From StudyingMed

< BPT
Jump to: navigation, search
Line 115: Line 115:
 
* Frontal variant AD - executive deficits
 
* Frontal variant AD - executive deficits
 
* Progressive aphasia: Fluent (anomic) or non-fluent (logopenic - hesitant speech production because of word finding difficulties. one-way anomia)
 
* Progressive aphasia: Fluent (anomic) or non-fluent (logopenic - hesitant speech production because of word finding difficulties. one-way anomia)
* Posterior cortical atrophy
+
* 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
 
** 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)
 
** 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
 
* Primary visual cortex (visual variant AD) - cortical blindness
* Congophilic angiopathy - lobary haemorrhages, infarcts, inflammatory
+
* 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
  
 
[[Category:BPT]]
 
[[Category:BPT]]

Revision as of 10:56, 17 July 2018

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