Alzheimers Flashcards
What is dementia: types + characteristics
a syndrome (neurodegenerative disease)
Loss of memory:
- Alzheimers (most common cause of dementia)
- Lewy body dementia
- Vascular dementia
- Frontotemporal dementia
Lewy body dementia
Cause: Alpha-synucleinopathy aggregation, i.e. Lewy bodies
Symptoms: Cognitive impairment, memory loss, hallucinations & motor problems
Difference with Parkinson’s dementia:
- Cognitive impairment predominate motor problems
- Earlier onset & faster disease progression
Vascular dementia
Cause: injury of blood vessels in or in direct connection to the brain (stroke, haemorrhage)
Symptoms: Judgement, memory and motor problems
> Region of injury is variable, therefore so are symptoms
Frontotemporal dementi
Cause: Tau/TDP-43 aggregation in frontotemporal regions
Symptoms: Behavioural changes, language problems
> Early onset, genetic ties to ALS
Alzheimer’s Disease - Epidemiology
Prevalence increase with age
Women > Men
Symptoms (typically) appear mid-60s or later
Alzheimer’s Disease – clinical symptoms
Memory impairment
Executive functioning
Paying attention, planning, performing tasks to completion, orientation
Language
Anosognosia – underestimation/ “alibi” for deficits i.e denying their symptoms strongly
Neuropsychiatric problems
Apathy, Social disengagement, irritability, personality
Other symptoms
Sleep disturbances, olfactory dysfunction, incontinence
Progressive symptoms!
Alzheimer’s Disease - progression
Preclinical AD (healthy or cannot be diagnosed in the clinic) > Mild cognitive impairment due to AD ‘prodromal’ > dementia due to AD (mild > moderate > severe)
Cognitive impairment arrives later in time, after ATN
Normal > MCI > Dementia
Spans 15-25 years
Amyloid-β pathology
(dont really need to know) APP protein (amyloid precursor protein) is cleaved into its decided proteins by alpha secretase
> cleaving of APP = extracellular amyloid beta amino acids
Abnormal cleavage of APP
APP mutations increase beta ecretase cleavage
PSEN1 and PSEN2 mutations increase gamma-secretase activity
They are EXTRACELLULAR aggregations
The longer amino acids are thought to be more toxic and prone to aggregation
Thal phases: for amyloid beta
Movement of Amyloid beta aggregation
Phase 1: neocortex
Phase 2: Entorhinal cortex & hippocampus
Phase 3: striatum, cingulate gyrus
Phase 4: brainstem nuclei
(mid-brain, medulla oblongata)
Phase 5: cerebellum and pons (most progressed state)
Tau pathology
(dont really need to know)
In AD:
Phosphorylation of Tau proteins = gives them too much energy = decreases their binding affinity to these microtubules = i.e stabilizers of these microtubules start to disengage = microtubules fall apart
Disengaged proteins start to form aggregates = tau tangles (this is WITHIN THE CELL)
Regional specificity & progression
Could be due to regional vulnerability between cases and diseases
Aggregation proteins have a seeding mechanism: if you have an aggregation of a protein and put it in another region it starts to seed the aggregation, aggregation encourages more aggregation and follows functional connections
Braak NFT staging: for TAU tangling
Stages I-II: Entorhinal cortex & midbrain
Stages III- IV: Limbic, frontal and
temporal regions
Stages V-VI: neocortical regions
Neurodegenerative nature of AD
Tau but not Amyloid correlates with neurodegeneration in AD
Typical initial volume loss in medial temporal lobe (hippocampus) (quantified by MTA value, the higher the greater the volume loss)
A/T/N criteria
If there is amyloid and tau build up + neurodegeneration = AD
If there is amyloid + tau build up but no degeneration = prodromal AD
Rest is non-AD, you need amyloid + tau for AD
Hippocampal loss - consequences
unable to form episodic memories over a minute
Immediate memory was intact
Remote events i.e. (very) long term existing memory was intact
Storage of new memories i.e. encoding was not intact
Risk factors – development of AD
Age
Gender
Family history (Familial vs Sporadic
5% vs 95%) I.e genetics
Environmental toxins
Head trauma (Chronic Traumatic
Encephalopathy ≠ AD)
Cardiovascular health
Education level (Cognitive reserve ”use it or lose it)
Life style
Genetic risk factors
Deterministic/Causative (early onset):
PSEN 1, PSEN 2, APP, TREM2
Risk genes
APOE4
APOE2 (protective gene)
Penetrance lower than 1 = protective genes e.g APOE2
Modifiable factors – mitigation of AD
Life style:
Healthy sleep schedule
Avoid Hearing loss
Avoid excessive smoking & alcohol
Education:
Cognitive activity
Social interactions
Cardiovascular health:
Physical activity
Diet choices
Avoid head trauma + env. toxins
Clinical subtypes - heterogeneity
- Typical AD
memory symptoms - Visual spatial AD
Visual symptoms - Language variant AD
Aphasia - Behavioural AD
Behavioural changes - (Dys)executive AD
predominantly executive symptoms - Corticobasal syndrome
Motor function symptoms
Therapy – treatment of AD: drugs
Disease progression modifying drugs: anti-amyloid drugs (target amyloid plaques)
Symptom treatment drugs
Cholinesterase inhibitors (cog enhancement)
Insomnia drugs (addresses sleep disturbances)
Anti-psychotics (adresses neuropsychiatric symptoms)
Diagnosis AD
Cognitive assessment
Anamnesis – Conversation and specific questions of clinician with patient and/or proxy (tackling anosognasia)
Cognitive tests – performing cognitive tasks and answering questionnaires (MMSE value: 0-30, the higher the better, less questions wrong)
Structural assessment
MRI:
MTA Value (Medial temporal Atrophy)
< 75 years: score 2 or more is abnormal. > 75 years: score 3 or more is abnormal
GCA (Global cortical Atrophy): Slightly uncommon in (earlier stages of) AD, indicative for vascular dementia
Fazekas scale for White matter lessions:
May be indicative for vascular dementia
Biomarkers
CSF/Blood or PET imaging to Measure molecules involved in the process of the disease
Cerebrospinal fluid (CSF) biomarkers
- Invasive (lumbar punction)
- Abundant molecules in fluid
- Relatively cheap
* Aβ concentrations decreased in CSF of AD patients
* Tau concentrations increased in CSF of AD patients
* soluble TREM2?
Blood based biomarkers
- Less invasive
- Lower concentration of molecules in fluid
- (More sensitive analysis methods needed)
- Relatively Expensive
PET-Scan (Amyloid PET)
- Relatively non-invasive
- Dependent of binding of radio tracer to molecules
- Very expensive
- measures cortical amyloid β deposition
Genetics
Look at medical history in family Tree
Genotyping for AD related genes
Heterogeneity
Structural/biomarker subtypes
- Typical AD
Hippocampal/mild GCA - Limbic predominant
Exclusively Hippocampal atrophy - Hippocampal sparing
No Hippocampal atrophy
Only GCA - No atrophy
No or only mild and diffuse atrophy
Impact of heterogeneity
- Possible misdiagnosis of patients
- Difficult to predict clinical progression
- Research design
- Therapeutic targets/effectiveness
- Fundamental question of why? Resilience?
General pathology
Amyloid β induces the spread of tau
pathology which is associated with degeneration
microglia-mediated inflammation
Risk-genes become upregulated when microglia are exposed to amyloid plaques
non-pharmacological treatment options
intensive blood pressure control to
reduce risk of cog impairment
Benefits on cognition: lifestyle changes
healthy balanced nutrition, physical exercise, cognitive training and social
activities, omega-3 fatty acids supplements
