Dementia And Stroke🤷♀️ Flashcards
(52 cards)
Dementia and Alzheimer’s Disease (AD)
Overview
Dementia = memory/thinking decline
Progressive neurodegenerative disease → worsening symptoms over time.
Alzheimer’s Disease (AD) is the most common type
Main risk factor: Age (1 in 11 people over 65); higher incidence in females.
Other types: Vascular Dementia (VD), Dementia with Lewy Bodies (DLB),
Alzheimer’s Disease
Formation of insoluble amyloid-beta plaques
Located extracellularly & in mitochondria
——-
Amyloid-beta (Aβ) plaques → extracellular protein aggregates.
Tau tangles → intracellular aggregates of hyperphosphorylated tau. (Tau protein)
Types of Alzheimer’s Disease
Early-Onset AD:
Onset ~30s–40s
Linked to mutations in:
APP (Amyloid Precursor Protein)
Presenilin 1 & 2 (components of γ-secretase)
Mutations are thought to affect production of amyloid-beta (AB1-42). Insoluble protein so aggregates in brain
Late-Onset AD:
Cause unknown, but risk factor includes:
APOE ε4 allele (less efficient at regulating Aβ aggregation)
Produced by astrocytes
ApoE Transports cholesterol to neurons.
ApoE binds Amyloid-beta and may regulate aggregation
ApoE*4 form of gene-less effective- risk factor for AD!!!!
ApoE=apolipoprotein E
AD hypothesis: Amyloid hypothesis
• Amyloid hypothesis:
• Amyloid precursor protein (AAP) is processed to Amyloid-B, leading to AD?
• Evidence:
- APP gene on Chromosome 21
- Down’s syndrome - trisomy 21
- Extra APP gene !!!
- These individuals invariably exhibit AD
characteristics by 40 yo
—-
AD caused by accumulation of Aβ from APP misprocessing.
🔸 APP Processing
1) Alpha + Gamma secretase: ✅
Produces non-toxic fragment (supports learning & memory)
No amyloid-beta formed
2) Beta + Gamma secretase:
Produces Aβ1–40 and Aβ1–42
Aβ1–42 = more insoluble and prone to aggregation
Happens when beta involved in cutting
APP cleavage by beta-secretase and gamma-secretase produces Amyloid-Beta which is 42 amino acids in length
Amyloid-Beta aggregation
🔸 Aggregation Process
Monomers → aggregate> Oligomers (toxic) → disrupts neuron function
Plaques (insoluble)>
Leads to:
Neuroinflammation
Synapse dysfunction
Neuronal death
N-terminal peptide of APP can bind Death Receptor 6, triggering further cell death.
Amyloid clearance & Amyloid-Beta transport
Amyloid-Beta transporter out of BBB endothelial cells by efflux transporters - may help amyloid-beta removal
Efflux transporters at the blood–brain barrier help remove Aβ:
P-glycoprotein (PGP)
BCRP
MRP5
Studies using pig brain barrier models confirmed transporter role in Aβ clearance.
AD hypothesis: Tau hypothesis
Microtubules:scaffolding system that readouts vesicles (nutrients, molecules) in cell
Phosphorylated Tau (Tau protein) stabilizes microtubules in neurons.
Hyperphosphorylated tau:
Unable to stabilise microtubules
Can’t bind microtubules → disrupted axonal transport
Cellular transport system disrupted leading to cell death
Hyperphosphorylated Tau aggregates into neurofibrillary tangles (characteristic of AD)
Leads to neuronal dysfunction and death
Current Treatments for AD
No cure; current therapies are symptomatic:
Mild–Moderate AD: Acetylcholinesterase inhibitors: -Donepezil HCl
- Galantamine
- Rivastigmine
Moderate–Severe AD: Memantine HCL (Glutamate receptor antagonist)
Emerging therapies:
Monoclonal antibodies targeting Aβ (e.g., Lecanemab, Donanemab). Target Amyloid-ß so it is recognised by the immune system.
Aim to reduce plaque burden via immune clearance.
Two types of stroke
Two types:
Ischaemic stroke (80%): Blockage → lack of oxygen/nutrients → brain cell death. Blood supply disrupted. Clot, plaque
Haemorrhagic stroke: Bleeding into brain → pressure, damage.
Ischemic stroke treatment
Tissue plasminogen activator (Alteplase) : thrombolytic effect
Dissolves clots.
Must be given within 4.5 hours of symptom onset.
Haemorrhagic stroke treatment
Surgery: craniotomy
Repair blood vessel
Clot removal
Manage blood pressure (ACE inhibitors, beta blockers) , lifestyle changes (diet/ exercise) , BP control
Causes of Ischaemic Stroke
Atherosclerosis → plaque rupture → clot formation.
Clot blocks cerebral arteries, causing brain infarction.
MRI: central core of irreversible damage (umbra) surrounded by penumbra (potential recovery).
Stroke
• Cells deprived of nutrients and 0, leading to cell death, brain damage.
• Umbra - area of irrecoverable damage
• Penumbra - area of potential recovery
Inflammatory Response in Stroke
Ischaemia triggers inflammation → production of cytokines.
Key mediator: Interleukin-1β (IL-1β):
Binds IL-1 receptor → activates NF-κB pathway → ↑ production of:
IL-6
TNF-α
These further promote brain inflammation and neuronal death. Exacerbates brain damage.
Strobe treatment: IL-1 Receptor Antagonist (Anakinra)
Blocks IL-1 receptor (binds on cell surface) , prevents signaling, preventing IL-1β from activating inflammation.
In animal models:
Reduces infarct volume (area of brain damage).
Potential for neuroprotection in early stroke intervention.
Summary of Key Concepts
AD pathogenesis involves Aβ aggregation and tau dysfunction.
APP can be processed down toxic or non-toxic pathways depending on enzymes involved.
Efflux transporters play a role in removing Aβ from the brain.
Stroke results in inflammatory cascades that worsen damage — IL-1β is a major target.
Treatments are limited but evolving (e.g., monoclonal antibodies in AD, anakinra in stroke models).
AD symptoms
Two main types of symptoms have been a focus for the treatment in dementia and related disorders
1. Cognitive Deficits
- Non-cognitive features (Behavioural and Psychological Symptoms of
Dementia [BPSD) consisting of affective, psychotic and behavioural disturbances
• Depression, Psychosis, Agitation, Apathy, Insomnia, Sexual disinhibition…..
• Up to 90% of people with dementia will develop BPSD at some point in their illness.
• Increase in caregiver burden … Precipitate institutionalisation..- cost of care ….
————
Major symptoms:
Cognitive decline: memory loss, disorientation, misplacing objects.
Non-cognitive symptoms: agitation, psychosis, depression (appear later).
AD risk factors
Age = strongest risk factor (↑ risk every 5 years after age 65).
Age, female sex, cardiovascular disease, Down syndrome.
Social isolation, sensory impairment, comorbidities common.
Mild Cognitive Impairment (MCI) is a risk factor.
Genetics:
Early-onset AD (EOAD): Linked to mutations in:
APP, Presenilin-1, Presenilin-2
Late-onset (sporadic) AD: Multifactorial, associated with APOE4 (↓ amyloid clearance).
Lifestyle: Vascular health, physical activity, diet influence risk.
Can cause depersonalisation and complete dependence
AD pathophysiology
Key concept:
2 abnormal proteins build in the brain
Form plaques / tangles
Beta Amyloid: plaques
Tau: tangles in neurones made from the tau proteins.
Tau is normally a protein that keeps neurons cytoskeleton stable. Hyperphosphorylation of tau = disrupts neurone causing it to die
Amyloid hypothesis : Amyloid beta aggregation triggers cascade of events reduction in AD
🔹 Amyloid Cascade Hypothesis
Central hypothesis explaining AD pathology.
APP (Amyloid Precursor Protein) → cleaved via:
Non-amyloidogenic pathway:
α-secretase + γ-secretase → harmless, neurotrophic peptides.
Bad > Amyloidogenic pathway:
β-secretase + γ-secretase → Aβ1–40 or Aβ1–42.
Aβ1–42 is more insoluble and prone to aggregation.
Amyloid olgimers are toxic to neurones. Induces inflammation in brain. (Aggregation of amyloid monomers causes this) . Widespread neuronal dysfunction and death.
🔹 Aggregation Cascade
Monomers → Oligomers (toxic) → Fibrils → Amyloid plaques (extracellular).
Aβ oligomers = most neurotoxic → trigger inflammation + neuron damage.
Induces hyperphosphorylation of tau → tau tangles (intracellular).
🔹 Tau Pathology
Tau stabilizes microtubules in neurons.
Hyperphosphorylated tau:
Loses function → cytoskeletal collapse.
Aggregates into neurofibrillary tangles.
Causes disrupted transport + neuronal death.
AD Biomarkers & Diagnosis
Imaging & Biomarkers
Amyloid PET scans: detect amyloid buildup (very expensive, limited access).
Tau PET: newer, used in research.
CSF biomarkers:
Aβ, tau, phosphorylated tau, inflammatory cytokines.
Invasive and technically demanding.
MRI: Detects structural brain changes, hippocampal atrophy.
Blood biomarkers: Under research (goal = early detection via routine testing).
🔹 Diagnostic Challenge
Pathological changes start years before symptoms (7–10+ years).
By symptom onset, significant neuronal loss has already occurred
AD novel & current treatments
3 NOVEL Disease-Modifying Approaches
- Secretase Inhibitors
Target β-secretase (BACE1) to reduce Aβ42 production.
Failed trials due to:
Poor CNS penetration
Side effects (BACE1 involved in other brain functions)
Late intervention - Aggregation Inhibitors
Prevent Aβ from clumping into oligomers/fibrils.
Failed due to late-stage targeting (too much damage already done). - Immunotherapies (Monoclonal Antibodies)
Lecanemab, aducanumab
Stick to amyloid configurations to aid immune clearance via microglia. Clears amyloid beta olgimers.
Examples: Aducanumab, Lecanemab (FDA approved in US, not yet NHS-approved).
Shown to modestly slow cognitive decline.
CURRENT TREATMENT:
🔹 1. Cholinesterase Inhibitors
Used for: Mild to moderate Alzheimer’s disease.
Drugs: Donepezil, Rivastigmine, Galantamine.
Mechanism:
Inhibit acetylcholinesterase (enzyme that breaks down acetylcholine).
Result: ↑ Acetylcholine in synaptic cleft → enhanced cholinergic transmission.
Target circuits: Brain regions involved in cognition.
Effect: Symptomatic relief only, not disease-modifying.
May temporarily improve memory or slow symptom progression.
🔹 2. Memantine
Used for: Moderate to severe Alzheimer’s.
Mechanism: NMDA receptor antagonist (glutamate receptor).
Rationale:
AD leads to excess glutamate (excitotoxicity) → neuronal damage.
Blocking NMDA receptors may prevent glutamate-induced neuron death.
Effect:
May reduce further degeneration or slightly improve cognition.
Still not disease-modifying.
🔹 3. Treatment of Non-Cognitive Symptoms
Symptoms: Agitation, psychosis, depression, anxiety.
Drugs used:
Antipsychotics, antidepressants, anxiolytics.
Approach: Treat symptoms using standard psychiatric medications.
Limitation: These also do not slow disease progression.
✅ Key Point
All current treatments are symptomatic, not disease-modifying.
They do not stop or reverse amyloid buildup, tau pathology, or neuron loss.
Need patients to come in early but hard as can be no symptoms for years
AD challenges in drug development
Most clinical trials have:
Recruited late-stage patients (with irreversible damage).
Failed to show meaningful outcomes.
Early-stage intervention needed to prevent degeneration.
AD cognitive impact
Impaired memory, language, orientation, attention, problem-solving.
Not normal ageing—dementia causes significant drop in function.
ADLs (washing, dressing, finances, etc.) gradually deteriorate.
3 stages of dementia severity (ICD11)
Mild: short term memory loss. Core activities of daily living (ADL) maintained but higher level functions impaired
Moderate: worsening cognition. Core ADL now affected.
Challenging behaviours may become more prominent
Severe: apathy and dependency prominent. Long term memory loss. Many patients receiving 24 hour care
Spectrum of symptoms for dementias
Loss of concentration/attention
Orientation problems
Memory problems
Mood and behaviour changes (and personality)
Impaired decision making and judgement
Recurrent nightmares
Later: Speech and swallowing difficulties
Later: Incontinence and mobility issues
Dementia diagnosis
•Accurate and comprenensive history, including physical and mental state exam:
Check routine haematology, biochemistry, thyroid, vitamin B12 and folate
Check mid-stream urine, X-Ray/ECG if required
Opportunistic screening - e.g. hospital admission, NHS Health Checks
CT and MRI scans can exclude space occupying lesions eg tumours
• According to ICD-11
Marked impairment in two + cognitive domains related to age/previous level
Cognitive impairment commonly includes memory, but not exclusively
Neurobehavioural changes e.g. personality, agitation, disinhibition
Cognitive impairment is not attributed to normal aging and interferes significantly with personal, family, social, educational, occupational or other functioning.
Need to inform DVLA on diagnosis
———-
Full clinical history (+ family), cognitive testing (MMSE, MoCA).
Rule out reversible causes (e.g., B12, thyroid, infection).
CT/MRI to exclude structural abnormalities (tumours)
Diagnosis often delayed due to symptom masking by routine.
