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!
Disease-specific seeds = cell vulnerability
Host cell - some provide the ideal conditions for the infectious conformational changes to occur
- Remember - needs to contain the endogenous protein to be templated!!!
- Some host cells may have defense mechanisms which prevents such conformational changes from occurring!
The host cell can select certain protein conformations to amplify in specific locations - leads to varied protein aggregate expression levels!!!
Mechanisms of seed spread
AB, huntington + a-synuclein can travel in anterograde + retrograde directions
Mechanisms of seed spread may differ with different protein conformations
Some translation mechanisms are selective for proteins
The differential trafficking of seeds by the host cell may contribute to the selective vulnerability of different cells to different proteins in different areas!
** Remember - the host cell provides the active + passive machinery required for the mechanisms that the seeds utilise to spread throughout the CNS
The heterogeneity of proteopathic seeds + evidence!
Conformational strains = the occurrence of strains of distant conformations is a predicted feature of all aggregative proteins; due to the polymoprhic nature of misfolded proteins; produce a spectrum of amyloidopathies/tauopathies/synucleinopathies
Variants of the same protein = “clouds” which contain several related conformations
= dependent on the chemistry (how proteins assemble, interactions etc.) and neuronal vulnerability - therefore affect different neuronal populations and lead to the phenotype of different diseases
= different conformational strain = different ND disorder
AD = AB aggregates obtained from the brains of patients affected by diverse clinicopathological AD phenotypes = structurally distinct AB fibrils
Tau = 18 different tau strains in inoculated mice produced strain-specific, intracellular tau aggregates in distinct cell types + brain regions, with different rates of propagation
Heterologous cross-seeding
Cross-seeding events may explain the frequent findings of mixed pathologies in which more than 1 protein aggregate is found in a patient’s brain
1 protein aggregate can trigger the aggregation of different proteins and can spread to different brain regions
Explains why Ps with PD develop dementia at late stage
AD = 50% also have a-synuclein PD = 80% also have amyloid plaques
Explains the large pathological overlap - produces difficulty in diagnosis + treatment
- not as simple as AB causes AD; a-synuclein causes PD etc.!
- a disease is initiated by one protein aggregate to drive a clinical phenotype, and over time the aggregate cross-seeds and leads to the accumulation of other protein aggregates which expands the clinical phenotype
ie. PD Ps eventually develop cognitive + memory deficits
Experimental evidence = aggregate AB have been shown to induce tau lesions and promote tauopathy in mice
ADDLs have been shown to promote tau hyperphosphrylation (and subsequent mislocalisation into dendritic spines)
These are maybe occurring due to cross-seeding interactions!
Host cell + co-factors
Assemblies of synthetic AB/tau/a-synuclein have been shown to have comparatively weak seeding compacities to seeds derived from the brain
The in vivo seeding efficacy of synthetic AB seeds is enhanced if the seed is aggregated on living ex vivo tissue slices in culture
= host culture is therefore a key element in the development of proteopathic seeds
Common neuronal pathways altered in multiple neurodegenerative pathways
Autophagy-lyosomal pathway = dysfunction in the pathway could underlie the accumulation of pathogenic protein aggregates
- Primary paper w/ young + old organotypic hippocampal slices
Synaptic toxicity/impairments
- HyperP tau promotes LTD (GluA2-PICK1)
- AB42 activates extra-synaptic NMDAR LTD-like currents; inhibits synaptic LTP-like currents
Stress granules = dense aggregations in the cytosol composed of proteins + RNA; appear when the cell is under stress
- Produce dynamics that favour aggregation and aberrant incorporation of misfiled proteins
Mitochondrial homeostasis
- Reduced energy production + dysfunctional proteostasis network
- ATP cannot be produced; collapse of ion gradients (many reliant of Na-K-ATPase) = high EC [glutamate]
- Excitoxicity
Therapeutic strategies to target prion-like spread of proteins
Protecting BBB = keep harmful proteins out
ABs to tag oligomers = BAN2401 - rely on endogenous mechanisms to clear out
Secretase inhibitors - but many failed clinical trials
ie. BACE1 inhibitor - problems have been due to BBB penetration and the high molecular weight; therefore looking at non-peptidogenic lead compounds!
Target transport mechanisms to prevent cell-to-cell spread; target the cellular pathways implicated in the spreading of seeds
ie. transsynaptic tranport, exocytosis, endocytosis
BUT - likely to produce several unwanted side effects due to the non-specific mechanisms
AND the exact mechanisms are unknown!
Disease diagnosis
Sensitive detection of misfolded seeds in biological fluids is required - early diagnosis is key!
Problem = oligomers are highly heterogeneous and present in very low concentrations in biological fluids and have the same amino acid sequence as the natively folded protein
Therefore - require high sensitivity detection
ie.
ELISA assays = enzyme-linked immunosorbent assay - detect the presence of a ligand in a liquid sample using ABs
Seeding-amplification assays = monitor as proteins interact and grow as aggregates
(PMCA = Protein Misfolding Cyclic Amplification; used to diagnose CJD in Europe)
Development of ABs selective for specific conformations (hard due to conformational hetereogenity)
ie. BAN2401 - selective for protofibrils!
Biosensors = retinal imaging - aggregates are found in the retina of AD Ps
- Quantify and selectively visualise protein aggregates in the retina before symptoms occur
- Autofluorescence imaging
- Non-invasive!
BUT
- Technical difficulties
- Difficulty differentiating between other pathological aggregates
- Presence of b-amyloid does not necessarily = AB plaques!!! Need thioflavin positive staining!!!
Novel treatment - primary paper
Focal ultrasound = increase the permeability of the BBB
Improved the bioavailability of endogenous ABs + caused a temporal activation of glial cells
Correlation = enhance glial activation and internalisation of ABs
Novel finding with brain slices - primary paper
Organotypic brain slices = young + old (diffuse AB plaques; positively stained for thioflavin)
Close proximity = young glial cells activated + released chemokines/cytokines which restored the function of microglial in the old brain to clear the AB42
‘Jump-started’ into a protective and functionally active state
LINK:
Activated P2Y-microglial = unknown mechanism; thought to adhere to and engulf injured and uninjured neurones - could be involved in AB42 clearance
Tauopathy = aggregation + seed hypothesis
Intracerebral infusion of tau seeds into transgenic mice expressing human tau = induces aggregation of hyperP tau
- spreads to axonally linked regions
Aggregated AB shown to induce tau lesions + promote the seed of tauopathy in mice
- Unknown whether AB triggers a self-sustaining mechanism or if it necessary to continually drive tauopathy
- Example of cross-seeding
a-Synucleinopathy = aggregation + seed hypothesis
SUPPORT
Fetal brain cells were transplanted intracerebrally into PD Ps to alleviate the behavioural manifestations of the disease = LBs appeared in the fatal neurones
Exogenous application of synthetic a-synuclein seeds induced progressive ND disorders which recapitulate some characteristics of human PD
Prion = aggregation + seed hypothesis
SUPPORT
CJD patients who received dura mata transplants contaminated with prion protein
Some children who received human-derived growth factor + developed CJD = the hormone was extracted from the glands of prion disease patients
Both examples of IATROGENIC CJD = illness caused by a medical treatment
