Lecture 10 - Alzheimers Disease Flashcards
Outline Alois Alzheimer 1901
Progressive neurodegenerative Disorder
Presented case Auguste D 1907
Outline Auguste D 1902
Profound cognitive and behavioural impairments
Difficulty memory, recognition, learning
Found strange deposits - Augustus triangles of filaments
1/3 cortical cells died off some way
Outline symptoms of Alzheimer’s
Impaired memory
Depression
Poor judgements
Confusion
Outline Neuropathology of Alzheimer’s Disease
Amyloid plaques
Neurofibrillary tangles
What proportion dementia cases are Alzheimer’s disease
50-80%
Outline symptoms of Vascular dementia
Similar Alzheimer’s
But memory less affected
Outline neuropathology of Vascular dementia
Decreased blood flow to brain owing series small strokes
Outline proportion dementia cases accounted for by vascular dementia
20-30%
Outline symptoms of frontotemporal dementia
Changes in personality and mood
Difficulties with language
Outline neuropathology of frontotemporal dementia
Damage limited to frontal and temporal lobes
Outline proportion dementia cases explained by frontotemporal dementia
5-10%
Outline symptoms of dementia with Lewy bodies
Similar Alzheimer’s
Also hallucinations, tremors
Outline neuropathology of dementia with Lewy bodies
Cortical Lewy bodies (of protein a-synuclein) inside neurons
Outline proportion dementia cases be explained by dementia with Lewy bodies
<5%
Outline statistics of dementia between 2015-2050
Low income countries increase 264%
227% upper middle
223% lower middle
116% high income
What regions have most people living with dementia
East Asia - 9.8million
Western Europe - 7.5million
South Asia - 5.1million
North America - 4.8million
What will the global increase in number people with dementia be from 2018 to 2050
From 50 million 2018 to
152 million 2050
204% increase
Main reason increase in dementia
Living longer
Biggest impact is age
Every day symptoms
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
How does DSM-V categories Alzheimer’s Disease
Evidence causative genetic mutation from family history or genetics OR
All 3 of:
1. Decline memory and learning based neuropsychological testing
- Steadily progressive gradual decline cognition
- No evidence other causes
Outline stage 1 of Alzheimer’s Disease
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
Outline stage 2 of Alzheimer’s Disease
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
Outline stage 3 of Alzheimer’s Disease
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
What happens to the brain as dementia progresses
Healthy: lots crevices
As develop fewer crevices and folds, shrinkage, loss gray matter
Cells destroyed
Outline histopathological feature of dementia Amyloid Plaques
Small insoluble deposits around neurons.
Start hippocampus and entorhinal cortex = responsible spatial learning and memory
Outline neurolitic plaques-dystrophic as histopathological features Schiz
Neurotic plaques-dystrophic and degenerating neuronal processes. Large bulbous structures
Outline how to diffuse amyloid plaques as histopathological features of dementia
Diffuse plaques - contain b-amyloid Ab protein fibres some unstructured amyloid earliest
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
Outline Perrin et al 2009 trends in plaques and tangles
Increase amyloid plaques and neurofibrillary tangles
Decrease neuronal integrity
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
What peptide does Perrin et al 2009 identify leading dementia
Peptide A-B
What new treatment does Perrin et al 2009 identify about plaques of dementia
Enzymes - secretases
New treatment try and stop action of enzymes
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
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
Outline link between Down syndrome and amyloid hypothesis of Alzheimer’s disease
Down syndrome extra copy of chromosome 21
Invariably develop AD
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
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
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
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
Outline age as cause of AD
Number people Disease approx doubles every 5 years after 65
Outline family history as cause of AD
Specific genetic mutations
Apolipoprotein E
Presenelin
Downs Syndrome Ch21
Outline Gender as cause of AD
Higher prevalence in females after 75 years
Significant increase 83 years
What are the 2 forms of AD
- Familial - known genetic mutations number families <10%
2. Sporadic - apolipoprotein only known risk factor
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
What gene mutations on chromosomes contribute to familial AD
1 presenelin 1
14 presenelin 2
21 amyloid precursor protein - APP
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
What is an alleles
Different forms same gene
Two or more alleles shape each human trait
Each person 2 alleles one from each parent
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
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
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
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
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
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
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
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
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
Outline prevalence of dementia those with AD in Swindon et als study
93% infarcts in areas basal ganglia, thalamus
57% without infarcts
Outline steps 1-3 of Acetylcholine NT important for memory
- Broken down in synapse by acetylcholinesterase - current drugs inhibit enzyme
- Acetyl CoA and choline join
- Acetylcholine formed
Outline steps 4 - 7 of Acetylcholine NT important for memory
- Acetylcholine packages leave axon
- Acetylcholine leaves neuron cross synapse
- Acetylcholine reaches other side synapse bonds to receptor causing message be sent
- After message sent, acetylcholinesterase released into synapse
What is Acetylcholinesterase
Breaks down Acetylcholine
Inactivating it
Outline Cholinergic System
Main areas degenerates initially nucleus of meynert
What are the 2 kinds of Acetylcholine Receptoes
- Nicotinic - nicotine agonist
- Muscarinic - receptors everywhere in brain.
Particularly midbrain, medulla, pons, brain stem, - attention, sleep wake
Outline Cholinergic Hypothesis of Geriatric memory dysfunction by Bartus 1982
- Functional disturbance aged and demented people
- Disturbances role memory loss and cognitive problems. Like scopolamine - used child birth amnesiac forget experience
- Restoration Cholinergic function significantly reduce severity cognitive loss
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
Treatment of AD Donepezil
Distinction between palliative and preventative
Treatment donepezil = aricept
Acetylcholinesterase inhibitor increasing level acetylcholine synapse
Treatment of AD prototype ache inhibitors Physostigmine
Prototype ache inhibitors physostigmine and tacrine improves cognitive function
Minimal efficacy: side effects
What is the Mini Mental State Examination - MMSE
24+ indicates normal cognition Blunt Not very discriminating Looked changes of baseline Study over a year
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
What aspects can be modelled of AD in animals
Selective lesion neurochemical pathways
Cholinergic antagonists
Aged animals
Transgenic animals
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
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
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
