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Psychology and the brain > topic 8 (neurodegeneration) lecture 1&2 (Alzheimer's disease) > Flashcards

topic 8 (neurodegeneration) lecture 1&2 (Alzheimer's disease) Flashcards

1
Q

what is alzheimers disease?

A
  • a neurodegenerative disease meaning there is a progressive loss in structure and function of neurons, which can result in the death of neurons
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2
Q

who discovered alzheimers disease?

A

Alois alzheimer

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3
Q

what percentage of those with dementia have alzheimers?

A

62%

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4
Q

what is the prevalance of alzheimers uk?

A

1 in 127

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5
Q

what is the duration of alzheimers?

A

about 4 years

we can see this because the yearly incidence rate is roughly 1/4 the prevalnce rate

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6
Q

is alzheimers more prevalent in women or men?

A

women

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7
Q

what percentage of those with dementia recieve a diagnosis in the uk?

A

44%

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8
Q

what percentage of people with dementia live in a care home?

A

1/3 live in a care home
2/3 live in the community

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9
Q

what are 5 steps involved in the diagnosis with alzheimers?

A
  • clinical interview and assesment with patient and informant
  • mental and physical health examination to rule out other conditions e.g thyroid conditions
  • blood test to rule out other conditions
  • CT/MRI scan
  • amyloid PET imaging if available
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10
Q

what are 9 symptoms of alzheimers?

A

memory loss
incorrect language
problems speaking reading writing and understanding
disorientation in time and space
poor or impaired judgement
impaired abstract thinking
misplacing things
personality changes
difficulties with daily function

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11
Q

what are 3 non-modifiable risk factors for AD?

A

AGE - risk doubles every 5 years after the age of 65

FAMILY HISTORY- some genetic component, especially with early onset

DOWNS SYNDROME- individuals with downs syndrome are at a greater risk of developing AD

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12
Q

what are 5 modifiable risk factors for AD?

A
  • alcohol and smoking
  • obesity
  • lower levels of education
  • isolation
  • excercise is a protective factor
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13
Q

what are gross changes to the brain in alzheimers?

A
  • loss of volume particualry to frontal and temporal areas
  • enlarged sulci between gyri
  • enlarged ventricles
  • loss is pronounced in the hippocampas
  • rate of loss of volume is correlated with the rate of loss of cognition
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14
Q

what are cellular changes to the brain in alzheimers disease?

A
  • selective loss of cholinergic neurons
  • changes in two key proteins:
  • beta amyloid which is produced from amyloid precursor protein (app), and forms amyloid(Senile) plaques throughout the cortex
  • hyperphospholated tau protein which is formed from normal tau protein and forms neurofibrilliary tangles throughout the cortex
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15
Q

what are 3 functions of amyloid precursor proteins?

A
  • synapse formation
  • neuronal plasticity
  • ion regulation
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16
Q

what chromosome is APP coded for on?

A
  • chromosome 21
  • this is the chromosome implicated in downs syndrome
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17
Q

how is APP normally cut up?

A
  • APP normally spans the cell membrane and the intracellular and extracellular space
  • It is typically cut up by secretase enzymes
  • alpha-secretase cuts it just outside the cell membrane
  • following this, gamma-secretase cuts it inside the cell membrane, leaving two segments in the membrane
  • the products are not harmful in anyway
  • in healthy people, this pathway is used 90% of the time
18
Q

how is APP cut up in Alzheimer’s?

A
  • instead of alpha secretase, beta secretase cuts it higher up than alpha would
  • gamma secretase then cuts it normally
  • the result is a longer segment sticking out of the cell membrane. this segment is the cause of the amyloid plaques
  • the availability of alpha vs. beta secretase determines the likelyhood of the harmful segment being formed
  • in healthy people this pathway is used about 10% of the time but the beta amyloid segment is normally cleared away easily
  • in alzheimers disease this pathway is used more and the segments cant always be cleared away
19
Q

how is tau protein involved in axon transport?

A
  • lengths of axons means mitochondria, lipids, proteins, synaptic vescicles, proteins and other organelles cannot travel along the axon by diffusion alone
  • also waste must be transported back to the cell body to get broken down by lysosomes
  • microtubules run along the length of the axons to support transport
  • tau proteins help stabilise the microtubules
20
Q

outline TAU in alzheimers brain?

A
  • the tau protein becomes hyperphosphorylated
  • this means it can no longer stabilise the microtubule and instead forms clumps or tangles within the cell
  • this impairs transport along the microtubules
  • the things needing transport get stuck in a kind of traffic jam and the axons eventually degenerate
21
Q

what is the difference between pathogenesis and pathology?

A
  • pathology is the changes in the brain
  • pathogenesis is the process by which these come about

-

22
Q

what are 5 alternative hypothesese for alzheimers disease?

A
  1. inflammatory hypothesis
  2. oxidative stress hypothesis
  3. vascular hypothesis
  4. cholestrol hypothesis
  5. cell cycle hypothesis
23
Q

whats the inflammatory hypothesis?

A

beta amyloid triggers a range of inflammatory actions involving glial cells, and the neuroinflammation could result in AD

24
Q

what is the oxidative stress hypothesis?

A

dysfunction in mitchondria results in high levels of reactive oxygen species which can damage cells

25
Q

what is the vascular hypothesis?

A

AD arises due to increased age and vascular risk factors

cerebral microvascular pathology and cerebal hypoperfusion may trigger the cognitive changes

26
Q

what is the cholestrol hypothesis?

A

cholestrol alters the secretase activity, increasing beta amyloid production

27
Q

what is the cell cycle hypothesis?

A

the normal process of cell division is interuppted

28
Q

what is the TAU hypothesis?

A
  • mutations result in increased phosphorylation of tau
  • this is then found in paired helical filament tau or tau tangle form, unnatached to microtubules
  • free tau accumulates which can trigger various reactions and cause cell death
  • microtubules can no longer be stabilised, microtubles then disintegrate and this can cause cell death
29
Q

what is the correlation between tau pathology and the clinical picture?

A
  • AD severity correlates well with the increasing accumulation of neurofibrillary tangles
  • there is also a high correlation between the hyperphosphorylated tau species in the CSF of AD patients, and the extent of cognitive impairment
  • target directed drugs that decrease TAU filiments also decrease cognitive impairment
  • TAU oligomers are found in those that go on to develop AD 20 years later suggesting they are in early cascade
30
Q

Outline animal research and the TAU hypothesis

A
  • stimulating excess production of TAU protein aggregates leads to characteristic behavioural symptoms and memory loss even when AB is inhibited
  • AD symptoms can be treated with TAU aggregation inhibitors which suppress the level of TAU protein expression
31
Q

what is the amyloid hypothesis

A
  • this is the dominant AD hypothesis
    1. There is an increase in the production of the beta amyloid harmful segment
    2. This accumulates into oligomers which has subtle effects on synapses
    3. AB oligomers clump together to form plaques
    4. Microglia and astrocytes are activated creating inflammation
    5. This leads to altered neuronal functioning and oxidative stress
    6. This leads to altered enzyme activity including phosphatases
    7. This results in TAU tangles
    8. This leads to neuron and synapse loss and dysfunction of neurotransmitters
32
Q

in the beta amyloid cascade hypothesis what caused the increase in beta amyloid in the first place?

A
  • there is more beta secretase than alpha secretase

or

  • theres a faliure to remove any amyloid beta before it can form plaques
33
Q

how does beta amyloid relate to the two forms of AD?

A
  • in the domintaly inherited early onset form there can be mutations in the Amyloid precursor protein or in two key genes (presenilin 1 or 2), which may affect the production of Beta Amyloid
  • In the non-inherited sporadic form there is a faliure to remove beta amyloid so that it can build up. This can be due to some genes and faulty clear up methods
34
Q

Name 4 genetic evidences in favour of the amyloid hypothesis

A
  • Mutations within and adjacent to the Amyloid Beta region of the Amyloid precursor protein cause aggressive forms of familial AD
  • Mutations that decrease amyloid beta give lifelong protection from AD and cognitive decline
  • Downsyndrome is 3 copies of chromosome 21. This chromosome has APP coded onto it. People with downs syndrome develop AD and show abundant plaques.
  • Presenilin is the catalytic subunit of y-secretase. Mutations in precenilin 1 or 2 are the most common causes of early onset AD.
  • A4epo is a gene that reduces beta amyloid clearance. Carriers have an increased risk of AD.
35
Q

What is other evidence in favour of the Amyloid hypothesis?

A
  • In rodents, human beta amyloid oligomers decrease synaptic density, inhibit LTP, and enhance long term synaptic depression in the hippocampus. Intraventricular injection of it also impairs memory in healthy adult rats.
  • Human beta amyloid oligomers induces TAU hyperphosphorylisation in cultured rat neurons. Coadministering beta amyloid antibodies fully prevents this.
  • Human biomarker studies show that low levels of beta amyloid in CSF and Positive amyloid PET scans precede other AD related changes by years
  • Trials of 3 different beta amyloid antibodies have suggested slowing of cognitive decline in post hoc analyses of mild AD patients.
36
Q

What is genetic evidence against the amyloid hypothesis?

A
  • onset of dementia in downs syndrome is highly variable despite plaques in 100% of individuals with downs syndrome by age 50.
  • Genetic factors linked to AD can be interpreted independently of amyloid
37
Q

What is other evidence against the amyloid hypothesis?

A
  • beta amyloid occurs in 40% of cognitively normal older individuals
  • the relationship between beta amyloid and TAU is unclear
  • There is a weak correlation between plaques and cognition
  • the triggers of synapse loss, neuronal loss and neuroinflammation are unclear
38
Q

How do acetylcholinsterase inhibitors treat alzheimers?

A
  • they prevent the breakdown of acetylcholine, which is reduced in alzheimers disease
  • By preventing breakdown its possible to increase acetylcholine binding to receptors
  • this gives a 40-70% benefit for mild to moderate AD
  • its results in reduced anxiety, increased motivation, memory and ability to do daily activities
39
Q

How do NDMA receptor antagonists treat AD?

A
  • they block the glutamate receptors, possibly reducing excitotoxicity
  • used in moderate Ad
  • its slows progression and helps disorientation, dellusion and aggression
40
Q

what are 8 side effects of Acetylcholinsterase inhibitors?

A

loss of appetite

nausea

vomiting

diarrehea

insomnia

dizzinesss

headaches

cramps

41
Q

what are 5 side effects of NMDA antagonists?

A

dizziness

headaches

tiredness

high bp

constipation

42
Q
A

Psychology and the brain (16 decks)

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