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Neuroscience > Lecture 10 - Alzheimers Disease > Flashcards

Lecture 10 - Alzheimers Disease Flashcards

1
Q

Outline Alois Alzheimer 1901

A

Progressive neurodegenerative Disorder

Presented case Auguste D 1907

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2
Q

Outline Auguste D 1902

A

Profound cognitive and behavioural impairments
Difficulty memory, recognition, learning

Found strange deposits - Augustus triangles of filaments
1/3 cortical cells died off some way

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3
Q

Outline symptoms of Alzheimer’s

A

Impaired memory
Depression
Poor judgements
Confusion

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4
Q

Outline Neuropathology of Alzheimer’s Disease

A

Amyloid plaques

Neurofibrillary tangles

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5
Q

What proportion dementia cases are Alzheimer’s disease

A

50-80%

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6
Q

Outline symptoms of Vascular dementia

A

Similar Alzheimer’s

But memory less affected

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7
Q

Outline neuropathology of Vascular dementia

A

Decreased blood flow to brain owing series small strokes

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8
Q

Outline proportion dementia cases accounted for by vascular dementia

A

20-30%

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9
Q

Outline symptoms of frontotemporal dementia

A

Changes in personality and mood

Difficulties with language

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10
Q

Outline neuropathology of frontotemporal dementia

A

Damage limited to frontal and temporal lobes

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11
Q

Outline proportion dementia cases explained by frontotemporal dementia

A

5-10%

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12
Q

Outline symptoms of dementia with Lewy bodies

A

Similar Alzheimer’s

Also hallucinations, tremors

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13
Q

Outline neuropathology of dementia with Lewy bodies

A

Cortical Lewy bodies (of protein a-synuclein) inside neurons

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14
Q

Outline proportion dementia cases be explained by dementia with Lewy bodies

A

<5%

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15
Q

Outline statistics of dementia between 2015-2050

A

Low income countries increase 264%
227% upper middle
223% lower middle
116% high income

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16
Q

What regions have most people living with dementia

A

East Asia - 9.8million

Western Europe - 7.5million

South Asia - 5.1million

North America - 4.8million

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17
Q

What will the global increase in number people with dementia be from 2018 to 2050

A

From 50 million 2018 to
152 million 2050
204% increase

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18
Q

Main reason increase in dementia

A

Living longer

Biggest impact is age

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19
Q

Every day symptoms

A

Regularly misplacing items
Problems everyday tasks - eating
Disorientation - confused, don’t recognise familiar streets
Difficulty finding words - inappropriate words
Diminished judgement - dressing inappropriately, unaware danger
Mood or behavioural problems - depression, agitation, irritability, lack care

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20
Q

How does DSM-V categories Alzheimer’s Disease

A

Evidence causative genetic mutation from family history or genetics OR
All 3 of:
1. Decline memory and learning based neuropsychological testing

  1. Steadily progressive gradual decline cognition
  2. No evidence other causes
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21
Q

Outline stage 1 of Alzheimer’s Disease

A 
Early, less energy and spontaneity 
No one notices 
Minor memory loss, mood swings
Slow learn and react 
Start shy away and prefer the familiar 
Affect job performance 
Confused, lost easily and exercises poor judgement
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22
Q

Outline stage 2 of Alzheimer’s Disease

A

May need assistance more complicated activities
Speech and understanding slower, lose train thought
Lost whilst travelling, forget pay bills
Aware loss control depressed, restless
Distant past recalled. Recent events difficult remember
Affect comprehension where are, day, time
Invent words not recognise familiar faces

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23
Q

Outline stage 3 of Alzheimer’s Disease

A 
Lose ability chew and swallow 
Essence person vanishing 
Memory very poor no one recognisable 
Lose bowel and bladder control 
Need constant care 
Vulnerable pneumonia, infection, illness
Respiratory problems worsen - bedridden 
Terminal
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24
Q

What happens to the brain as dementia progresses

A

Healthy: lots crevices
As develop fewer crevices and folds, shrinkage, loss gray matter
Cells destroyed

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25
Q

Outline histopathological feature of dementia Amyloid Plaques

A

Small insoluble deposits around neurons.

Start hippocampus and entorhinal cortex = responsible spatial learning and memory

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26
Q

Outline neurolitic plaques-dystrophic as histopathological features Schiz

A

Neurotic plaques-dystrophic and degenerating neuronal processes. Large bulbous structures

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27
Q

Outline how to diffuse amyloid plaques as histopathological features of dementia

A

Diffuse plaques - contain b-amyloid Ab protein fibres some unstructured amyloid earliest

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28
Q

Outline histopathological features of Neurofibrillary Tangles of dementia

A

Helical filaments

Paired filaments wound around each other, helical arrangement

Mainly abnormal tau (protein) also immunoreactive number other substances

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29
Q

Outline Perrin et al 2009 trends in plaques and tangles

A

Increase amyloid plaques and neurofibrillary tangles

Decrease neuronal integrity

30
Q

Outline formation of Plaques according to Perrin et al 2009

A

Formed protein molecule amyloid precursor protein molecule APP
Number enzymes come along and cut this protein unusual position
Liberating small fragment - peptideA-B insoluble doesn’t break down
Fathers up forms A-B plaques

31
Q

What peptide does Perrin et al 2009 identify leading dementia

A

Peptide A-B

32
Q

What new treatment does Perrin et al 2009 identify about plaques of dementia

A

Enzymes - secretases

New treatment try and stop action of enzymes

33
Q

Do plaques correlate dementia Blessed Tomlinson and Roth 1968

A 
Correlation between plaque number and cognition 
Correlation not significant 
Everyone low test score had Plaques 
Some good test scores did 
People without dementia had plaques
34
Q

Outline Amyloid Hypothesis and Alzheimer’s Disease

A

AD = amyloid plaques mainly aggregated Ab derived APP

Mutations near chromosome 21 = contains APP gene discovered in familial AD

Abnormal levels Ab in cerebrospinal fluid

35
Q

Outline link between Down syndrome and amyloid hypothesis of Alzheimer’s disease

A

Down syndrome extra copy of chromosome 21

Invariably develop AD

36
Q

Outline Sunderland et al 2003 reduced Ab and increased Tau In cerebrospinal fluid AD

A

Decreased Ab - because Ab being deposited in plaques - amyloid sink
Sample CSF
Increase in Tau

37
Q

Outline Amyloid Cascade Hypothesis by Citron 2004 on Ab42

A

Overproduction, decreases clearance or enhanced
aggregation Ab42 peptides

Ab42 oligomerisation and depositing as diffuse plaques

Subtle effects of Ab42 oligomers on synapses

38
Q

Outline Amyloid Cascade Hypothesis by Citron 2004 on microglial and astrocytic activation

A

Progressive synaptic and neuritic injury
Altered neuronal iconic homeostasis, oxidative injury
Altered kinase/phosphatase activities -> tangles
Widespread neuronal/neuritic dysfunction and cell death transmitter deficits

39
Q

Outline Karran et al 2011 aggregating stressors on Alzheimer’s dementia

A 
APP ->
Ab42 aggregation ->
Subtle forms oligometric and deposited amyloid B peptide ->
Aggregate stress ->
PHF formation ->
Neuronal dysfunction and death ->
Dementia
40
Q

Outline age as cause of AD

A

Number people Disease approx doubles every 5 years after 65

41
Q

Outline family history as cause of AD

A

Specific genetic mutations
Apolipoprotein E
Presenelin
Downs Syndrome Ch21

42
Q

Outline Gender as cause of AD

A

Higher prevalence in females after 75 years

Significant increase 83 years

43
Q

What are the 2 forms of AD

A
  1. Familial - known genetic mutations number families <10%

2. Sporadic - apolipoprotein only known risk factor

44
Q

Outline Familial AD

A 
Rare, <10% 
Early onset. Before 65 years. 
Caused gene mutations in chromosomes
If inherited almost always develop AD 
Autosomal dominant inheritance 
50/59 chance developing if 1 parent had it
45
Q

What gene mutations on chromosomes contribute to familial AD

A

1 presenelin 1

14 presenelin 2

21 amyloid precursor protein - APP

46
Q

Outline Bateman et al 2012 Ab peptide visualised in AD

A

PET study inject radio active dye
Visualised Ab peptide

Significant Ab deposition in caudate and cortex in mutation carries more 10 years before expected symptom onset

Ab deposition throughout Cortex and neostriatum at estimated time symptom onset

47
Q

What is an alleles

A

Different forms same gene
Two or more alleles shape each human trait
Each person 2 alleles one from each parent

48
Q

Outline the ApoE gene

A

Gene chromosome 19 invoked making ApoE
Helps carry cholesterol in bloodstream
Influence age of onset
Not sole cause AD. No cause and effect

49
Q

Outline ApoE and AD

A

Chromosome 19 3 common forms E2, E3, E4
Having 1-2 copies E4 increases risk AD but not certain
Rarer E2 lower risk AD
E3 most common plays neutral role

Exact degree risk AS can not be determined ApoE status

50
Q

Is ApoE better used in groups or individuals

A

Used identify study volunteers May be higher risk AD
Look early brain changes
Better large groups not determining one persons individual risk
Predictive screening

51
Q

Outline Nun study by Snowdon et al sample

A 
678 sisters Norte Dame 
Ages 75-103 
Live together, similar lifestyles 
Like keeping environment constant 
Pure sample
52
Q

How were the nuns tested in Snowdon et al study

A

Joined convent had write full autobiography their lives

Tested annually on cognitive function and health

Post mortem plaques and tangles

53
Q

Outline individuals with overt dementia in nun study Swindon et al

A

Signs infarct stroke addition plaques and tangles
Oxygen cut off to brain
Independent having amyloid

54
Q

Outline the affects of nuns being active and engaging in hobbies in Swindon et al study

A

Cognitive abilities near perfect

How functioning daily life and independence prevent cognitive losses

55
Q

Outline association between autobiographies and the nuns in Swindon et als study

A

Whose who were positive in their autobiographies were more likely to live longer

56
Q

Outline findings of plaques and tangles in Swindon et als study

A

Even those cognitively functioning brains full of plaques and tables

Some cognitive impairment no plaques or tangles

57
Q

Outline prevalence of dementia those with AD in Swindon et als study

A

93% infarcts in areas basal ganglia, thalamus

57% without infarcts

58
Q

Outline steps 1-3 of Acetylcholine NT important for memory

A
  1. Broken down in synapse by acetylcholinesterase - current drugs inhibit enzyme
  2. Acetyl CoA and choline join
  3. Acetylcholine formed
59
Q

Outline steps 4 - 7 of Acetylcholine NT important for memory

A
  1. Acetylcholine packages leave axon
  2. Acetylcholine leaves neuron cross synapse
  3. Acetylcholine reaches other side synapse bonds to receptor causing message be sent
  4. After message sent, acetylcholinesterase released into synapse
60
Q

What is Acetylcholinesterase

A

Breaks down Acetylcholine

Inactivating it

61
Q

Outline Cholinergic System

A

Main areas degenerates initially nucleus of meynert

62
Q

What are the 2 kinds of Acetylcholine Receptoes

A
  1. Nicotinic - nicotine agonist
  2. Muscarinic - receptors everywhere in brain.
    Particularly midbrain, medulla, pons, brain stem, - attention, sleep wake
63
Q

Outline Cholinergic Hypothesis of Geriatric memory dysfunction by Bartus 1982

A
  1. Functional disturbance aged and demented people
  2. Disturbances role memory loss and cognitive problems. Like scopolamine - used child birth amnesiac forget experience
  3. Restoration Cholinergic function significantly reduce severity cognitive loss
64
Q

Outline evidence for Cholinergic Hypothesis

A

Correlation severity dementia and cholineacetyltransferase activity - chAT
And cell loss in Cholinergic cell containing area nucleus basalis Meynert = associated memory and cognitive impairment

Cholinergic antagonists induce amnesia people and animals

65
Q

Treatment of AD Donepezil

A

Distinction between palliative and preventative

Treatment donepezil = aricept
Acetylcholinesterase inhibitor increasing level acetylcholine synapse

66
Q

Treatment of AD prototype ache inhibitors Physostigmine

A

Prototype ache inhibitors physostigmine and tacrine improves cognitive function

Minimal efficacy: side effects

67
Q

What is the Mini Mental State Examination - MMSE

A 
24+ indicates normal cognition 
Blunt 
Not very discriminating 
Looked changes of baseline 
Study over a year
68
Q

Effects of Donepezil drug on Mini Mental State Examination

A

Placebo - control AD scores decreases -2.5

Taking Donepezil drug - still decline not same rate - 0.5

69
Q

What aspects can be modelled of AD in animals

A

Selective lesion neurochemical pathways

Cholinergic antagonists

Aged animals

Transgenic animals

70
Q

Outline plaques in brains of Transgenic mice containing mutations in APP and presenelin gene

A

Induce mutation
Increase plaques over time
10 months - 2 plaques
19 months - multiple plaques

71
Q

Outline behavioural test of water maze

A

Measures spatial memory - find safe platform hidden
Record pattern and time find platform
Use room cues create cognitive map - uses hippocampus
Escape latency measured differing attempts

72
Q

Outline Moran 1995 study on mice expressing human amyloid precursor protein with mutation known familial AD

A

Water maze
Once trained find platform remove platform
Measure where go
No mutation - return straight where platform was
Mutation - random pattern searching

Neuroscience (12 decks)

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