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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
Outline histopathological feature of dementia Amyloid Plaques
Small insoluble deposits around neurons. | Start hippocampus and entorhinal cortex = responsible spatial learning and memory
26
Outline neurolitic plaques-dystrophic as histopathological features Schiz
Neurotic plaques-dystrophic and degenerating neuronal processes. Large bulbous structures
27
Outline how to diffuse amyloid plaques as histopathological features of dementia
Diffuse plaques - contain b-amyloid Ab protein fibres some unstructured amyloid earliest
28
Outline histopathological features of Neurofibrillary Tangles of dementia
Helical filaments Paired filaments wound around each other, helical arrangement Mainly abnormal tau (protein) also immunoreactive number other substances
29
Outline Perrin et al 2009 trends in plaques and tangles
Increase amyloid plaques and neurofibrillary tangles | Decrease neuronal integrity
30
Outline formation of Plaques according to Perrin et al 2009
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
What peptide does Perrin et al 2009 identify leading dementia
Peptide A-B
32
What new treatment does Perrin et al 2009 identify about plaques of dementia
Enzymes - secretases | New treatment try and stop action of enzymes
33
Do plaques correlate dementia Blessed Tomlinson and Roth 1968
``` 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
Outline Amyloid Hypothesis and Alzheimer’s Disease
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
Outline link between Down syndrome and amyloid hypothesis of Alzheimer’s disease
Down syndrome extra copy of chromosome 21 | Invariably develop AD
36
Outline Sunderland et al 2003 reduced Ab and increased Tau In cerebrospinal fluid AD
Decreased Ab - because Ab being deposited in plaques - amyloid sink Sample CSF Increase in Tau
37
Outline Amyloid Cascade Hypothesis by Citron 2004 on Ab42
Overproduction, decreases clearance or enhanced aggregation Ab42 peptides Ab42 oligomerisation and depositing as diffuse plaques Subtle effects of Ab42 oligomers on synapses
38
Outline Amyloid Cascade Hypothesis by Citron 2004 on microglial and astrocytic activation
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
Outline Karran et al 2011 aggregating stressors on Alzheimer’s dementia
``` APP -> Ab42 aggregation -> Subtle forms oligometric and deposited amyloid B peptide -> Aggregate stress -> PHF formation -> Neuronal dysfunction and death -> Dementia ```
40
Outline age as cause of AD
Number people Disease approx doubles every 5 years after 65
41
Outline family history as cause of AD
Specific genetic mutations Apolipoprotein E Presenelin Downs Syndrome Ch21
42
Outline Gender as cause of AD
Higher prevalence in females after 75 years | Significant increase 83 years
43
What are the 2 forms of AD
1. Familial - known genetic mutations number families <10% | 2. Sporadic - apolipoprotein only known risk factor
44
Outline Familial AD
``` 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
What gene mutations on chromosomes contribute to familial AD
1 presenelin 1 14 presenelin 2 21 amyloid precursor protein - APP
46
Outline Bateman et al 2012 Ab peptide visualised in AD
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
What is an alleles
Different forms same gene Two or more alleles shape each human trait Each person 2 alleles one from each parent
48
Outline the ApoE gene
Gene chromosome 19 invoked making ApoE Helps carry cholesterol in bloodstream Influence age of onset Not sole cause AD. No cause and effect
49
Outline ApoE and AD
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
Is ApoE better used in groups or individuals
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
Outline Nun study by Snowdon et al sample
``` 678 sisters Norte Dame Ages 75-103 Live together, similar lifestyles Like keeping environment constant Pure sample ```
52
How were the nuns tested in Snowdon et al study
Joined convent had write full autobiography their lives Tested annually on cognitive function and health Post mortem plaques and tangles
53
Outline individuals with overt dementia in nun study Swindon et al
Signs infarct stroke addition plaques and tangles Oxygen cut off to brain Independent having amyloid
54
Outline the affects of nuns being active and engaging in hobbies in Swindon et al study
Cognitive abilities near perfect | How functioning daily life and independence prevent cognitive losses
55
Outline association between autobiographies and the nuns in Swindon et als study
Whose who were positive in their autobiographies were more likely to live longer
56
Outline findings of plaques and tangles in Swindon et als study
Even those cognitively functioning brains full of plaques and tables Some cognitive impairment no plaques or tangles
57
Outline prevalence of dementia those with AD in Swindon et als study
93% infarcts in areas basal ganglia, thalamus 57% without infarcts
58
Outline steps 1-3 of Acetylcholine NT important for memory
1. Broken down in synapse by acetylcholinesterase - current drugs inhibit enzyme 2. Acetyl CoA and choline join 3. Acetylcholine formed
59
Outline steps 4 - 7 of Acetylcholine NT important for memory
4. Acetylcholine packages leave axon 5. Acetylcholine leaves neuron cross synapse 6. Acetylcholine reaches other side synapse bonds to receptor causing message be sent 7. After message sent, acetylcholinesterase released into synapse
60
What is Acetylcholinesterase
Breaks down Acetylcholine | Inactivating it
61
Outline Cholinergic System
Main areas degenerates initially nucleus of meynert
62
What are the 2 kinds of Acetylcholine Receptoes
1. Nicotinic - nicotine agonist 2. Muscarinic - receptors everywhere in brain. Particularly midbrain, medulla, pons, brain stem, - attention, sleep wake
63
Outline Cholinergic Hypothesis of Geriatric memory dysfunction by Bartus 1982
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
Outline evidence for Cholinergic Hypothesis
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
Treatment of AD Donepezil
Distinction between palliative and preventative Treatment donepezil = aricept Acetylcholinesterase inhibitor increasing level acetylcholine synapse
66
Treatment of AD prototype ache inhibitors Physostigmine
Prototype ache inhibitors physostigmine and tacrine improves cognitive function Minimal efficacy: side effects
67
What is the Mini Mental State Examination - MMSE
``` 24+ indicates normal cognition Blunt Not very discriminating Looked changes of baseline Study over a year ```
68
Effects of Donepezil drug on Mini Mental State Examination
Placebo - control AD scores decreases -2.5 Taking Donepezil drug - still decline not same rate - 0.5
69
What aspects can be modelled of AD in animals
Selective lesion neurochemical pathways Cholinergic antagonists Aged animals Transgenic animals
70
Outline plaques in brains of Transgenic mice containing mutations in APP and presenelin gene
Induce mutation Increase plaques over time 10 months - 2 plaques 19 months - multiple plaques
71
Outline behavioural test of water maze
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
Outline Moran 1995 study on mice expressing human amyloid precursor protein with mutation known familial AD
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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