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  • 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


  • 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)
  • Found to have very low incidence of Alzheimer's disease AND age related cognitive decline (similar mechanism?)
  • Supports amyloid hypothesis

Late onset AD

  • Unknown proportion is due to domnant gene (~10%?)
  • Genetic risk factors
    • ApoE - e4 allele, chromosome 19 (also potent vascular risk factor)
    • Other accelerators of Abeta deposition:ABCA7 (adenosine triphosphate-binding cassette subfamily A member 7), FERMT2 (fermitin family homologue 2) only in MCI stage
    • >20 gene loci reported (including on chromosome 10 and 12) using GWAS and amyloid deposition correlations eg CLU (clusterin 1, aggregate clearance), FERMT2 (accelerates tau toxicity and AD progression), CASS4 (Abeta toxicity may require this in PO4 form), ZCWPWI and others CRI, SORLI...
    • Mechanisms yet to be worked out

Apolipoprotein E in AD

  • ApoE exists as 3 alleles: e2, e3, e4
  • Frequency of e4 allele in Australia: 26%e4 and 1-2% e4e4
  • 1xe4 allele carries RRx4 of AD
    • e4e4 carries RRx19 of AD
    • age specific risk - 10y per e4 (if you get AD, each e4 allele decreases age of onset by 10y) (it also affects your cognition earlier)
  • but half of AD patients have no e4 and even e4/e4 may not get AD
  • screening for ApoE status not recommended (not deterministic that you get AD)

Environmental risk factors for AD

  • Risk factors
    • Age (prevalence x2 from ~1% at 60 every 5y to 32% at 85, 47% over 85)
    • Family history (1st degree relative with AD or Down Syndrome - x2-4, higher >1, esp <70)
    • Female sex (in older patients only); singlehood/widowed (!)
    • Cardiovascular risk factors (HTN, T2DM, cholesterol/obesity mid life, homocysteine, heart disease), congenital heart disease (x2 for early onset)
    • Not head injury (debunked in larger population studies)
    • Low education, leisure activites, socialisation, physical inactivity, cynicism, and mid life depression (higher in Abeta + persons)
  • Protective factors
    • Physical exercise
    • ?Education/stimulation (?reserve/threshold effect, not rate) -- measured with cognitive tests, which low education do poorly at
    • ?Oestrogen/HRT (but not in prospective prevention trials)
    • ?Statins, dietary fish oils, NSAIDs (no proven benefit)
    • May only delay onset of disease, not prevent it

Research criteria for AD

  • Clinico-pathological criteria NINDS-ADRDA, 1984
  • Definite
    • Pathologically confirmed
  • Probable
    • Dementia (40-90 years)
    • Memory + at least one other cognitive domain affected
    • Progressive worsening and other causes excluded
  • Possible
    • Atypical course or features

Why were these criteria revised

  • Continuum of disease
    • Pathology progresses continually without distinct stages
    • AD and MCI criteria create indistinct lines in the sand
    • MCI criteria became very complex ?usefulness in clinic
    • MCI vs AD depend largely on definition of functional abilities
  • Biomarkers of AD pathology
    • Imaging, CSF, blood and cognitive
    • Potentially reduce heterogeneity/improve specificity
    • Allow "earlier" detection and quantitation of disease stage
  • Awareness of prodromal/preclinical stages
    • May allow more effective interventions
    • Need operational definitions for such stages

Which biomarkers?

  • Amyloid (only detect fibrillar amyloid; good for following newer treatments)
    • CSF - low Abeta42 and low Abeta40/42 ratio
    • PET - 11C-PIB, 18F-flutemetamol, 18F-florbetapir
    • Indicates brain accumulation of cortical fibrillar amyloid
    • Blood - Abeta immunoprecipitation and mass spectrometry using composite APP669-711/Abeta1-42 and Abeta1-40/Abeta1-42 with ~90% w.r.t. PET
      • Nakamura et al Nature 2018
  • Neurodegeneration
    • CSF - high t-tau, p-tau (correlates with cognition)
    • SPECT - parieto-temporal hypoperfusion
    • 18FDG-PET - precuneus (medial part of parietal lobe), parieto-temporal hypometabolism
    • MRI atrophy including visual scales, cortical thickness, regional and whole brain (FMRI, MRS)
    • Hippocampal atrophy over the age of 70 is a reasonably good sign, younger than that it's a great sign but it's rare (then FDG PET is more useful)
  • Other
    • Blood - proteomic, lipidomic, metabolomic markers including apoJ/clusterin (an amyloid chaperone protein). Also oxidative stress, inflammatory markers etc
    • Cognition - early episodic memory deterioration and accelerated long term forgetting at 7 days in pre-symptomatic FAD carriers
      • Weston Lancet Neurol 2018

NIA-AA research criteria for AD (2011) -- incorporates biomarkers

  • Probable
    • Core dementia criteria (decline in cognitive/behavioural features interfering with ability to work/usual activities, ≥2 domains including memory, executive, visuospatial, language, behaviour, no other identifiable cause)
    • Insidious onset, gradual worsening, core amnestic (EM) or nonamnestic (language, visuospatial, executive), presentations
  • Possible
    • Atypical course or features of other possible causes (e.g. vascular, DLB, FTD, other)
  • Either of above + AD biomarker (or gene mutation)
    • Biomarkers: brain amyloid (CSF Abeta, PET), neuronal degeneration (CSF tau, FDG-PET, MRI atrophy); positive, negative, indeterminate. Increases certainty of AD process but standardisation is currently incomplete. Others also
    • Pathophysiologically proved AD/Dementia unlikely due to AD

NIA-AA Research criteria for preclinical AD=

  1. Asymptomatic cerebral amyloidosis
    1. Amyloid biomarkers positive (A+)
  2. (1) + "downstream" neurodegeneration
    1. Amyloid and neuronal injury markers (A+N+)
  3. (2) + subtle cognitive/behavioral decline
    1. Additional subtle cognitive change (A+N+C+ or A+C+ MCI)

Dominantly inherited alzheimer's network (DIAN) - CSF changes 15-20 years earlier than onset

  • The biomarkers (Abeta, tau) can be positive 15-20 years earlier than symptom onset

11C-PiB PET in different dementias

  • Nonspecific binding in healthy controls
  • DLB can have false positives and look like AD (or co-diagnosis)
  • AD - frontal and parietal involvement
  • FTD - no different to control
  • PiB detects Abeta in fibrillary plaques - not Abeta oligomers
  • Source: Rowe CR et al Neurology 2007

Abeta deposition over time (30 years)=

  • The prodromal period before dementia can be up to 30 years -- the period we have to intervene in the future
  • As found using SUVR (quantitative measurement of Abeta in brain on PET)

Translation of PET SUVR into Abeta mass units

  • 2-5% decrease in clearance rates in Abeta amyloid in dementia -- which contributes to accumulation of Abeta
  • Mechanisms underlying failure of clearance are poorly understood but include:
    • Phagocytic/autophagocytic and other forms of cellular uptake (microglia, perivascular macrophages, astrocytes, oligodendroglia, neurons) (genetic risk factors include TREM2, CD33, CR1, ABCA7, PLGC2, AB13, SPI1/PU.1, TYROBP/DAP12)
    • Active Brain-blood barrier transport to peripgeral vascular circulation (LRP1, Pgp)
    • Bulk flow through normal CSF egress pathways (perivenular and capillary pathways, aquaporins in astrocytes and arachnoid villi)
    • Proteolytic degradation (NPE, IDE, MMPs...)
    • Abeta42 chaperones may work through all of the above mechanisms (ApoE, ApoJ (Clusterin), ATIII, etc)
    • Idiosyncratic auto-antibody clearance (e.g. aducanumab discovered in healthy elderly without cortical amyloid, or slower than usual progression)

Suspected non-AD pathophysiology (SNAP, A-N+)

  • Based on AD biomarkers (NIA-AA criteria of prodromal AD) - Abeta negative, but neurodegeneration positive (pathology is not able to be clinically determined eg PDG-PET is "AD-like")
  • Clinically can be normal (CN) or impaired (MCI, dementia)
  • CN 50-60Y 0% >65Y ~23%, MCI ~25% SNAP, AD dem ~7%
    • ApoE4 is less (13%) vs A+ (40%) vs A-N-(24%)
    • Risk of progression similar to A+N- (stage 1) if use PET
    • No distinct clinical phenotype for CN SNAP vs A+
    • Tend to be older ?more vascular/DLB than A-N-
    • 42% CN SNAP transition to A+N+ (some are initially Abeta subthreshold)
  • MCI SNAP progress to dementia (21-47%) > A-N-, A+N-, <A+N+
    • Different causes possible given FDG-PET AD-like pattern vs MRI hippocampal atrophy
    • PET: AD (subthreshold), Tauopathy (eg PART), AGD, FTD (PRGN), CBS, alpha-synucleinopathy, VCI
    • MRI: HS, TDP-43 proteinopathy, FTD (tauopathy), anoxic-ischemic injury
    • Mixed causes are very common
  • SNAP - "A" for amyloid vs "AD" controversy (ie amyloid=AD?)
  • Jack et al, Nature Reviews Neurol 2016