Dementia Flashcards
Diagnosis
Neurological examination = standardised tests (Mini Mental State Examination (MMSE), reflexes, motor, sensor
Lumbar puncture - protein aggregates
PET scan - amyloid PET tracers have been successfully developed; tau tracers developed and undergoing clinical trials but inflammation may be affecting with tracer binding
** no tracers developed for Lewy bodies
Definition of dementia + AD
STRUCTURALLY caused PROGRESSIVE/PERMANENT decline in several dimensions of intellectual function which interferes substantially with the person’s normal, social or economic activity
Structural - ie. loss of neurones, brain shrinkage
Permanent/progressive - unlike drugs which are transient and reversible
Development of multiple cognitive deficits, which include: aphasia (language), agnosia (sensations), apraxia (motor), disturbance in executive functioning (higher cognitive processes necessary for the control of behaviour to plan, understand, achieve goals etc.)
Alzheimer’s = progressive, irreversible declines in memory, abstract thinking, space orientation, language/communication skills; includes personality changes and impairment of judgement
Classifications of dementia
Static - usually following a single major injury; fixed in degree
Progressive dementia - can accompany several major brain disorders;
- Primary cerebral cortical degeneration ie. AD
- Cerebrovascular disease
ie. Multi infarct dementia - due to insufficient blood supply (ischaemia; excitoxicity), clogged vessels leading to the loss of discrete group of neurones over time - Primary subcortical degeneration
ie. PD/HD - Prion diseases - fast, progressive diseases
- Tumours - increase intracranial pressure therefore cause loss of neurones
Causes of dementia
Degenerative diseases - AD, Lewy Body dementia, PD, MS, MND etc.
Vascular - multi-infarct dementia
Metabolic/endocrine - hypothyroidism
Infective - AIDs, Creutzfeld-Jacob disease
Neurological trauma
Toxic - alcohol, heavy metal poisoning
Space occupying lesion - tumour, haemotoma
Subcortical vs Cortical dementias
Cortical:
- Severity = more severe earlier in course
- Speed of cognition = normal but with frequent errors
- Neuropsychology = more severe memory impairment, dysphasia, dyspraxia, agnosia
- Mood = depression less common
- Motor abnormalities = uncommon
- Neuropathology = prominent changes in cortical association areas
Subcortical:
- Severity = mild to moderate (dementia is usually an end-stage symptom)
- Speed of cognition = slow
- Neuropsychology = memory impairment
- Mood = apathy, depression
- Motor abnormalities = extrapyramidal
- Neuropathology = prominent changes in the striatum + thalamus
AD Pathophysiology
Severe brain atrophy = enlarged ventricles, shrunken gyri
Intracellular hyperphosphorylated tau tangles
Extracellular amyloid plaques
Defitive diagnosis - post-mortem (Nissl staining; see high density of plaques + tangles)
Major neurones affected in AD = cholinergic neurones in the nucleus basalis of Meynert + septal nucleus - projects to the hippocampus
Severe loss; healthy adult = 500,000 neurones whereas advanced AD patient = 100,000 neurones
AD distribution of plaques/tangles - initially in the hippocampus + frontal lobes; becomes more widespread as the disease progresses
Main symptoms; aphasia, agnosia, dyspraxia, incontinence, loss of appetite (weight loss)
Risk factors
Diabetes - APP has glycosylation domains; could diabetes could increased glycosylation leading to aberrant APP misprocessing?
APOE4 - linked to cholesterol metabolism; non-causitative risk factor = enhances protein aggregations
In vivo - accelerates early seeing of amyloid by increasing AB40 half-life, perturbing AB clearance, enhancing amyloid-related gliosis
Chromosome 21 = Down’s syndrome - 2 copies
Contains APP gene therefore Down’s = too much APP production
Age - risk rises exponentially with age
Gender - women more at risk BUT is this due to the increased longevity of women?
AB40/42 effects
- Activate microglia/astrocytes = P2X3 (microglia; BDNF); P2X4 (macrophages; interleukin; EAAT1/2); P2Y (microglial; engulf neurones)
- Cause abberant phosphorylation + mislocalisation of tau in dendrites (ADDLs)
- Causes an imbalance of kinases/phosphatases
- AD decreases choline uptake activity and decreases cell surface CHT (choline transporter levels) protein levels =
Tau
Physiological, heathy functioning = microtubule associated protein; enhances LTD via P @ Ser396, enhance GluA2-PICK1
AD = hyperphosphorylation leads to disocciation form microtubules (detaches from microtubules); abberant LTD (cognitive impairment), spine shrinkage (due to instability of spines lacking GluA2); compromised axonal transport
Pharmacology - current + links from Pharma!
Donepezil = acetylcholinesterase inhibitor - increased synaptic ACh within the cortex
Memantine = partial NDMA antagonist - blocks tonic, spontaneous activation of NMDARs (noise), therefore allows the transmission of weaker phasic signals
BUT Lewy body dementia - could cause worsening of psychiatric symptoms due to NMDA antagonism
(Ketamine/PCP = SZ model of psychosis/negative symptoms)
Linopiridine = suppresses M-current; cognitive enhancer licensed for the treatment of vascular dementia + age-related cognitive impairment
BK channel opener = AD suppresses function of BK (fAHP + repolarisation of AP) therefore broadens AP spike; ‘slower’ = novel therapeutic target in AD!
Future of AD
Prevention, treatment + care
- Reliable + timely diagnosis
- Identification and validation of biomarkers
- Implement non-pharmacological strategies to promote independent living
- Development of harmonised, international databases for population-based studies ie. GWAS
- Promote regulated collection of DNA; raise awareness of the importance of donating brains to brain banks
- Increase collaboration between research groups + government
- Coordinate clinical drug development
CJD
Creutzfeld-Jacob disease = a progressive, fatal neurodegenerative disease associated with prion proteins; fatal, rapid dementia with loss of motor coordination
Neuropathology = vacuoles in the neuropil of grey matter (“sponge-like” = spongiform); neuronal loss; gliosis
Requires a compromised BBB - must have direct contact
Average survival length = 6 months
Pathophysiology of CJD/spongiform encephalopathy
Accumulation of abnormal form of PrP(Sc; scrapie) - self-replicating, amplifying: INFECTIOUS
Prion protein (PrP[C; cellular]) = normally expressed protein; membrane-associated amyloid-forming protein
Protein aggregation + pathological tranmission
Molecule-to-molecule = template-induced conversion (conformational change) of the natively folded endogenous protein; leads to auto-catalytic growth of aggregates
Most toxic = partial oligomers - act as templates for other proteins
Formation of protobrils from oligomers is irreversible - cannot dissociate back into monomers!
Cell-to-cell = aggregates can pass from one cell to another and induce similar conformational changes in healthy proteins
Brain region-to-brain region
Large polymers/protofibrils can fragment to produce more seeds to propogate the reaction
Disease-specific seeds
Whether disease-specific seeds are produced throughout life and are usually actively removed or whether the generation of seeds is a rare event which marks the beginning of a disease is yet to be determined
Both = the emergence + persistence of seeds is thought to be promoted by the age-related deterioration of the host proteostasis network
BUT Study:
- Old (with diffuse plaques) + young organotypical hippocampal slices in close proximity
- Production of chemokines + cytokines from the young activated glial cells = restored the ability of the microglial in the old brain to clear the AB42
- ‘Jump-started’ the old microglial into a protective and functionally active state
= implies that they are produced throughout life and removed by healthy, functioning glial cells \
= supports the deterioration of the old brain promotes seed-spread!
