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NMH BSc > Module 2: Part 2 > Flashcards

Module 2: Part 2 Flashcards

1
Q

What is the prevalence of Huntington’s disease?

A
  • 5 per 100,000
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2
Q

What is the pattern of inheritance for Huntington’s disease?

A
  • Autosomal dominant
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3
Q

What is the genetic defect and underlying mutation responsible for Huntington’s disease?

A
  • Mutation in Huntingtin gene (HTT) on Chromosome 4 (4p16.3) which codes for Huntingtin protein (function unknown) - Causes expansion of CAG trinucleotide repeat
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4
Q

How is Huntington’s disease diagnosed?

A
  • Genetic test to count CAG repeats within Huntingtin gene - <28: normal - 29-34: normal, next generation at risk - 35-39: some develop HD, next generation at risk - >=40: will develop HD - Increase in CAG repeats associated with younger onset of symptoms and increased in severe disease
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5
Q

How does abnormal Huntingtin protein lead to gradual damage of neurons?

A
  • ? induce apoptosis - Degeneration of Medium Spiny GABAergic neurons in Caudate and Putamen (Caudate > Putamen) - Decreased GABAergic inhibition of Dopaminergic neurons —> Increased DA release —> Movements
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6
Q

What are the neuropathological changes that occur in the brains of Huntington’s disease carriers?

A
  • General atrophy (widening sulci, narrowing gyri, enlarged ventricles) - Basal ganglia atrophy
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7
Q

What is the prognosis of Huntington’s disease?

A
  • Progressive disorder - Death within 10-15 years from symptom onset
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8
Q

What are early symptoms of Huntington’s disease?

A
  • MILD SYMPTOMS - Choreic movement (rapid jerky movements of trunk, arms and face) - mask as socially acceptable movements - Depression | Clumsiness | Lack of concentration | Short-term memory lapses
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9
Q

What are late symptoms of Huntington’s disease?

A
  • PROGRESSIVE DECLINE - Choreic movements - worsen until patient is fully incapacitated - Loss of coordination and balance - Difficulty swallowing - Cognitive decline/dementia
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10
Q

How are HD symptoms measured?

A
  • Unified Huntington Disease Rating Scale (UHDRS) - Tongue protrusion (cannot) | Maximal chorea | Gait (Decreased mobility) | Dysarthria (mute) | Retropulsion pull test (falls) | Cognitive assessment (dementia) | Behavioural assessment (depression) | Function capacity (full-time nursing care) - (Brackets indicate parameters for maximal score)
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11
Q

What brain imaging can be used to assess HD pathology?

A
  • MRI: Atrophy in Caudate and Putamen - 11C-Raclopride PET
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12
Q

How does 11C-Raclopride PET assess HD pathology?

A
  • Medium Spiny GABAergic neurons express D2 receptors (these are lost in the Caudate and Putamen in HD) - 11C-Raclopride is a ligand for D2 receptor (reversible binding) = indirect marker of neuronal loss in HD (can cross BBB) - 11C attachs to Raclopride which binds to D2 receptor therefore 11C radiation only detected where there are D2 receptors - Need to account for background counts due to remaining tracer in blood - HD: decreased PET signal in Caudate and Putamen due to loss of D2 receptors/neuronal loss
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13
Q

Describe the management of HD

A
  • Pharmacological: Tetrabenazine (only drug for HD) - Psychotherapy - Speech therapy - Physical therapy - Occupational therapy - Experimental treatments
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14
Q

How does tetrabenazine work?

A
  • Tetrabenazine inhibits VMAT —> Decreased DA packaged in vesicles —> Decreased synaptic release of dopamine —> Decreased movements
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15
Q

What is an example of HD experimental treatment?

A
  • Cell transplantation therapy (allogenic transplant fetal neuronal cells into Caudate/Putamen to replace lost cell) - Variation in success | Proof-of-principle that transplanted DA neurons can successful integrate (Increased 11C-Raclopride PET signal)
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16
Q

What is the amyloid cascade and its role in neuroinflammation?

A
  • Unknown trigger —> Increased amyloid production —> oligomers —> activate Microglia —> neurotoxicity —> neuronal damage —> NFT - Neuroinflammation —> Microglial activation —> Neuronal death as a catalyst for microglial activation —> vicious cycle
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17
Q

How does PET imaging work?

A
  • PET ligand with radioisotope binds to target | Radiation (positrons) detected by scanner - Radiation detected from tissue and tracer in blood | Arterial line to take blood sample to subtract radioactivity in blood
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18
Q

Describe 11C-PIB PET

A
  • Measures amyloid - Cerebellum is devoid of amyloid in AD and control (Can use Cerebellum as a reference instead of Art. line) - By 75 years, 20% of cognitively normal people will have Amyloid deposition
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19
Q

How does AD present in 11C-PIB PET?

A
  • Significant amyloid throughout the cortex (+ve in 90% of AD) - Initially starts in the basal forebrain and then spreads | 1st deposition 10-15 years before symptom onset - Longitudinal study over 20 months: AD has no change in Amyloid over time BUT decreased glucose metabolism
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20
Q

How does MCI present in 11C-PIB PET?

A
  • 60% MCI have high amyloid (50% of Amyloid +ve MCI will develop into AD within 2 years - However, even when Amyloid +ve MCI converts into AD after 2 years, there is no change in Amyloid
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21
Q

How does DLB present in 11C-PIB PET?

A
  • Amyloid throughout - 80% DLB have high amyloid (Amyloid is not specific to diagnosing AD)
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22
Q

How does PDD present in 11C-PIB PET?

A
  • Amyloid throughout - 20% PDD have high amyloid
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23
Q

Describe PK11195

A
  • Measures activated Microglia (binds to TSPO) | Increased microglial activation is associated with decreased MMSE - AD: significant Microglial activation throughout cortex - Some areas overlap with amyloid deposition, some do not - MCI: 60% of Amyloid +ve MCI has increased microglial activation | 30% Amyloid -ve MCI has increased microglial activation (can occur w/o amyloid) - AD: Bimodal peak in microglial activation (1st peak: M2 protective | 2nd peak: M1 damaging - PDD: significant increase in microglial activation compared to PD - In established disease, Microglial activation is associated with neuronal damage and decrease Glucose metabolism
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24
Q

Describe FGD PET

A
  • Measures Glucose metabolism - AD: hypometabolism in Medial Temporal Lobe and Temporal-Parietal Cortices - With disease progression —> Decreased glucose metabolism - Glucose metabolism is a surrogate measure of measuring cognitive function (Tau is best correlated but limited Tau PET) - Longitudinal study over 20 months: AD has no change in Amyloid BUT decrease in glucose metabolism - MCI: hypermetabolism (short compensatory phase) precedes hypometabolism - PDD & PD: Decreased glucose metabolism (therefore neuronal damage occurs throughout cortex even before cognitive symptoms)
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25
Q

What are limitations to imaging techniques used to assess PD and AD?

A
  • These imaging techniques are not routinely available as they are expensive and no treatment available (no point in knowing)
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26
Q

Describe the disease progression in AD

A
  • With time: (1) CSF Amyloid-beta, (2) Amyloid PET, (3) CSF Tau, (4) MRI Changes + Glucose PET, (5) Cognitive impairment - All these biochemical changes occur before onset of symptoms - CSF: Increased CSF Tau, Decreased CSF Amyloid (Amyloid sequestration theory: Decreased CSF Amyloid as it becomes deposited as plaques in the brain) - Imaging: Increased Amyloid, Increased Tau (T807 is a Tau PET tracer) - Both Tau (marker of disease) and FDG (marker of neuronal death) changes correlate with cognitive disease
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27
Q

What is the clinical presentation of typical AD?

A
  • Impairment of Episodic Memory (recent memories - dysfunction in medial temporal lobe/hippocampus, spared older memory) - Disease progression: Increased impairment in Executive Function, Attention (frontal/parietal atrophy) | Eventually —> Apraxia (disability/dependence) - Head-turning sign (look at family for reassurance) | Difficulty following conversation | Word-finding issues
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28
Q

What is the clinical presentation of atypical AD?

A
  • May not have Episodic Memory Impairment as presenting Sx but may happen later in disease course - Younger onset | Posterior Cortical Atrophy (visuospatial issues) | Primary Progressive Aphasia (asymmetric L atrophy)
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29
Q

What is dementia?

A
  • Cognitive issue that impairs function AND affects 2 cognitive domains (1 of which is Memory) - DSM-IV - Syndromic diganosis - no assumption on cause
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30
Q

What are different types of dementia?

A
  • AD: associated with Amyloid + Tau | most common cause of neurodegenerative dementia - Dementia with Lewy Bodies (DLB): cognitive impairment before or within 1 year of PD symptoms | 2nd most common dementia - Vascular dementia: step-wise deterioration due to multiple small infarcts (cerebrovascular disease) - Frontotemporal Lobar Degeneration (FTLD): Types: Behavioural variant, Sementic Dementia, Progressive non-fluent Aphasia
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31
Q

What are different investigations for AD?

A
  • MMSE, MoCA, ACE - Neuropsychological assessment: tests multiple cognitive domains, exclude other DDx (e.g. depression), establish baseline - Structural imaging: MRI: AD: General atrophy + hippocampal atrophy, MRI to exclude DDx | CT | Longitudinal imaging studies - Functional imaging: Amyloid PET | FDG PET | Tau PET (no validated Tau ligand, would be useful since Tau ~ clinical pathology) - CSF analysis: Decreased CSF Aβ | Increased CSF Tau | Definitive diagnosis only in Brain biopsy or Post-mortem
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32
Q

What is the neuropathology of AD?

A
  • Extracellular amyloid-β plaques - Intracellular Neurofibrillary Tangles (Tau) - Neuronal loss
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33
Q

What is the aetiology of AD?

A
  • Inflammation | Oxidative Stress | Mit. dysfunction | Interaction with vascular damage | Amyloid/Tau pathology - Amyloid accumulation —> Increased Aβ accumulation —> Tau hyperphosphorylation —> Neurofibrillary Tangle - Tau pathology correlates well with Cognitive deficits in AD | 1st degree relatives will have 2x increased lifetime risk of AD
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34
Q

What are risk factors of AD?

A
  • Increased age - Vascular risk (DM, HTN) - Female > Male (2:1) - Trauma (TBI —> Inflammation & Increased amyloid) - Dementia pugilistica - Genetics: Familial AD (APP, Presenilin 1/2) - APOE (E4 - 5x risk homozygote, E2 protective) - Trisomy 21 (100% have AD by age 40)
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35
Q

What are protective risk factors of AD?

A
  • Diet - Education (Cognitive reserve effect, neuropathology occurs but onset of AD takes longer) - Exercise
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36
Q

How long prior to symptoms/diagnosis of AD does AD pathology start?

A
  • 10-20 years- Bateman, 2012 - Decreased CSF Aβ, Increased CSF Tau and Aβ deposition, decreased Hippocampal volume, decreased glucose metabolism - However, data based on Familial PD - not typical case | Typical AD has multiple co-morbidities
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37
Q

How does AD develop?

A
  • Asymptomatic (Increased Aβ) —> MCI (Higher increase in Aβ, Increase in Tau, Decrease in Memory) —> Dementia (Even higher increase in Aβ, Higher increase in Tau, higher decrease in Memory) - MCI has memory/cognitive issues BUT no function impairment (not dementia) - Should we target MCI (if this is early AD?) | MCI has many causes: AD, depression, hypothyroidism
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38
Q

What are some new terms in AD?

A
  • Subjective Cognitive Impairment (subjective memory issue, some will develop MCI) - Pre-clinical AD stage (normal cognition, pathogenic biochemical changes - if decreased CSF Aβ or increased PET amyloid —> fMRI change - Prodromal AD-symptomatic pre-dementia stage (memory loss, +ve AD biomarker)
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39
Q

What treatments are in development for AD?

A
  • Acetylcholinesterase inhibitors (Tacrine) - Memantine - Anti-psychotics - Aducanumab
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40
Q

Describe the use of acetylcholinesterase inhibitors

A
  • Mild-moderate AD | small benefit (avg. increase of 1 point MMSE over 1 year) | No effect on survival - Francis 1999: mAChR leads to tau phosphorylation | nAChR leads to APP —> Aβ - Cholinergic Hypothesis: AD cholinergic denervation of cerebral cortex, especially in Temporal Lobe - Cholinergic innervation is mainly from Nucleus Basalis of Meynert | AChR antagonists cause memory impairment
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41
Q

How does Memantine work?

A
  • NMDA glutamate receptor antagonist - For severe AD if AChEi is not tolerated - Increase in 1 point in MMSE - Synergistic with AChEi
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42
Q

When would anti-psychotics be given?

A
  • If severely agitated or hallucinations - Avoid if possible (decreases cognition, PD S/E, decreased life expectancy)
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43
Q

What is Aducanumab?

A
  • Monoclonal antibody against Aβ - Dose-dependent response - Amyloid cleared from CNS but no clinical effect - given too late? - May slow cognitive decline (awaiting Phase III results) | S/E: oedema, haemorrhage
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44
Q

What are ideal approaches for AD?

A
  • Preventative Strategies —> - Aβ- or Tau-modification strategies (immunotherapy, enzyme inhibitors, anti-aggregants, kinase inhibitors) - Symptomatic treatment
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45
Q

What is sudden deterioration of AD patient?

A
  • Likely new condition - atypical symptoms e.g. for UTI - Withdrawing or giving medications
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46
Q

What are key neuropathological features of AD?

A
  • Extracellular plaques: within brain parenchyma, poor correlation with clinical picture | Senile plaques = neuritic plaques - Classical (Neuritic) vs Diffuse - Dustbin hypothesis: cells expel out Abeta and it accumulates in the EC space —> Glial reaction - Neurofibrillary Tangles - Tau tangles have best correlation to Dementia (used to grade pathology) | contains Paired Helical Elements - Stained using Antibody against hyperphosphorylated Tau or Silver staining | Found as NFT or Neuropil threads (dendrites) - Cerebral amyloid angiopathy: Abeta deposition in the blood vessels - Neuronal loss: cerebral atrophy (esp hippocampus, frontal and temporal atrophy, widening sulci/narrowing gyri, S1/M1/Occipital unaffected
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47
Q

What is the cholinergic hypothesis?

A
  • Increase in age —> Decreased ACh turnover | AD is characterised by cerebral cholinergic denervation - Cholinergic deficits underlie memory loss and cognitive problems | Decrease in cholinergic markers correlate with dementia severity - Lessathine: ineffective - precursor unable to reach pre-synaptic terminal - Ligand (minimally effective) - AChEi (main treatment)
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48
Q

What treatments are used for AD?

A
  • Anticholinesterases (Tacrine, Donepezil): mild benefits in early AD but do not prevent disease progression - Glutamate antagonist: Memantine: believed neuron loss may be due to excitotoxicity - nAChR: Galantamine: MOA Unknown
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49
Q

What is the amyloid hypothesis?

A
  • Any factor that alters to favour Abeta production could favour Alzheimer’s disease - Altered APP metabolism —> Abeta deposition —> Neuritic Abeta plaques (—> NFTs) —> Neuronal damage —> Dementia
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50
Q

What is Braak Staging of tau in AD?

A

(1) Medial temporal lobe (2) Posterior hippocampus (3) Adjacent Entorhinal Cortex (4) Rest of Temporal Cortex (5) Occipital cortex (visual association areas) (6) Occipital cortex (primary visual cortex) | Cognitive symptoms between Stage 3/4 - Tangles highlighted using Antibody to hyperphosphorylated Tau | Pathology builds 10-15 years before Sx | >65 years have pathology

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51
Q

What are some features about Abeta and APP?

A
  • Amyloid-beta isolated from CAA (Glenner), from Plaques (Masters), Monoclonal Ab to Abeta (replace silver staining) (Allsop), APP isolated (Kang) - Amyloid precursor protein is a membrane bound glycoprotein (Carboxy intracellular, NH2 Extracellular, Abeta in membrane regions - APP is found in all cells (function Unknown) - Non-amyloidogenic cleavage (alpha-secretase cuts within Abeta sequence, non-pathological, main physiological pathway) - Amyloidogenic cleavage (beta-secretase and γ-secretase to release intact Abeta, pathological proteins, physiological role) - La Ferle, 2007: Intracellular Abeta oligomers link to hyperphosphorylated Tau (converts Tau to Tau-P —> Tangles) intracellular Aβ —> Ca2+ dysfunction, inhibit mitochondria (—> ROS) and proteasome | Extracellular plaque is just a dustbin
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52
Q

What are risk factors for AD?

A
  • Age - Family - Down’s syndrome - Previous head trauma - PD - Depression
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53
Q

What are features of familial AD?

A
  • APP mutation: Codon 717 (point mutation Val —> Ile) London mutation (1st genetic cause of AD) - Hardy J 1990 - Presenilin 1/2: accounts for most Familial AD | Presenilin has role in intracellular signalling | Presenilin has γ-secretase - Hardy J
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54
Q

What are the AD risk genes?

A
  • ApoE4: ApoE has role in lipid metabolism | 50% of AD have E4 allele | E4 homozygote —> 10x increased risk | associated with late-onset AD - TREM2: Heterozygous variant associated with increased risk of AD - GWAS SNPs: modify risk, e.g. APOE4
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55
Q

How is head injury associated with AD?

A
  • Acute head injury associated with AD-like changes “dementia puglistica” —> If they survived, would they develop AD? - 30% head injury develop Aβ deposits within weeks (these 30% have a high incidence of APoE4 - links environmental and genetic factors) - Cytokine cycle: Microglial activation - normally resolves but +ve feedback —> neuroinflammation (IL-1, APOE4) —> neurodegenerative
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56
Q

What are possible therapeutic approaches to AD?

A
  • Stop Aβ aggregation: but if extracellular plaques are a dustbin, this would lead to increased intracellular accumulation (toxic) - Clear Aβ plaques: vaccination - Animal studies showed vaccination —> antibodies against Aβ —> clear pathology in Brain - Alzheimer vaccine studies in humans stopped due to Meningoencephalitis - Birmingham 2002 - Case report of autopsy showed Aβ cleared but no change to disease course - do we need to immunise earlier? - But 25% did not actually have AD therefore results hard to interpret - Reduce APP expression: But APP is a normal physiological protein - Alter APP metabolism: enhance alpha-secretase, inhibit beta- and γ-secretase - Anti-inflammatories: epidemiological association between NSAID use (e.g. Osteoarthritis) and low risk of AD - Tissue transplant
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57
Q

How does Tau contribute to AD pathology?

A
  • Tau stabilises microtubules - Hyperphosphorylated tau —> destabilises microtubules —> Decreased axonal transport - Aggregates —> neuronal death
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58
Q

How may memory loss occur in AD?

A
  • Possibly synaptic loss due to Aβ - Synthetic Aβ —> Decreased LTP (amyloid binds to NMDA? Amyloid activates microglia?
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59
Q

Describe APP processing

A
  • β-secretase releases Aβ peptide - Non-amyloidogenic pathway: α- and γ-secretase | releases APP soluble α fragments, p3 and AICD | more common - Amyloidogenic pathway: β-secretase | release APP soluble α fragments, Aβ peptides and AICD | pathological - APP formed in ER and phosphorylated/glycosolated in Golgi —> secretory vesicles to membrane —> re-internalised in endosomes
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60
Q

What does β-secretase do?

A
  • Acts in endosomes - BACE-1 —> intracellular APP cleavage (—> Increased Aβ), also cleaves Neuroregulin (myelination) - BACE-2 (no amyloid)
61
Q

What does α-secretase do?

A
  • Acts in vesicles/endosomes - ADAM family | ADAM-10 and ADAM-17 involved in APP cleavage | also cleaves other proteins (e.g. TNF-α)
62
Q

What does γ-secretase do?

A
  • Contains Presenilin-1 which cleaves at cell surface —> extracellular Aβ | Presenilin-2 acts at lysosomes —> intracellular Aβ - γ-secretase is a protein complex (Presenilin domain has cleavage enzymatic activity) | also cleaves other proteins
63
Q

How does clearance of Aβ occur? - Tanzi, 2004

A
  • Phagocytosis (by Microglia and Astrocytes) - Enzymes degrade Aβ: Insulin Degrading Enzyme (IDE) and Neprilysin (NEP) - ApoE removes Aβ (ApoE4 is ineffective at clearing amyloid, ApoE4 carriers have an increased risk of AD - α2 macroglobulin binds to amyloid and directly removes it or indirectly via LRP receptor - Aβ can re-enter the Brain via RAGE - could extra CNS Aβ contribute to AD? Unlikely as BACE-1 and APP expression in CNS
64
Q

What are genetic risk factors for AD development?

A
  • Early onset —> Familial AD (mutations in APP, PS1, PS2) - Late onset —> ApoE4, GWAS (e.g. CR1 SNP), Epigenetic modifications - SNPs confer risk of developing AD but may not necessarily develop AD - APP mutations: London mutation near γ-secretase cleavage site | Icelandic mutation protective against AD (Decreased Aβ) - Presenilin-1 mutations: >150 mutations, tend to have more Aβ-42 and more intracellular Aβ (more endosome cleavage)
65
Q

What are environmental risk factors for AD development?

A
  • Ageing - Vascular risk factors (T2DM, HTN) - Head injury - F > M - Prions
66
Q

What is the relationship between Aβ and prions?

A
  • Iatrogenic prion cases due to human GF —> CJD also had increased Aβ pathology (prion-like spread or auto-catalytic change) - Aβ and Tau spread in a prion-like fashion | Was amyloid already present (>65 likely to have Aβ changes) | Presence of Aβ may not necessarily cause AD | This population required GH - not representative of general population
67
Q

What is the Amyloid Seeding Hypothesis?

A
  • Amyloid behaves like a prion - Inject AD amyloid into young WT transgenic mice - Results: WT mouse with AD Amyloid develop plaques BUT not in transgenic mice without APP or if synthetic amyloid is used
68
Q

Describe the Parabiosis experiment

A
  • Transgenic animal with APP linked to WT animal —> WT had increased amyloid plasma and CNS amyloid deposition - Can you get AD from blood transfusions? Unlikely as Amyloid likely to stick to blood vessels rather than enter Brain
69
Q

What are the current Aβ-based therapeutic approaches being researched to treat AD?

A
  • Albright, 2008 - BACE inhibitors and γ-secretase inhibitors - Aβ modulators (affect length of Aβ, make more Aβ-37 than Aβ-42) - Catabolism inducer (Increases Aβ metabolism) - Immunotherapy
70
Q

How does immunotherapy work in AD treatment?

A
  • Inject Aβ —> Good evidence base in Animals (Decreased Aβ in Brain, Increased memory) | Clinical trials have an increased risk of sepsis - Inject antibodies to Aβ (passive immunisation) —> Many clinical trials prove unsuccessful
71
Q

What Tau-based therapeutics are used to treat AD?

A
  • Tau aggregation inhibitors: Autophagy enhancers, Tau assembly inhibitors, Methylene blue - Tau kinase inhibitors (GSK3, CDK5): e.g. Lithium (psychiatric S/E effects) - Microtubule stabilisers - Hsp90 inhibitors (affect proteasome degradation of Tau)
72
Q

What neuronal-based therapeutics are used to treat AD?

A
  • Growth factors: BDNF, NGF (but does not cross BBB, gene therapy to introduce NGF - limited benefit) - NMDA antagonists: Decreased glutamate excitotoxicity - Anti-oxidants: Decreased oxidative stress - Anti-inflammatories - Anti-diabetic drugs: Decreased risk of AD (e.g. Pioglitazone)
73
Q

How do anti-inflammatories work to treat AD?

A
  • Regular taking of NSAIDs have lower incidence of AD - NSAIDs reduce Aβ formation and Tau hyperphosphorylation - NSAIDs target COX-1, COX-2, NFkb (Increases TNF-α), PPAR-γ (Increases BACE-1), Presenilin activity (γ-secretase) and Cytoskeleton (Rho, Rock) - Many clinical trials with NSAIDs are unsuccessful - too short? Need long term intake? Need to take earlier on? Use in MCI?
74
Q

Describe AD progression

A
  • Amyloid plaque (starts in basal forebrain, spreads to rest of cortical areas) | NFT (Tau) start in medial temporal lobe - Pathology starts 5-10 years before onset of symptoms (Aβ plaque and hyperphoshorylated already accumulated by time of Dx) - Therefore clinical trials unlikely to show benefit
75
Q

How can you identify patients in asymptomatic phase?

A
  • Alzheimer’s Prevention Initiative
76
Q

What are the different stages to those who are at risk of AD?

A

(1) Increased PET amyloid, decreased CSF amyloid (2) Increased CSF Tau (3) Cognitive changes

77
Q

What is the order of AD pathology?

A

(1) Aβ pathology (CSF/PET) (2) Tau pathology (CSF) (3) Brain structural changes (MRI) (4) Cognitive changes

78
Q

What in vitro models used in Alzheimer’s research?

A
  • Transfect cell lines with APP: Neuroblastoma (tumour cell line, as neurons do not replicate) | Measure Aβ level in medium - AD patient-specific iPSCs: same mutations (BUT difficult to find a control, as different people have differences unrelated to AD)
79
Q

What in vivo models are used in Alzheimer’s research?

A
  • Rats/Mice: Similar brain anatomy, behavioural tests, NFT/Plaque staging VS Time-consuming, Expensive, No Aβ plaques - Fish: Giant neurons (microinjections) VS Different brain anatomy, Behaviour/Staging difficult - Worm: Easy + Fast to breed, Cheap, No ethical issues, Powerful genetics VS Different brain anatomy, Behaviour/Staging difficult - Drosophilia: Easy + Fast to breed, Cheap, No ethical issues, Powerful genetics VS Different brain anatomy, Behaviour/Staging difficult
80
Q

How are rodent models good for AD modelling?

A
  • Behavioural / Cognitive dysfunction - Impaired synaptic plasticity - δ APP processing - Amyloid plaques
81
Q

What are issues with rodent models for AD?

A
  • Rat and mice do not develop Aβ plaques: amino acid differences —> Aβ does not aggregate - Therefore transgenic animals express human protein (e.g. APP, Presenilin, Tau) - E.g. APP-23 mice overexpress APP with Swedish mutation | Tau models have mutations similar to FTLD (not true AD) - Double/Triple Transgenic animals may express APP, Presenilin and Tau —> these will have Aβ plaques & NFTs - However, mice models do not have large neuronal loss / atrophy (seen in human AD)
82
Q

What is the Cre-LoxP strategy for conditional gene KO?

A
  • Certain gene KO is embryonically lethal (e.g. Presenilin KO) - Conditional KO = gene KO in certain cell type or specific brain area | Method: cross Floxed mouse with Cre mouse - Floxed mouse has LoxP sites around target gene (removed) | Cre mouse has Cre-Recomb enzyme inserted after specific promote - Cre recombinase only expressed in certain cell type therefore KO (LoxP site + gene removed) only in specific cell types - E.g. Conditional KO of Presenilin (—> Decreased γ-secretase) mice crossed with APP transgenic mice do not develop plaques
83
Q

How are AD rodent models assessed?

A
  • Behavioural tests: assess memory (e.g. Morris water maze, Y maze with Food, Object recognition - only curious of novel objects) - Electrophysiological measures/Long term potentiation: assess strength of synapses - Brain imaging: difficult to distinguish certain brain regions as mouse brain is small, rat models are preferred for imaging
84
Q

What do intracerebral injections of AAV-vectors into Wild-Type Mice do?

A
  • Adenovirus with Tau —> neuronal loss in hippocampus (not seen in transgenic Tau, overpression of Tau affects neuronal survival - Adenovirus with APP —> plaques (some, not all - due to variation in experimental technique)
85
Q

What are the syndromes of FTDs?

A
  • Syndrome: Semantic dementia | Behavioural variant | Progressive non-fluent aphasia - Pick’s disease
86
Q

What are key neuropathological features of Pick’s disease?

A
  • Frontal symptoms - sporadic Tauopathy (no MAPT mutation) - Front-temporal atrophy (knife-edge atrophy) - Neuronal loss (atrophy) - Balloon neurons - Tau +ve Pick bodies (intraneuronal inclusions of hyperphosphorylated Tau)
87
Q

What are the different types of Tau antibodies?

A
  • PHF1 Tau antibody (general) - 4R-Tau antibody - 3R-Tau antibody (Pick bodies)
88
Q

What are the different tauopathies?

A
  • 3R/4R tauopathy: AD | FTLD with 3R and 4R Tau (V337M, R406W)
  • 4R tauopathy: CBD | PSP | FTLD with 4R Tau (P301L)
  • 3R tauopathy: Pick’s disease | FTLD with 3R Tau (K257T, G389R)
89
Q

What are key neuropathological features of Tau FTD pathology?

A
  • PiD (Pick bodies) - CBD (Astrocytic plaques) - PSP (Coiled bodies, tufted astrocytes)
90
Q

What is the role of progranulin in FTD?

A
  • Some FTD had Tau -ve neuronal inclusions - Function of progranulin is unknown, not know if part of inclusions - Separate gene mutation in Proganulin gene (adjacent to MAPT gene for Tau) | Intracytoplasmic and intranuclear inclusions - MRI imaging changes: Progressive marked asymmetrical atrophy (Laterality) - Fox et al
91
Q

What is TDP-43?

A
  • Tau subtype based on molecular changes and clinical phenotype: - A (Semantic dementia) - B (C9orf72) - C (Progranulin, FTD) - D
92
Q

What is FUS?

A
  • Fused in Sarcoma - Characteristic inclusion - Accounts for some atypical FTLD Ubiquitin +ve (aFTLD-U)
93
Q

What is C9orf72?

A
  • Commonly associated with ALS - Ubiquitin +ve TDP-43 -ve C9orf72 +ve inclusions in Cerebellum (other parts TDP-43 +ve)
94
Q

What is the current classification of Tau +ve FTLD?

A
  • 4R tauopathy: CBD | PSP | FTLD with 4R Tau - 3R tauopathy: Pick’s disease | FTLD with 3R Tau - 3R/4R tauopathy: AD | NFT-dementia | FTLD with 3R and 4R Tau
95
Q

What is the current classification of Tau -ve FTLD?

A
  • TDP-43 +ve Ubiquitin +ve: FTLD-TDP (subtype A-D) - TDP-43 -ve Ubiquitin +ve: FTLD-FUS | FTLD-UPS - TDP-43 -ve Ubiquitin -ve: DLDH (dementia lacking distinctive histology)
96
Q

What is the clinicopathological correlations seen in FTDs?

A
  • FTLD-Tau: Pick’s disease (3R Tau) | CBD/PSP (4R Tau) | NFT-Dementia - FTLD-TDP: Type A-D (molecular subtypes associated with different clinical phenotypes) - FTLD-FUS: accounts for some aFTLD-U - FTLD-UPS: Mutation in CHMP2B gene
97
Q

What is Charles Bonnet Syndrome?

A
  • Complex visual hallucinations in individuals with acquired visual loss and insight and no cognitive impairment
98
Q

What is the DDx of visual hallucinations?

A
  • Neurological: PD, DLB, Epilepsy - Psychiatric: Schizophrenia - Drugs - Sleep deprived
99
Q

What is dementia?

A
  • Insidious onset of progressive mental decline that interferes with ADLs - Is a syndrome not a disease | Consciousness is clear (no stupor or delirium) - Multiple deficits: Behaviour | Attention | Memory | Language | Visuospatial function - Situation stress may lead to deterioration and bring out dementia - Types: Reversible vs Irreversible | Slow or rapidly progressive | Multiple or isolated deficit
100
Q

What are different types of neuerodegenerative dementia?

A
  • AD (most common) - Insidious amnesia, language impairment - DLB - Parkinsonism, Fluctuation, Agitation, Hallucinations, Visuospatial function - PDD - PSP, CBD - FTLD - Personality change, poor planning, lack of hygiene - HD - MND - Wilson’s disease
101
Q

What are some investigations for dementia?

A
  • History and Neurological examination —> Dementia is a clinical diagnosis - Occupational Hx | Education background | Baseline personality | Self Care (ADL) | Memory | Language | Sleep - MMSE | Addenbrooke’s Cognitive Examination | MoCA - Biomarkers: CSF Tau, CSF Amyloid - EEG: in dementia —> slow wave activity (delta waves replace normal organised brain waves) - Imaging: CT | MRI | PET | SPECT - Brain biopsy: (definitive diagnosis)
102
Q

What can result into traumatic/structural dementia?

A
  • Subdural haematoma - Head injury - Dementia pugilistica - Diffuse Axonal Injury - Cerebral contusions - Normal Pressure Hydrocephalus - Neoplasm
103
Q

What can result in vascular dementia?

A
  • Multi-infarct dementia - Cerebral Amyloid Angiopathy - Vasculitis (Wegener’s)
104
Q

What are metabolic causes of dementia?

A
  • Hypoxia/Hypercapnia - Uraemia - Hepatic encephalopathy - Thiamine/B12 - Hypoglycaemia
105
Q

What are toxic causes of dementia?

A
  • Medication (Anticholinergic, Valproate) - Alcohol - CO
106
Q

What are psychiatric causes of dementia?

A
  • Schizophrenia - Depression (pseudodementia) - Bipolar disorder
107
Q

What are DDx of Dementia?

A
  • Normal aging - Psychiatric Disease - Drugs e.g. Alcohol, Wernicke-Korsakoff’s - Focal neurological syndromes - MCI - MS
108
Q

How does psychiatric disease cause dementia?

A
  • Depressive pseudo-dementia - prevalent in those who have multiple losses, refuses to engage, give up - Depression: often misdiagnosed as dementia in 8-15% of patients | Only 20% of demented patients have depression
109
Q

What are examples of focal deficits in dementia?

A
  • Aphasia - Anomia - Amnesia - Inattention - Hemi-neglect - Apraxia - Alien limb - Prosopagnosia
110
Q

What is delirium?

A
  • Impaired stream of thought and cognitive deficit
111
Q

What are symptoms of delirium?

A
  • Impaired attention - Hallucinations - Fluctuating course - Apathy - Agitated - Tremor - Asterixis
112
Q

What is MCI?

A
  • Cognitive impairment insufficient to reach criteria for dementia - Types: Amnestic vs non-amnestic | 10% convert to Dementia every year - Ix: Serial scanning to examine those at risk
113
Q

How is MS involved in dementia?

A
  • Extensive MS lesions throughout hemisphere may present with dementia or cognitive impairments - Symptoms: Optic neuritis, sensory, motor, gait, autonomic, fatigue
114
Q

What are some features of TBI

A
  • Disease process - Difficult to research due to heterogeneity - Increased 2x long-term mortality (Glasgow cohort) | Repeated TBI —> Increased risk of Alzheimer’s disease and dementia
115
Q

What are features of primary injury?

A
  • Mechanical input —> Primary injury —> Secondary injuries | These + Restorative processes influence long-term outcome - Force —> Stress/deformation/strain | If energy applied > threshold —> Primary injury - Primary injury - impacts effects: Tissue deformation | Contusions | :Lacerations | Haemorrhages - Primary injury - non-impact effects: Diffuse axonal injury | Swelling - Primary injury occurs immediately therefore primary injury is sensitive to preventative measures BUT not therapeutic measures
116
Q

What is focal injury?

A
  • Contusions | Haemorrhages | Laceration
117
Q

What is diffuse injury?

A

DAI | Swelling/Herniation | Ischaemia | Vascular injury

118
Q

What is the pathophysiology of Secondary injury?

A
  • Primary injury - Ca2+ influx - Release of NT —> Excitotoxicity - Mitochondria damage —> ROS - Trigger gene expression - BBB opening —> inflammation - Oedema —> Increased ICP —> Herniation
119
Q

Describe inflammation of secondary injury

A
  • Inflammation: (DAMPs, Chemokines, Cytokines) released at site of injury —> Neutrophils, Monocytes —> Microglia/Astrocytes
120
Q

Why are in vivo models of TBI necessary?

A
  • Single model cannot truly reproduce complex pathophysiological spectrum of TBI - Catch 22: Balance between reducing complexity to be able to model it VS retain overall validity for translation - BUT animal models are necessary to identify mechanisms and test therapies
121
Q

How do you assess validity of a model?

A
  • Face validity: same phenomenology - Construct validity: similar underlying mechanisms - Aetiological validity: similar changes in aetiology - Predictive validity: predictive value, accuracy and reliability
122
Q

What are features of primary mammalian TBI models?

A
  • Gross histopathology: Contusion | BBB disruption | Cell loss | Brain atrophy - Molecular changes: Inflammation | Apoptosis | Oxidative stress | Axonal injury - Functional deficits: Memory and Learning deficits - Long term effects detectable in rodents up to 1 year
123
Q

How is management for stroke approached?

A
  • Medical history - Vital signs - Neurological exam (NIHSS stroke severity scale) - Imaging (CT)
124
Q

What does Modified Rankin Scale do?

A
  • Measures level of disability (0-6)
125
Q

What imaging is used for Stroke?

A
  • MR Angiogram (vascular occlusion) - DWI (infarct core) - Perfusion MRI (hypoperfusion) - MRI Perfusion - DWI —> core + penumbra
126
Q

What are the two types of recanalisation therapy?

A
  • IV Thrombolysis (within 4.5 hours symptom onset) - Mechanical Thrombectomy (with 6-24 hours) (If no haemorrhage —> remove obstruction)
127
Q

Describe IV thrombolysis

A
  • Thrombolysis increases proportion of patients with good functional outcome (mRS) - For every 100 people, 32 benefit - Early treatment after symptom onset —> Increased Odds ratio of good outcome (? Ambulance with CT Scanner) - EXTEND Trial: Phase III RCT IV Thrombolysis with rtPA vs Placebo (attempting to increase window 4.5-9hr
128
Q

Describe mechanical thrombectomy

A
  • Types: Ultrasound | Shock-wave | Laser | Stent retrievers | Aspiration - Recanalisation rates: Mechanical recanalisation (80%) effective vs IV rtPA alone (50%) - Rha, 2007 - 5 RCTs shown higher % good outcomes with Endovascular treatment vs Standard care (number to treat = 5) - Goyal - Benefit has shown 4.5 hours BUT faster is still better - European Stroke Organisation recommendations: Mechanical Thrombectomy (+/- IV tPA) recommended for large artery occlusions in Anterior circulation up to 6hr after symptom onset, should not delay IV thrombolysis, should be done ASAP
129
Q

What types of neuroprotection is done for stroke?

A
  • Surgery (if severe) - e.g. basilar artery thrombosis | 50-90% mortality | Severe morbidity | Early recanalisation is key - Davis, 2006 - Hemicraniectomy (allow Brain to swell to prevent increased ICP —> respiratory depression | DESIRE trial —> major reduction in mortality BUT survivors had long-term disability - Physical (hypothermia) - Pharmacological: Energy failure | Peri-infarct depolarisation | Excitotoxicity | Microglial activation | Inflammatory infiltrate
130
Q

What is involved in stroke unit care?

A
  • Stroke unit (interdisciplinary team consisting of vascular surgery, neuroradiology/surgery, cardiology, SALT, OT, PT - Monitor acute stroke patient >24 hours (as high risk of 2nd stroke) | Monitor vital signs | Prevent complications - Need to know the cause (affects management - antiplatelets for stroke prophylaxis BUT anticoagulant for AF) - Stroke Units —> Decreased morbidity, mortality and inpatient treatment - Cochrane Review, 2004
131
Q

What % of strokes are intracerebral haemorrhages?

A
  • 10-15% - 2x higher mortality than Ischaemic stroke
132
Q

What are the causes of non-traumatic ICH?

A
  • Hypertensive arteriography (70%) - Cerebral amyloid angiopathy (20%)
133
Q

What is a haematoma extension?

A
  • Minor symptoms/small bleed —> few hours later, extensive bleed - Occurs in 1 in 3 cases - “Spot sign” patients more likely to undergo haematoma extension (1st desc Becker) | Recent trial found no difference
134
Q

What are two types of management of ICH?

A
  • Haemostatic therapy - Minimise risk of ICH in patients taking Oral Anticoagulants - Anti-hypertensive therapy - Surgery
135
Q

How does haemostatic therapy work?

A
  • Recombinant Factor VIIa: F7 interacts with TF to activate coagulation cascade —> Decreased risk of haematoma expansion - Phase III trial: r7a reduces risk of haematoma expansion c.w. placebo BUT no difference in outcomes - Mayer et al - Tranexamic acid - TICH-2 trial: Administration of Haemostatic drug not currently recommended for ICH
136
Q

How do you minimise risks in patients taking Oral Anticoagulants?

A
  • Oral Anticoagulants responsible for 10% of all ICH strokes | Oral anticoagulation —> Increased risk of haematoma enlargement - RCT: INR reversal comparing Prothrombin concentrate vs Fresh Frozen Plasma - Steiner, 2016 - Prothrombin concentrate more effect at decreased haematoma expansion and decreased mortality - Reverse effects of NOACs - Idarucizamab (human Fab fragment of Antibody) reverses effects of Dabigatran (immediate) - Animal models show Idarucizamab —> Decreased haematoma expansion, decreased mortality - Na, 2015 - Andexanet-alfa (recombinant modified human factor 10a) to reverse F10a inhibitors - ANNEXA-4 trial: ongoing
137
Q

Outline anti-hypertensive therapy

A
  • Haemorrhage pressure pushes on torn vessels - should treat HTN? Controversial as area around haematoma already hypoperfused - INTERACT-2 Trial: intensive BP lowering < 140mmHg vs Standard: Decreased mortality, decreased disability - ATACH-2 Trial: Intensive BP lowering to 110 - 140mmHg: no significant difference in intensive lowering - NICE guidelines (2008): Not recommended to lower BP (unless SBP > 200mmHg)
138
Q

What has the STICH trial (surgery) shown regarding management of ICH?

A
  • No difference in survival
139
Q

Why are animal models used in stroke?

A
  • Animal models help understanding important aspects of molecular, cellular and systemic process - Pre-clinical models useful to evaluate the effects of drugs and other therapeutic interventions
140
Q

What percentage of ischaemic stroke models are rodent models?

A
  • 80%
141
Q

What are the limitations of rodent models for stroke?

A
  • Humans have a gyren-cephalic brain - Rodents have a Thelissencephalic brain - Compared to humans, rodents have - Increased capillary density - Decreased inter-capillary diffusion distance - Increased CSF turnover - GM/WM ratio
142
Q

What are translational issues regarding use of rodent models for stroke?

A
  • Statistical issues (randomisation, blinding etc) - Method in lab vs clinical trial - Different time windows
143
Q

What are examples of models of Haemorrhagic stroke?

A
  • Collagenase-injection model: collagenase dose-dependent of basal lamina of cerebral blood vessels BUT foreign protein - Blood injection model: direct injection of defined amount of blood into Striatum BUT no vessel damage and Trauma
144
Q

What is stroke-induced immunodeficiency?

A
  • Lymphocytopenia, decreased responsiveness of immune cells to in vitro stimulation - Release of stress hormones bind to receptors on Immune cells —> Immunosuppression - Biphasic modulation: Day 1 (massive upregulation of immune cells), Day 2 (downregulation, splenic atrophy), why?
145
Q

How does stroke lead to infections?

A
  • Increased infarct size —> Immunosuppression —> Increased infections - 30% stroke patients develop infections - Pneumonia is main cause of death
146
Q

How does acute ischaemia increase infarct size?

A
  • Acute ischaemia —> Acute inflammation (harmful) —> Infarct enlargement - Microglial activation —> Pro-inflammatory cytokines —> Increased adhesion molecules/chemokines —> Increased transmigration
147
Q

What’s the role of T cells in stroke mediated immunodeficiency?

A
  • Rag2 transgenic mice lack lymphoctyes —> small infarcts - Liesz
148
Q

How does Natalizumab work?

A

(Originally treatment for RR MS) - Blocks Integrin-alpha4 on T cells —-> Decreased VCAM-1 and VLA-4 interaction —> Decreased transmigration - Phase II: Natalizumab administered up to 9h after stroke onset did not reduce infarct growth BUT increased outcomes - Elkin, 2017 - Translation failure

NMH BSc (7 decks)

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