SAQ's Flashcards
Evaluate the relevance of mouse models for understanding 3 conditions
- NTD allowed the identification of mutations of proteins in planar cell polarity pathway - different labs found NTD in their mice when mutationswere here + allows us to get an idea of development of anencephaly:
2 stages: failed cranial neuralation -> exencephaly -> anencephaly - Prion - strain typing
- DS -> developmental stages of DS
Briefly explain the variation in clinical phenotype based on the processes of normal neurulation in the embryo
1o neurulation defects:
• craniorachischisis, anencephaly, open spina bifida
The whole process aims at wrapping up this plate of cells into a tube which will fuse and separate – be covered
by surface layer that will eventually fuse so that we get a tube. It follows that the problem here is it leads to an
open defect because this fusion never finally occurs.
2o neurulation defects:
• closed spina bifida, often with lipoma
Half of neural tube is formed by secondary neuralation. - no closure process - problem with separation since
neural tube here forms by canalisation. The process can be interrupted by tethering.
Explain the pathogenesis underlying anencephaly
Two step process:
- anerior neuropore fails to close - skull doesn’t form
- exencephaly - then amniotic fluid degrades brain
- anencephaly -> still birth
Define anencephaly and spinal bifida; explain the role of planar cell polarity signalling in their formations.
If the anterior neuropore fails to close, then we anencephaly. It’s the zippering down that doesn’t finish to completion and we get open spina bifida (sack contains CSF) Planar cell polarity signalling:
- mutations in proteins of this pathway lead to NTD
- they all have different functions but act together for closure 1 to occur
- > closure 1 is needed or whole body will not close i.e. craniorachisis
- e.g. Scrb1 -> cellular localisatiton
- e.g. Vngl2 - tail closure in mice + frogs
Outline the evidence for hypoxia playing a role in MS
If we inject liposaccharide which induces hypoxia inducible factor 1
- a pattern III MS lesion appears after 10 days
- Lesion will always appear at base of DH
- > vascular watershed
- Cerebral angiograms - we know that arteries run over the surface then branch inwards
- as fine vessels go deeper - less O2 in blood
- FAD fluoresce in mitochondria also elude to hypoxia since FAD can only be made in the presence of O2
What are the main pathological features of MS?
Demyelination - conduction block
Inflammation - conduction block
Mitochondria - lack of ATP -> Na+/K+ pump less efficient -> RMP setting
Degeneration -> loss of function
How does the pathophysiology of MS dictates some of the symptoms experienced?
Uhthoff’s - Cooling increases safety factor – kinetics of sodium channels
-> warm up proteins they work faster – sodium channels open and close faster if they get warmer – if normal is green – the duration shortens in demyelinated preparation – AP just about making it across – AP shorter – may go into conduction block
Tingling: ectopic activity -> generator potential generating AP -> more regular depolarizing potential generating each individual action potential
– inward K and inward Na develop at demyelinated state
If the brain is receiving burst of impulses
– pin prick going to interpret as a tingling sensation.
Permanent symptoms: continuing outflow of axoplasm has caused transected axons. CNS axons don’t regenerate these are permanently functionless
Describe the common types of TBI
Focal Damage: characterised by fractures, intercerebral contusions, bleeding: subarachnoid haemmorhage, extradural and subdural haematomas and intracerebral haemmorhage
- CT better to identify
Diffuse axonal injury: damage to connections between regions - MRI better to identify - clearer (SWI)
Describe the cognitive deficits following network disruption due to TBI
- DAI leads to disruption of large-scale brain networks
- Leads to typical pattern of cognitive deficits
- Poor attention / working memory
- Executive dysfunction
- Behavioural issues
- Social cognition difficulties
- Psychiatric problems, criminality, relationship/job breakdown, substance abuse and risk taking behaviour
What are the current methods used to assess TBI
Neuropsychological tests to assess executive dysfunction, lack of insight, central cognition problems, impulse issues, attention and memory, intelligence
Executive e.g. Stroop/ Trail making test
Insight from employer + friends may be more useful since Neurpsych tests: removed from day to day function, lacks sensitivity for high level deficits, poor detection of social cognitive deficits, mood/somatic symptoms can affect results
Paedeatric/autism tests might be useful
Validated - criminals may abuse tests
MRI can also be used to predict outcome
- Gliosis and scarring
– brain volume loss
What is the potential role of advanced imaging in TBI
Serial MRI - ? progressive atrophy
- Gliosis and scarring
– brain volume loss - longitudinal volumetric imaging
- yearly – if you see atrophy by more than 1% -> even
after a single concussion there seems to be some atrophy 6 months later
Investigation of advanced imaging (DTI, Tau-PET)
and novel CSF markers (CCL11)
PET – ligand that binds to tau in brain -> red is tau binding
-> more controls were done and it’s not very specific
– lots of people have tau in their brain
Briefly explain the relationship between TBI and neurodegeneration
if you have mTBI – you’re 4 times more likely to develop AD and a younger age
– if you are hospitalised for your TBI – 6 times more likely for psychiatiric disorders + early death
Scott et al., 2018 - found chronic microglial activation associated with degeneration but turning off micro glia with minocycline worsens degeneration
Cole et al., 2018 found progressive brain atrophy over time
Anne McKee 2009 -> abnormal tau deposition in 47 cases of athletes
Key features of Down syndrome clinically
Invariant features:
- Cognitive impariment
- Hypotonia - lack of muscle tone
- AD-like pathology
Variable features:
- Spontaneous abortion (2% of all)
- Heart defects
- Autoimmune disorders
- Leukaemia
- Dementia
Key features of Down syndrome genetically
French group 1959 – year that the first chromosomal disorders were
really pinned down in humans
– it was very difficult to look at chromosomes before this
– by the late 50’s it became clear that humans have 48 chromosomes
– Gautier learned how to make chromosomes from myocytes
-> chromosome 21 had 3 chromosomes in down syndrome -> trisomy 21
47 mega bases of extra DNA - Hsa21 ~230 protein coding genes +
29 miRNA’s with lots of non-coding elements
Not due to mutant gene due to a dosage problem
– genes like to be in 2 doses not 3
List mechanism and therapies for neurological consequences of DS
in vitro – if you take pluripotent stem cells and try to grow neurospheres
these also develop reduced neuronal number -> slower cell cycling
going on -> excessive GABA transmission
-> DS cognition -> 40% IQ 50-60
ACEI not worked in mice or in humans – lots of other trials in place
– anti-inflammatories – anti depressants - -> trial
– pregnant women Prozac fluoxetine – affect neurogenesis
-> DS fetuses + fluoxetine
• Other trials NMDA antagonists, anti-inflammatories
(damp down effects of microglia),
antidepressants (affecting neurogenesis).
• Excess GABA inhibition, some data from mouse on a GABAA antagonist,
large well-controlled Roche trial. Not worked.
Inverse agonist of alpha5 subunit of the GABA A receptor
