Week 7 - Pathophysiology of Dementia and Stroke Flashcards
Alzheimer’s Disease (AD) Background INFO
inc. risk factors
- Several types of dementia but AD is most common type of dementia
- Higher incidence in women
- A neurodegenerative disease (affecting brain)
- Symptoms are only seen when in late MCI stage
- this is when AD is diagnosed, by then damage to brain is extensive
RISK FACTORS:
- Age (BIGGEST risk, >65 yo)
- immune cell function decline = can’t get rid of amyloid-β
- Genetic inheritance
- down syndrome
- Have learning disabilities
- mutation in APOE4 transporter = buildup of amyloid-β
- Female
- Ethnic minority
- lifestyle / general health
Whats the cause of Alzheimer’s Disease
- Formation of INSOLUBLE amyloid-β plaque
- amyloid precursor protein (APP) is processed into amyloid-β
- found extracellularly (outside cell + in mitochondria)
- Formation of neurofibrillary tangles
- tangles formed from Tau (protein)
- found intracellularly (inside cell)
NOTE:
- Tau and Amyloid-β are hallmarkers / diagnostic features for AD
Whats the 2 types of Alzheimer’s Disease
Early onset AD
- Occurs in 35-65
- is a small % of AD cases
- CAUSE: mutations in genes encoding APP, and presenilin 1 or 2
- mutations affect production of amyloid-β
Late onset AD
- Occurs in >65
- majority (90%) of cases
- CAUSE: unknown, studies suggest genetic (involvement of apolipoprotein E - ApoE)
- ApoE (produced by astrocytes) binds to amyloid-β + regulates / helps aggregation
- have diff. versions of ApoE
What are the symptoms of AD
2 main types of symptoms
- Cognitive (relates to brain)
Memory impairment is most PROMINENT feature- memory loss
- disorientation
- misplacing things
- confusion
- Problems perfoming ADL (washing, dressing, eating)
- Loss of speech / Language
- Mood and behaviour
- Non-cognitive (is BPSD)
BPSD - Behavioral and psychological symptoms of dementia
- Depression
- Psychosis
- Mania
- Agitation
- Aggression
- Appathy
NOTE: seen in later stages + is due to widespread degeneration
How is AD diagnosed
- ICD-11
- Specialist conducts cognition tests
- i.e. memory tests - PET scans
- Blood based biomarkers
- Post-mortem (visible plaques)
List biomarkers specific to AD
- Tau neurofibrillary tangles
- Amyloid-β plaques
- amyloid / tau in brain can only be measured via PET scan
- usually measure them in CSF - Astrocytes and Microgial (immune cells)
- MRI brain structure
- Clincial function
- Cognitive checks
AIM: identify changes in biomarkers sooner = earlier diagnosis
- as patients are coming in with symptoms in late stage MCI = extensive brain damage
Explain amyloid precursor protein (APP) processing (in brain)
APP is a membrane bound peptide
- APP is cut by alpha (α) and gamma (γ) secretases producing a protein that helps with learning and memory
- APP is found in plasma membrane
- BUT when APP is cut by beta (β) and γ secretases = amyloid-β is produced
- amyloid-β can aggregate within brain
Amyloid precursor protein (APP) is processed into amyloid-β = leads to AD
- APP is found on chromosome 21
- people with down’s syndrom have extra copy of APP = show symptoms of AD by 40
APP is expressed on cells in brain + body
Explain the mechanism of amyloid-β plaque production
amyloid-β = amyloid-beta
- Start with APP
- APP is processed into amyloid-β monomer
- The monomers begin to aggregate = oligomer formed
- toxic to brain and disrupts neuronal function - Amyloid-β oligomers aggregate = insoluble amyloid-β plaque formed
- Plaques cause cell death, brain inflammation, synapse disruption
What is the amyloid cascade hypothesis
That the neurodegeneration in AD is caused by abnormal accumulation of amyloid- β plaques / protein in areas of the brain
The neurofibrillary tangles, cell loss, vascular damage, and dementia follow as a direct result of this deposition of amyloid-β
How might amyloid-β be removed from the brain
Efflux transporters on BBB / apical membrane
- remove it from brain and into blood
4 Transporters:
1. P-gp
2. BCRP
3. MRP5
4. APOE4
- mutation to this transporter is seen in late onset AD = unable to transport amyloid-β
What 2 ways can cell death (in brain occur)
- APP processing leading to plaque formation
- APP processing leading to formation of N-APP
- APP is processed into N-APP
- N-APP binds to neuronal death receptor 6 = cell death
What role does Tau have in AD
Tau = a protein
Formation of neurofibrillary tangles
- when neurodegeneration is seen
On healthy neurone will have Tau associated to microtubules
- phosphorylated Tau binds to microtububles = stabilises them
In AD Tau is hyperphosphorylated = unable to bind to tubules properly = no stabilisation
- = disrupted transport system = cell death
- hyperphosphorylated Tau aggregates = formation of tangles
Microtubules:
- transport vesicles (nutrients) in cell
- provide strctural support
What are the 2 current treatments for AD
- NO CURE
- MORE info in week 8 ‘ all dementia treatments’ flashcars
Managing mild-moderate AD:
- Use acetylcholinesterase inhibitors
- includes Rivastigmine, Galantamine, Donepezil HCl
Managing moderate-severe AD:
- Mematamine HCl
What are the 3 novel / new treatments for AD
- Secretase modulaters
- ↓ amyloid-β overproduction
- inhibits β-secretase (BACE1)
- ISSUE = β-secretase is involved in other pathways = SE
- getting required level into brain is difficult - Anti-aggregants
- prevent amyloid-β aggregating
- getting required level into brain is difficult - Immunotherapies
- clear amyloid-β deposits
- monoclonal antibodies that target diff. amyloid-b structures (NOT plaques)
- MoA: bind to structures = more noticable to immune cells = destroyed
- when plaques were targetted + broken down = toxic oligomers formed = even more harm
- used as immune cells function may be declining due to age
Stroke Background INFO
Types of strokes,
- leading acsue of diability
- 3rd most common cause of death
- has a high mortality rate
- 80% of strokes are preventable
- Have 2 types
- Ischaemic (MOST COMMON)
- blood supply is disrupted due clot or plaque - Haemhorrhagic
- bleeding in the brain
- Ischaemic (MOST COMMON)
