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Dementia

  • Definition
    • Impairment in memory and at least one other cognitive domain (language, visuospatial, executive)
    • Not confused - alert and clear sensorium, attention stable
    • Loss of functional independence (vocational, social)
  • Prodromal stages
    • Emphasis on early detection
  • Conditions - Alzheimer's disease, frontotemporal dementia, Parkinson's dementia (PDD, DLB), rapidly progressive (CJD etc)

Abnormal gene products in dementias

  • Neurodegenerative diseases are associated with abnormal protein conformations (toxic gain of function)
    • Alzheimer's disease - APP and Abeta amyloid
    • CJD - Prion protein
    • Parkinson's disease - alpha synuclein
    • ALS/MND - SOD1, TDP-43
    • FTD (ALS/MND, HS) - Progranulin, TDP-43
    • FTD/ALS-DPR - C9ORF72 dipeptide repeat
    • FTD-17, PSP, CBD - Tau
    • Huntington's disease - Huntingtin/PolyQ
    • AMD - (CFH, a risk factor?)

Pathognomonic aggregates (intracellular or extracellular)

  • Amyloid beta
  • Phosphorylated tau
  • Prion protein
  • Alpha synuclein
  • Polyglutamine
  • TDP 43

Annual incidence of neurodegenerative diseases

  • AD 1/300 (1-2% population > 65)
  • PD 1/5 000
  • DLB 6/100k
  • FTD 3/100k
  • ALS 2/100k
  • HD 6/1mil
  • CJD 1/1mil

Alzheimers Epi

  • Most common dementia (increases with aging, stable after 95)
  • Worldwide epidemic related to aging populations
    • >230k in Australia, >6mil USA, >35mil world
    • Incidence doubles every 5 years after age 60 (1%), 32% at 85
    • 90% of dementia overall is AD
    • By 2050, 500k (Aust), 16mil (USA), 130mil (global)
  • Current costs in Australia ~6 billion per annum (including indirect)
    • USA $200 billion 2012, will rise to 1.1trillion in 2050
  • Family history of late onset AD only increases your risk by 10%

Natural history

  • Normal --> Preclinical (~30 years) --> Prodromal (MCI) ~5 years --> Dementia 9-10 years
  • Typical progression of cognitive impairment:
    • Episodic memory --> Semantic memory --> Attention: executive (frontal) and visuospatial
  • Reflects pathological spread (esp. NFTs):
    • Medial temporal --> Temporal neocortex --> Other multimodal association cortex

Clinical features

  • Cognitive
    • episodic memory loss (rapid forgetting)
    • language (anomia, empty speech, logopenic aphasia)
    • visuospatial (constructional)
    • ideomotor apraxia
    • executive (judgment, problem solving, planning, abstraction)
    • geographic disorientation, R/L confusion, agraphia, acalculia
    • visual defects in contrast and spatial frequency, motion detection, figure ground discrimination
    • anosognosia (50+%, denial of illness, impaired insight)
  • Non-cognitive:
    • apathy (55%)
    • depression (can be prodromal)
    • paranoia (esp of theft, infidelity).
    • agitation
    • delusions
    • misidentifications (Capgras syndrome, reduplicative paramnesia)
      • Capgras syndrome = doesn't recognise a familiar person eg spouse - they think they are an imposter. Often due to memory problem - remember the loved one as young, not old. They also then tend to blame the person instead of themselves - impaired judgment
      • reduplicative paramnesia - same sort of thing for their house (non human object)
  • behavioural
    • emotional: depression (40%), anxiety, evanescent outbursts
    • thought content/delusions (20%) esp later in course
    • motor: restlessness, purposeless eg pacing, rummaging, "picking", later in disease EPS, seizures (<20%), myoclonus, gait changes
    • circadian rhythm changes (25%): sundowning, insomnia, hypersomnia
    • weight loss: common (40%) and early (predicts higher mortality)
  • Functional: work, driving, instrumental and domestic ADLs

Addit

  • episodic anomia - one way - prompting can help them (featured in Alzheimer's)
  • semantic anomia - two way - no amount of prompting will help them with getting the correct answers
  • Alzheimer's = one way anomia and problems with repetition
  • Cortical "?"sign = involvement of the phonemic coding areas in the dominant hemisphere -- long stream of phonemes starts to overwhelm this area

Triggers for evaluation of possible dementia

  • Learning and retaining information
    • Repetitiveness
    • Trouble remembering conversations
    • Frequently misplaces items
  • Handling complex tasks
    • Eg meal preparation and finances
  • Reasoning ability
    • Planning and problem solving eg response to flooding a bathroom
    • Following rules of social conduct
  • Spatial ability and orientation
    • Driving
    • Household organisation
    • Finding one's way around familiar setting
  • Language
    • Word finding
    • Following conversation
  • Behaviour
    • Passive of less responsive
    • Irritable
    • Suspicious
    • Misinterprets visual or auditory stimuli
  • Forgetfulness associated with ageing is due to an unhealthy brain, even though it's 'normal' for the older population

Atypical presentations of AD

NB: initial main features are focal but not episodic memory, atypical in symptoms not age of onset or course. AD here may be accompanied by incidental pathologies - CAA, vascular ,Lewy bodies etc

  • Frontal variant AD - executive deficits
  • Progressive aphasia: Fluent (anomic) or non-fluent (logopenic - hesitant speech production because of word finding difficulties. one-way anomia)
  • Posterior cortical atrophy - they look bemused, because they can't work out what's wrong. Difficulty dressing, sitting on chairs. Mapping of objects around the room - location doesn't match their internal map, have a confused view of where things are
    • Occipito-temporal: ventral "what" pathway (object, face word), a/w visual object agnosia/alexia
    • Biparietal: dorsal "where" pathway (location), a/w attention/agraphia/apraxia/Balint's syndrome (optic ataxia, visual disorientation, simultanagnosia)
  • Primary visual cortex (visual variant AD) - cortical blindness
  • Congophilic angiopathy - lobary haemorrhages or siderosis, infarcts, inflammatory

AD Gross Pathology

  • Atrophy
    • Medial temporal
    • Ventricles (global)
  • Vascular disease
    • 60-90% of cases with AD pathology have vascular lesions
    • 33% have major strokes
    • Exacerbates cognitive impairment

AD Microscopic pathology

  • Plaques - neocortex, dystrophic neurites
    • Dense plaques - silver stain
    • Throughout the brain, don't correlate with symptoms
  • Tangles - NFTs esp medial temporal lobe
    • Neurofibrillary tangles in CA1 (silver stain) -- hyperphosphorylated tau
    • Do correlate with symptoms
      • Shown on Tau PET scans
  • Synaptic loss (correlates with cognitive deficit)
  • Neuronal loss (correlates with cognitive deficit)
  • (Hirano bodies, granulovacuolar degeneration)
  • Congophilic angiopathy (CAA)
    • Present in 90% of AD cases
    • A-beta protein toxic to endothelium and smooth muscle, amyloid angiitis (and rarely infarcts)
    • Microhaemorrhages, lobar haemorrhage, superficial siderosis (haemorrhage follows the sulcus line - seen on SWI or GRE (Gradient Echo) sequences), cortical SAH
      • (Transient focal CNS deficits - ?irritation not seizures)
  • Amyloid is toxic to endothelium

Misfolded protein accumulation is the likely basis of AD beta amyloid oligomers

  • Lipophilic ball formed. Disrupt synapses as earliest toxic change
  • Although A-beta 40 higher concentration, it is less toxic than A-beta 42 which is also more prone to aggregate into oligomers
  • Can't be seen with PET scan

Fibrillar beta-amyloid

  • Forms plaques (from dimers); probably not toxic
  • Can be imaged with PET ligands in vivo

Tau pathology

  • May be secondary to beta-amyloid accumulation (abnormal phosphorylated may be triggered by trimeric Abeta*56)
  • Tau spreads in a prion-like fashion from cell to cell

Amyloid precursor protein

  • Transmembrane protein - APP gene on chromosome 21
  • Function?
    • Possibly a cargo vesicle receptor for the kinesin motor protein complex essential for axonal transport
    • However knockout mice are viable with subtle synaptic and learning defects only
  • 3 main cleavage enzymes
    • Secretases: BACE-I (beta secrease), gamma secretase, alpha secretase
    • Beta secretase and gamma secretase cleavage creates A-beta
      • Somehow this process is upregulated in those who get alzheimer's (versus clearance of Abeta)

Amyloid hypothesis of A-beta toxicity

Sequential proteolysis leads to a-beta monomers

  • Non-toxic forms if alpha-secretase first
  • Toxic forms of Abeta if beta-site APP cleavage (BACE-I) then gamma-secretase (PSI core)
  • Excess production over clearance/degradation leads to imbalance
  • Basis of amyloid hypothesis- gene mutations, trisomy 21 (Down's)

Abeta 42 aggregates - dimers, oligomers (2-6 peptides), intermediate assemblies, fibrils, beta-pleated sheets (insoluble plaques)

  • Soluble forms are most neurotoxic especially to synapses
  • Cognitive deficit correlates with oligomer brain levels rather than total Abeta burden
  • Synaptic A-beta production increases with neuronal activation (vesicle release)
  • A-beta may normally dampen excitatory transmission and prevent neuronal hyperactivity
  • Soluble forms degraded by proteases (eg neprilysin, insulin-degrading enzyme)
  • Transgenic knockout mice models confirm key role of these proteases in Abeta balance

Metabolic pools of Abeta

  • ISF/CSF - feeds TBS extractable pool and carbonate extractable pool
  • TBS extractable pool - 0.2%
  • Carbonate extractable pool - 7%
  • Urea detergent extractable pool - 48%
  • Formate extractable pool - 45%
  • Urea/detergent extractable and formate extractable pools feed the Abeta fibril, extracellular "PLAQUES" pool
    • = PET-Abeta
  • Total brain Abeta in control = 1.7mg, in AD = 6.5mg

Neurofibrillary tangles

  • Tau is a glue protein, holds microfilaments together, important for cytoskeletal structure of neurons and for transport of molecules up and down long process including axon
  • Filamentous intra-cytoplasmic inclusions
  • Seen in cortical pyramidal neurones
  • Not specific for AD (and vary in composition)
    • Tauopathies - Progressive supranuclear palsy (PSP), Frontotemporal lobar dementia/primary subcortical gliosis (FTLD/PSG), DRPLA, CBGD/PPA, AGD, CTE (Chronic traumatic encephalopathy)
  • Correlate with clinical features more than does total amyloid
    • Braak and Braak staging in typical disease
    • Newer PET ligands can now image in vivo in AD

Braak & Braak

  • transentorhinal = 1-2
  • limbic = 3-4
  • isocortical = 5-6

Microtubules and MAPs

  • Polymerised units form microtubules. Several types of microtubule associated proteins (MAPs): large and small eg tau
  • Tau (MAPT) binds to tubules and stabilises aggregates (and to membrane). Microtubule binding domain optimal with 4 repeats
  • Transporters bind to tubule with motors and to vesicles
  • Kinesin (toward and peripher)
  • Dynein (toward - neuron)
  • In AD: Abnormal hyperphosphorylated tau loses affinity for tubule binding domain and destabilises tubules impairing axonal transport. Tau intermediaries toxic and associated with cognitive decline. P-tau forms paired helical filaments (PHFs) which may not be toxic

Plaques and tangles in Alzheimer's disease spreading/propagating, and asymmetrical at first, then through pathways and networks

  • There is a Braak and Braak classification of plaques, too

Synapse changes in AD

  • Hippocampal synapses preferentially vulnerable (activity dependent)
    • ?related to neurogenesis
  • Impairs impulse transmission
    • Long term potentiation loses to long term depression
  • Abnormal endocytosis of NMDA and AMPA surface receptors
  • Increased turnover and synapse loss is very early change (UDP, choline, DHA)
    • Increased membrane turnover led to a treatment with a dietary supplement called Souvenaid

Reduction of Hippocampal Hyperactivity improves cognition in amnestic mild cognitive impairment

  • Bakker et al Neuron 74, 464-474 May 10 2012
  • Bakker A et al Neuroimage Clin. 2015; 7:688-98
  • Using Keppra 125mg bd in people with MCI, you can reverse (temporarily) the symptoms and signs
    • Tested with episodic memory FMRI task
  • Suggests some abnormalities with episodic memory may be reversalbe

Chemical changes in AD

  • Decreases seen (with some initial compensation)
  • Projection neurotransmitters
    • Cholinergic, DA, NA, 5HT
    • Eg basis of 0.2mg scopolamine challenge a/w vulnerable memory
  • Excitatory cortical transmitters
    • GABA, glutamate
  • Cortical peptides
    • Somatostatin, CRF

Genes for AD

  • Autosomal dominant genes only make up about 3%
  • Causes AD: PSEN1, PSEN2, APP
  • Medium risk: APOE4 (hetero or homo), ADAM10, PLD3, TREM2

Early onset familial AD

  • They get asymptomatic amyloidosis in their teens
  • FAD ~40% of all EOAD (FAD~3% of all AD)
  • Amyloid cascade hypothesis
    • Increased Abeta (especially Abeta1-42) amyloidogenic
    • Neurotoxic soluble oligomeric fibrils -- inert plaques
  • APP (amyloid precursor protein) mutations
    • On chromosome 21 (trisomy 21 -- overproduction in Down syndrome)
    • Mutations disrupt normal APP processing (increase/decrease Abeta)
    • Clustered at APP secretase cleavage sites
  • Presenilin 1 and 2 mutations
    • PS1 is one of four proteins forming gamma-secretase
    • Also modulates calcium homeostasis (esp in endoplasmic reticulum)
    • Mutations result in increase Abeta 1-42/43:Abeta1-40 ratio
    • PS1 (chromosome14) mutations are the major characterised cause of EOFAD (~50% characterised cases), >100mutations
    • PS2 (chromosome1) homologous proteins on chromosome 1, mutations cause variable penetrance, Volga Germans description in 1995, 40-75+ years onset, 12 mutations
      • The only genetic form in older patients

Icelandic A673T mutation

  • The A673T mutation reduces Abeta formation by 40%
  • Found by GWAS of 1795 Icelanders
  • Near the beta-secretase cleavage side (disrupts BACI cleavage)