate
  • In LOAD – not overproduction but deficits in Ab clearance
46
Q

What does the Tau Hypothesis explain about AD?

A
  • Better correlation of phosphoTau with severity of disease
  • Tau important regulator of axonal transport, post-synaptic scaffolding protein?
  • Human tau mutations associated with frontotemporal dementia not AD
47
Q

What is the current debate about the role of Ab in AD?

A

Poor correlation between Ab load and clinical disease

Toxic intermediates such as oligomers of Ab peptide – artefact from isolation procedure?

48
Q

What are the risk factors for AD?

A
  • Age
  • Head trauma
  • Vascular health – structural abnormalities in cerebrovasculature leading to ischemic damage, cerebral amyloid angiopathy
  • Obesity and diabetes – AD is known as the diabetes of the brain where central insulin resistance has been suggested
  • Physical and mental inactivity – “use it or lose it”
  • Smoking
  • Low education attainment
49
Q

Why is AD diagnosis problematic?

A

No reliable biomarkers of disease in CSF (total tau/phosphoTau; Ab42)

Post-mortem confirmation of pathology

50
Q

What are the two types of AD treatment?

A

Symptomatic

Disease modifying

51
Q

True or False:

Only symptomatic treatments have been approved by the FDA for AD

A

True

52
Q

What types of symptomatic treatments of AD have been approved?

A

cholinesterase inhibitors, NMDA receptor antagonist

53
Q

What could disease modifying treatments of AD target?

A
  • Amyloid plaque formation - Ab vaccine, g-secretase inhibitors
  • Tau hyperphosphorylation – kinase inhibitors, phosphatases
  • Synaptic dysfunction – neuroprotective agents
  • Hippocampal atrophy
54
Q

How would amyloid β therapies treat AD?

A

Inhibitors of Ab synthesis

Anti-aggregation of Ab

55
Q

How would tau therapies treat AD?

A

Inhibitors of tau phosphorylation

Anti-aggregation of tau

56
Q

What types of AD animal models are there?

A

Expression of the human transgene in mice – replication of some but not all characteristics of AD

BMS3052 (26 decks)

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