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Etiology of Dementia Progressive cognitive decline resulting in new…

- - - - Retrograde Amnesia
        Memory loss of events prior to brain damage
        Anterograde Amnesia
        Memory loss of events after brain damage
- - - - Amyloid beta-protein
        
        various molecular species --> most common 40 residues long
        
        increased production of C-terminally extended forms
        
        Soluble forms --> toxic --> responsible fro synaptic function
        
        Produced from normal protein - from APP by secretases:
        --> non-amyloidogenic --> release p3 fragment + sAPPapha (neuoprotective and memory-ehancing effects)
        --> amiloidogenic --> release Abeta (no action of alpha secretase, beta secretase instead)
        
        oligomers block LTP -->
        
        Mutations in APP, PS1, PS2 --> early onset of familial aurtosomal dominant
        PS1 + PS2 --> presenilins __> components of gamma-secreatse --> enhance production of A-beta42 --> tends to form stable trimeris/tetrameric oligomers
        Alelles for apoliprotein E4 + alpha2 macroglobulin --> increased risk for late onset
        mGluR5 - coreceptor for Abeta oligomer
        APP mutations + what is more toxic + linking of vascular dysfunction
        ApoE4 - isoforms linked by breakdown of beta amyloid - >
        Alzheimer's disease - 2015/6 - lancet- philip sheletons
      - Tau
        
        helps stabilize microtubules
        
        changes --> microtubules colapse + clump together --> tangles
        
        phosphorilated --> inhibts binding --> depolimerization
        
        abnormally phosphorilated __> aggregates --> paired helical filaments
      - ApoE
        
        recycles lipids after neuronal degenration --> for proliferation, membrane repair and remyelination of new axons
        
        when no lipids --> stable complex with Abeta peptides --> may increase accumulation and plaque formation
      - mitochondrial dysfunction
        
        oxidative stress
        
        neurodegeneration (loss of synapses and neurons - e.g. glutamatergic excitotoxicity)
        
        glial dysfunction
        
        cellular and molecular risk factors
        
        mechanism for different lengths (APP)
        
        apoptosis/necrosis/autophagy
  - - - Diagnosis
        The diagnosis is Parkinson's disease dementia when a person is originally diagnosed with Parkinson's based on movement symptoms, and dementia symptoms don't appear until a year or more later.
        
        diagnosis if appearance of dementia and PD symptoms are within one year
      - Causes
        
        increase in Lewy bodies - filamentous cytoplasmic inclusion - alpha-synuclein
        
        accumulation of tau neurofibrillary tangles
        
        Failure of UPS
        
        overexpression of a-synuclein and mutations i---> accumulation of toxic oligomeric fibrillary species--> nhibits the proteasome (unfolds an degrades)--> toxic species to accumulate and Lewy bodies formation
        
        3 ubiquitin enzymes: E1, E2, E3 --> muation in 1 (UCH-L1) and 3 (Parkin) --> inhibition UPS --> familial PD --> autossomal recessive PD (mitochondrial dysfucntion)
        
        Mutation in Parkin (can induce mitophagy) --> no Lewy bodies + mito pathology + + vulnerability to oxidative stress
        Muattion PINK1 --> no Lewy bodies
        Act in common pathway - PINK is upstream Parkin --> may quaratine damaged mitochondria before clearance
        high mito membrane potenial > PINK1 into mito --> degraded --> low levels of PINK1 in basal conditiond
        low (unoupling agent CCCP)--> acummulation of PINK1 in surface > recruit Parkin --> translocation of Parkin into mito --> ubiquinates proteins in outer membrane --> recruits adaptor proteins (p62) --> phagophores --> autophagosome --> lysosome --> degradation
        Parkin --> neuroprotective role against cell death in stress situations
        Mutation in UCH-L1 --> autossomal dominant PD slow progresssion
        Mutation in LRRK2 --> early onset of autossomal dominant
        autophagy suggested too!
        
        Alpha-synuclein
        
        disorderd protein - no defined secundary structure
        
        mutations on N-terminal (A30P, E46K, A53T) --> promote Lewy body formation
        
        NAC (non-amyloid B component) domain --> protein aggregation = toxic (in cytoplasma and mitochondria - inhibs complex I of e~transport chain)
        
        maybe by inducing mitochondrial fragmentation --> dysfunction -->death
        
        maybe triggers inapropriate + excessive mitophagy
        
        Mitochondrial Dysfunction
        PINK1--> has canonical mitocn«hondrialtargeting sequence (n-Terminal)
        MPTP --> stret heroin --> similar symptoms -_>oxidated MPP+ inhibits cellular respiration by complex 1 in dopaminergic neurons
        
        Evasion of Quality Control Mechanisms
      - Symptoms
        
        tremors
        
        bradykinesia
        
        rigidity
      - Brain Structures
        
        loss of dopaminergic neurons from substancia nigra in pars compacta -- deficiency in release to caudate and putamen
        
        D1 - excitatory; D2 inhibitory ---> increase of cortical output --> in PDD --> loss of thalamic output
      - Therapies
        
        Levodopa - treats symptoms
        
        COMT inhibitors + MAO-O inhibitors (rasgiline) + L-dopa --> receptor activation and prolongation of bioavaliability
        
        cell replacement therapy
        
        electrode implantation- ?
        
        Possible:
        
        endogenous neurotrophic factors
        
        chelation of iron and other heavy metals? - prevent inflammation
        
        reduction of alpha synuclein aggragation
        
        immunotherapy
        
        inhibition of neuroinflammation
        
        caffeine and adenosine receptors
        
        antioxidant - creatine - delay worsening
        
        selective noradrenaline reuptake inhibitor atomoxetine
        
        acetylcholinesterase inhibtor - donepezil
      - Facts and ffigures
        
        1-2% population
        
        1 million in EU
      - Risk Factors
        Positive:
        
        age
        
        family history
        
        men
        
        rural living
        
        Negative:
        
        cigarette smoking
        
        caffeine consumption
      - Prion-like transmission
        
        spread od pathology - transmission via endocytosis
    - - if cognitive symptoms predate physical symptoms from more than a year
    - - Symptoms
        
        Changes in thinking and reasoning
        
        Confusion and alertness that varies significantly from one time of day to another or from one day to the next
        
        Parkinson's symptoms, such as a hunched posture, balance problems and rigid muscles
        
        Visual hallucinations
        
        Delusions
        
        Trouble interpreting visual information
        
        Acting out dreams, sometimes violently, a problem known as rapid eye movement (REM) sleep disorder
        
        Malfunctions of the "automatic" (autonomic) nervous system
        
        Memory loss that may be significant but less prominent than in Alzheimer's
      - Diagnosis
        The diagnosis is DLB when:
        Dementia symptoms consistent with DLB develop first
        When both dementia symptoms and movement symptoms are present at the time of diagnosis
        When dementia symptoms appear within one year after movement symptoms.
      - Brain Structures
        cortical
  - - - Behavior variant frontotemporal dementia (bvFTD)
      - Primary progressive aphasia (PPA)
      - Disturbances of motor (movement or muscle) function
        e.g.Amyotrophic lateral sclerosis (ALS), Corticobasal syndrome, Progressive supranuclear palsy (PSP)
  - - - Symptoms
        
        Progressive impaired motor, cognitive and psychiatric functionc
        (development varies between individuals)
      - Causes
        
        40 CAG repeats (=glutamine) in exon 1 of Huntingtin (BDNF trasncription, embryonic development, trafficking) - in spermatogenesis + variation in replication
        
        Expanded polyQ stretch = propensity fro abnormal conformation and nuclear/cyroplasmic aggregates (short truncated derivates of mHtt due to cleavage)
        
        stretch = + propensity
        
        Fragment is more toxic than full-length mutant protein
        Aggregate - coping mechanism
        
        Decreased BDNF expression:
        no binding to transcriptional factor REST
        rescue of LTP and learning deficits - + survival of neurons and activity
        
        Mitochondrial Dysfunction
        Htt is transcriptional regulator of PGC-1 (regulator of mitochondrial biogenesis) -reduced levels in patients
        
        Decreased glutamate transporter expression in astrocytes - glial dysfunction
        increase in extracellular glutamate
        mHtt reduces expression in mice
        
        Incapability of degradation by UPS
        toxicity
        
        Impaired autophagy - cytoprotective
        only clears mutant Htt
        crosstalk: aggregation of ubiquinated induces autophagy
      - Brain Structures
        Basal ganglia - "braking" in movement - inhibitory output
        (cerebellum - counterpart - initiation of movement)
        
        degeneration - chorea -dance-like movements
        
        Later: spreading to cortex through resulting in stimulation (direct and indirect pathway)--> excitotoxicity --> neuronal death
      - Areas to Study
        
        context of understanding the role of abnormal development.
        
        very little is known about the normal function of HTT, which is vital to brain development.
        
        Therapies
- - - - 3 autossomal dominant genes - reponsible for amyloid cleavage - associated with early onset-ADD
      - Apoliprotein E allele
        TREM-2 allele
        
        implicated in amyloid processing and neuroinflammation