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Brain and Behaviour Year 2 > Dementia > Flashcards

Dementia Flashcards

1
Q

What is the histological changes in dementia

A
  • brain atrophy particularly in the temporal lobe
  • ventricles are larger
  • sucli and gyre are lost
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2
Q

name the warning signs of dementia

A
  • Memory loss
  • Difficulty performing familiar tasks
  • Problem with languages – might forget the name of a toothbrush
  • Disorientation in time and place – forgotten at what time they have dinner or what time they do normal activities
  • Poor or decreased judgement
  • Problems keeping track of things
  • Misplacing things such as keys
  • Changes in mood and behaviour
  • Trouble with images and spatial relationships
  • Withdrawal from work or social activities
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3
Q

What is the definition of dementia

A
  • Term used to describe a syndrome that is caused by a number of illnesses in which there is progressive decline in multiple areas of function
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4
Q

Which 3 things is there a decline of in dementia

A
  • Decline in memory and recognition
  • Decline in communication skills
  • Inability to carry out daily activities
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5
Q

Name other behaviour and psychological symptoms of dementia

A
  • agitation
  • aggression
  • wandering
  • shouting
  • repeated questioning
  • sleep disturbance
  • depression and psychosis.
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6
Q

name some types of dementia

A
  • vascular dementia (17%)
  • Alzheimer’s disease (62%)
  • Parkinson’s disease (2%)
  • frontal temporal (2%)
  • dementia with lewy body (4%)
  • mixed AD+ VaD (17%)
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7
Q

name some ways of reducing the risk of dementia

A
  • look after your heart
  • be physically active
  • follow a healthy diet challenge your brain
  • enjoy social activity
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8
Q

What are the risk factors for dementia (modifiable and non-modifiable)

A 
Non-modifiable risk factors
•	Age (greatest risk factor)
•	Genetic predisposition
•	Family history
•	Downs syndrome

Modifiable risk factors
• Vascular Risk factors (high cholesterol, hypertension, diabetes)
• Cognitive inactivity (low education attainment)
• Environment (head injury)
• Depression

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9
Q

What are the two things that cause dementia pathophsilogically

A
  • plaques and tangles
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10
Q

describe where plaques and tangles are

A
  • Amyloid plaques – these are deposited outside of the neurones so they are extracellular
  • Tangles – these are found inside the neurones so there intracellular
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11
Q

How do you get a definitive diagnosis of demintia/Alzehiemrs

A
  • need to have plaques and tangles but you can only find this out in an autopsy post mortem
  • therefore they can only be given a diagnosis post mortem
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12
Q

name the 3 hallmarks of dementia

A
  • extracellular deposits of beta- amyloid peptide in senile plaques
  • deposits of beta-amyloid peptide in cerebral vessels
  • neurofibrillary tangles - the tau protein hyperphosphorylated and forms neurofibrillary tangles in cell bodes
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13
Q

What do plaques and tangles cause to happen

A
  • neurotic dystrophy
  • synaptic loss
  • selective neuronal cell loss
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14
Q

how many neurones are lost before people have specific memory impairment

A

20-40% of cholinergic cells are lost

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15
Q

what 3 genes are associated with early onset alzhimeres disease

A

Amyloid precursor protein (APP) Chromosome = 21

Presenilin 1 (PSEN1) Chromosome= 14

Presenilin 2 (PSEN2) Chromosome= 1

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16
Q

describe the APP protein

A
  • a single transmembrane polypeptide (110-140 kD)
  • APP is abundantly expressed in neurones
  • APP also expressed in glial cells and endothelial and smooth muscle cells
  • helps neurone growth and repair
  • over time APP is broken down and recycled
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17
Q

What do APP proteins produce

A
  • Abeta peptide is a normal metabolic event
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18
Q

What happens when there is a mutation of APP

A
  • they are associated with an increase in a beta production
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19
Q

what diseases are mutations in APP associated with

A

• Mutations in APP are associated with familial forms of early onset Alzheimer’s disease as well as with Cerebral amyloid angiopathy (CAA)

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20
Q

what mutation in APP is protective of Alzheimer’s disease

A

• One particular mutation A673T decreases Aβ production and is protective of AD

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21
Q

Describe the normal recycling pathway of APP

A

o Transmembrane protein is cleaved secretase enzymes (alpha, beta and gamma).
 (!) The γ-secretase is made up of subunits. Of note are PSEN1 and PSEN2 because mutations in these can cause Alzheimer’s .
o In normal non-amyloidogenic pathway, alpha and gamma secretases do not form amyloid-beta peptides but cleave up the protein into soluble form which is recycled.

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22
Q

What is the most common mutation that causes alzherimers

A

PSEN1 being the most common

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23
Q

What does PSEN1 encode

A
  • PSEN1 encodes presenilin-1
24
Q

What are the Y secretease made up of

A
  • it is made up of subunits

- PSEN1 and PSEN2 are impotent as mutations in these can cause AD

25
Q

What does PSEN2 encode for

A
  • Presenilin-2
26
Q

• Missense mutations in …..

A

PSEN2 are a rare cause of early onset AD

27
Q

How does the recycling of the APP protein lead to Alzheimer’s disease

A
  • In diseased amyloidogenic pathway, the transmembrane protein is wrongly cleaved by beta and gamma secretases which leads to formation of non-soluble amyloid-beta peptides (most commonly of the types A-beta 40 and 42.
  • These peptides aggregate to form senile plaques
28
Q

what is APP cleaved by

A

3 “secretase enzymes”: alpha, beta and gamma-secretase

29
Q

what is the difference between the non-amyloidogenic pathway and amloidogenic pathway in alzhiemers in APP synthesis

A
  • Non-amyloidogenic pathway: alpha-sec and gamma-secretase
  • Amyloidogenic pathway: beta-sec and gamma-sec: and generates A- amyloid peptide (A39-43) (form plaques in alzipehrems)
30
Q

What can senile plaques do that are harmful

A

o Can potentially get in-between the neurons which disrupts signalling.
 Therefore, impairs various functions like memory.
o Start an immune response which causes activation of microglia.
o Can also cause amyloid angiopathy when around cerebral vessels
 Weakens walls and increases risk of haemorrhage.

31
Q

What is the normal function of Tau proteins

A

• Neurons are held together by their cytoskeleton made up of microtubules.
o Ship nutrients and molecules along the cell.
o Located within the neuron.
• Tau stabilises microtubules through coordinated binding through kinases/phosphates

32
Q

What encodes Tau protein s

A

• Encoded by MAPT

33
Q

what happens if there is a mutation in MAPT

A

o Mutation can cause fronto-temporal dementia (FTD).

o Rare mutation in Alzheimer’s, not an actual cause.

34
Q

what does MAPT encode

A

Tau proteins

35
Q

how do TAU proteins become diseased

A

• Oxidative stress from amyloid plaques cause disregulation of kinase activity
o Kinase binds phosphate to the tau protein and causes it to become tangled (hyperphosphorylation) = neurofibrillary tangles.
• Tangles stop microtubules form signalling and can cause apoptosis.

36
Q

What is late onset dementia associated with

A

• Associated with apolipoprotein E.

37
Q

what are the three isofroms of poE and what are they linked to

A

APOE2, APOE3, APOE4

  • ApoE4 has greater risk for AD
  • ApoE2 is protective
38
Q

why does APOE4 have an increased risk for AD

A
  • ApoE4 polymorphorphism located chromosome 19

- ApoE4 protein decreases clearance of extracellular Aβ from the brain

39
Q

Where can you look for biomarkers in AD

A

in the CSF

40
Q

What are the biomarkers that you can look for in the CSF

A
  • Current CSF biomarkers are amyloid Amyloid beta - Abeta40 and Abeta42
  • And also in the CSF can look for fragemnets of Tau – phospho-tau (p-tau181,231) Total tau
41
Q

what happens to the amyloid in the CSF versus Tau

A
  • As a consequence of a disease amyloid will be reduced in CSF because you have more amyloid in the brain but it is not deposited in to the CSF and is being deposited in plaques whereas tau increases in neurodegeneration
42
Q

What are the blood based biomarkers that are being hoped to use for AD

A
  • Protein
  • DNA/RNA
  • Lipids
43
Q

name other ways you can determine AD

A

MRI

- not usually PET

44
Q

what markers in an PET can you use to determine ad

A
  • C11 Pittsburgh Compound B (PIB) Aβ plaques
  • Fluorine 18 fluorodeoxyglucose (FDG)
  • Fluorine-tagged ligands [18F} T807 and T808 (Tau ligands)
45
Q

How do people currently get diagnosed for AD

A
  • Go to GP and offer you a memory test
  • Do routine bloods
  • Then brain scan
    Rule out reversible things
  • Brain tumour
  • Vitamin deficiency
  • Things that look like dementia but are not
46
Q

what do biomarkers tell us about Alzheimers

A
  • scientist can look at how much amyloid has been produced and this can tell us about staging dementia
  • but by the time someone already has clinical symptoms there has already been so much amyloid that it has plateaued
  • this also means if you want to look for a cure you have to look in people who do not have clinical symptoms
47
Q

why are acetylcholinesterase inhibitors used in the treatment of dementia

A

cholinergic forebrain pathways innervating the cortical and limbic structures degenerate in alzeihmers disease
- by blocking acetylcholinesterase inhibitors it blocks the breakdown of acetylcholine which can be modestly efficacious on the cognitive symptoms

48
Q

what are the main two treatments for Alzheimer’s disease

A

Acetylcholinesterase inhibitors

NMDA receptor antagonist

49
Q

name examples of acetylcholinesterase inhibitors

A

donepezil
galantamine
rivastigmine

50
Q

name the NDMA receptor antagonist

A

Memantine

51
Q

what correlates more with cognitive decline tau or amyloid

A

tau

52
Q

when is the NDMA receptor antagonist used

A
  • Moderate Alzheimer’s disease who are intolerant/contraindication to AChE inhibitors
  • Severe Alzheimer’s disease
53
Q

How do NMDA receptor antagonists work

A
  • azhiemers is thought to be to do with a slow for of excitotxicity and increased glutamate release
  • therefore by blocking the glutamate receptor NDMA this will inhibit the glutamate
54
Q

what are the side effects of memantine

A 
- less common and less severe than the cholinesterase inhibitors 
side effects; 
- dizziness 
- headahces
 - tiredness 
- increased blood pressure 
- constipation
55
Q

what other symptomatic medication in AD

A
  • Antidepressant drugs
  • Antipsychotic drugs
  • Mood stabilisers
56
Q

name some disease modification therapy

A
  • Anti fibrillization
  • Secretase inhibitors
  • Increased clearance immunisation
  • GSK3 inhibitors
  • Public health measures such as diabetes and diet
57
Q

name some potential disease modification therapies

A 
•	β-secretase inhibitors 
•	Notch-sparing γ-secretase inhibitors 
or modulators
•	Aβ vaccines and monoclonal antibodies
•	Aβ aggregation inhibitors
•	Tau lowering/anti aggregation compounds
•	Regulation of abnormal anti-inflammatory
•	 mechanisms

Brain and Behaviour Year 2 (36 decks)

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