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Neuroanatomy and neurodegenerative disorders > Alzheimer's disease > Flashcards

Alzheimer's disease Flashcards

1
Q

What is dementia?

A
  • An irreversible, progressive brain disease that slowly destroys memory and cognitive skills
  • Affects comprehension, calculation, learning, language, personality, mood and behaviour
  • Does not affect consciousness
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2
Q

What is the mean life expectancy following AD diagnosis?

A

7 years

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3
Q

Why is the temporal lobe an important region in AD?

A
  • It is involved in auditory perception and is home to the primary auditory cortex.
  • It is also important in both speech and vision.
  • The temporal lobe contains the hippocampus which plays a key role in the formation of long-term memory.
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4
Q

What are some of the features of mild dementia/AD?

A

Memory loss, language problems, mood swings, personality changes

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5
Q

What are some of the features of moderate dementia/AD?

A

Unable to learn/recall new info, long-term memory affected, wandering, agitation, aggression, require assistance with activities of daily living

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6
Q

What are some of the features of severe dementia/AD?

A

Gait, incontinence, motor disturbances, bed ridden, unable to perform ADL, placement in long-term care needed

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7
Q

How is AD diagnosed?

A
  • Confident diagnosis can only be made by autopsy
  • Diagnostic criteria designed to detect short term memory loss, difficulties with ADL and changes in personality
    • collateral history taking
    • physical exam
    • MSE
  • Supported by neuroimaging
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8
Q

What are some newer diagnostic techniques used to detect AD?

A
  • PET - detects metabolically active cells/brain regions or cerebral blood flow
  • CSF biomarkers - total Tau increases to about 300%, amyloid beta decreases to about 50% (increased plaque deposition)
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9
Q

How can PET distinguish between AD and frontotemporal dementia (FTP)?

A

AD shows rear brain inactivity, FTD shows inactivity in the frontal part of the brain

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10
Q

What are amyloid beta plaques?

A

Insoluble aggregates of amyloid beta proteins that form outside neurons

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11
Q

What are neurofibrillary tangles?

A

Insoluble aggregates of hyper-phosphorylated Tau protein that form inside neurons

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12
Q

What variant of the amyloid beta peptide is found more in cerebral plaques? AB42 or AB40?

A

AB42 - more hydrophobic, more prone to fibril formation and is the predominant isoform found in cerebral plaques

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13
Q

What is the toxic form of AB peptide - soluble or insoluble aggregates?

A
  • Fibrillar/aggregated forms of AB peptide but not soluble monomeric AB peptide are toxic to cells in culture and brain of rhesus monkeys
  • Neurodegeneration appears prior to the appearance of plaques in mouse models of AD
  • Plaques are found in people without dementia or brain injury
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14
Q

Are the majority of AD cases sporadic or familial?

A
  • Majority of cases are sporadic
  • Hereditary forms of AD generally induce earlier onset of neurodegeneration
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15
Q

What do most AD-related mutations cause?

A

Increased formation of amyloid plaques

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16
Q

Why do people with Down’s syndrome have an increased likelihood of developing AD?

A
  • The APP gene is located on chromosome 21
  • There are three chromosome 21s and therefore 3 APP genes which leads to increased plaque formation
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17
Q

What evidence is there to support AB as a cause for AD?

A
  • Increased number of plaques in brains of AD patients
  • Mutations in familial AD cause increased production of AB peptides
  • AB plaques appear in Down Syndrome patients that carry an extra copy of the APP gene
  • APOE4 allele increases the risk of sporadic AD
  • Transgenic mice expressing mutant human APP genes develop plaques and neurodegeneration
18
Q

What makes amyloid beta toxic to cells?

A
  • Induce production of reactive oxygen species (ROS), leading to cell damage and apoptosis
  • May directly insert into cellular membranes and disrupt cellular integrity, act as a non-selective ion channel, or allow release of ROS
  • May promote aggregation of tau to form neurofibrillary tangles
19
Q

What are the 2 major hypotheses for AD?

A
  • BAPtists - Beta Amyloid Protein - accumulation of a fragment of APP (AB42) leads to the formation of plaques that sometimes kill neurons
  • TAUists - abnormal phosphorylation of tau proteins makes them sticky, leading to the break up of microtubules. The resulting loss of axonal transport causes cell death
20
Q

How does tau cause neuronal death?

A

Disintegrates microtubules

21
Q

What makes tau toxic in AD?

A

Tau is normally found in axons but in AD aggregates and is redistributed to cell bodies and dendrites

22
Q

What happens to tau in AD?

A

It is hyperphosphorylated early in AD which impairs its ability to bind microtubules and promotes it’s aggregation, forming neurofibrillary tangles

23
Q

Describe the importance of tau pathology in AD

A
  • NFTs show higher correlation with AD progression than plaques
  • Familial AD is due to mutations in APP processing molecules and result in high levels of plaques and tangles, FTD has NFT but never plaques
24
Q

What is the current theory for the pathogenesis of AD?

A
  • Multifactorial - involving several pathways
  • Protein accumulation -> plaques and tangles
  • Inflammation - unregulated activation of glia
  • Lipid distribution - lipid membrane site of APP cleavage
25
Q

Describe the multifactorial threshold model

A
  • Many common alleles with low penetrance, most people will have several risk alleles
  • Risk alleles are additive, plus there are many additive environmental factors
  • Genes + environment -> liability
  • Once liability reaches a certain value i.e. a threshold, a disease process begins
26
Q

What is apolipoprotein E and where is it produced?

A
  • An amino acid glycoprotein
  • Produced in high levels in the liver and brain
  • Synthesised by glia in the brain (mainly astrocytes)
27
Q

What does apolipolipoprotein E bind to?

A

Binds to soluble and aggregated amyloid beta

28
Q

What is the main function of ApoE?

A

Body’s primary cholesterol transport protein

29
Q

Which ApoE allele triples the risk of developing AD?

A

Presence of ApoE4 allele triples the risk of developing AD and decreases onset by a decade

30
Q

What are some of the influences ApoE has on AD progression?

A
  • Regulation of membrane cholesterol levels by ApoE influences amyloid beta production
  • ApoE influences AB clearance i.e. ApoE and low density lipoprotein related receptor (LRP) tranpsport AB peptide across the BBB
31
Q

What receptor mediates influx of amyloid beta across the BBB?

A

RAGE - receptor for advanced glycation end products

32
Q

What are the 2 main proteases involved in amyloid beta degradation?

A
  • IDE and NEP
  • Presence of IDE or NEP decreases AB accumulation
  • Inactivating mutations of IDE and NEP have been detected in AD patients
33
Q

What happens to acetylcholinesterase activity in AD?

A
  • One of the earliest changes in AD progression is loss of acetylcholinesterase activity in the cortex and hippocampus
  • This contributes substantially to the characteristic cognitive and non-cognitive symptoms
34
Q

How do acetylcholinesterase inhibitors work in treating AD?

A

They are designed to combat impairment of cholinergic neurons by slowing degradation of acetylcholine after its release at synapses

35
Q

How effective are AChE inhibitors in treating AD and what are some examples?

A
  • Donepezil, rivastigmine, galantamine
  • All 3 drugs improve memory and thinking in around 50% of patients
  • AChE inhibitors delay neurodegeneration by ~6 months
36
Q

What is the role of glutamate in AD?

A
  • Glutamate is the major excitatory neurotransmitter in the CNS.
  • Glutamate signalling is important for information storage, processing and retrieval in the cortex/hippocampus but high levels are neurotoxic
37
Q

How does excitotoxicity via glutamate occur?

A
  • Excitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate.
  • This occurs when glutamate receptors e.g. NMDA receptor and AMPA receptor are overactivated.
  • Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate can cause excitotoxicity by allowing high levels of Ca ions to enter the cell.
  • Ca inflex activates a number of enzymes which go on to damage cellular structures
38
Q

How does memantine work in treating AD?

A

Memantine is an NMDA receptor antagonist, therefore it blocks the excitotoxic effects of pathologically high levels of glutamate

39
Q

What are the 3 main opportunities for the treatment of AD?

A
  1. Reducing amyloid beta production
  2. Plaque build-up
  3. Clearance
40
Q

What are some proposed methods for reducing amyloid beta production?

A
  • Gamma-secretase - certain NSAIDs allosterically modulate gamma-secretase to favour production of AB40 over AB42
  • Beta secretase - lacks other substrates and is therefore a safer target
  • Alpha-secretase - stimulating its activity could decrease AB since it cleaves within the peptide
41
Q

What drug has been shown to prevent amyloid beta aggregation?

A

Clioquinol, an antibiotic and Cu/Zn chelator

42
Q

What are some potential methods of increasing clearance amyloid beta?

A
  • Immunotherapy for removal of amyloid beta plaques
  • The antibody aducanumab has been shown to reduce AB plaques in AD

Neuroanatomy and neurodegenerative disorders (7 decks)

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