Mechs of demyelinating disease Flashcards
What are the different types of remyelination mechanisms
Scaffolding
OPCs (source, migration, activation, effectiveness)
Oligodendrocytes (not massively useful)
What are the effects of demyelination on neuronal function
Effects are both long term and short term
What disorders might you find demyelination
There are demyelinating lesions in MS
What pathological features are found in MS
- inflammation
- demyelination
( grey matter effected greater overall and highest for PPMS) - axonal transection
- neuronal loss
- gliosis
- grey matter lesions (67% in sulci of cortical area)
What are the features of white matter lesions in MS
- they tend to occur around the lateral ventricles
- tend to form around veins
- BB disruption may occur at onset,
What are the types of short term effects of demyelination
Acute demyelination
- sheath degeneration and message unable to propagate down the axon
Chronic demyelination
- sheath degeneration, increase of channels along axon allow propagation to the next node of ranvier
What are the long term effects of demyelination
The loss of myelin sheath allow for an increase of Na (sodium) channels along that axon
The increase of sodium eventually leads to unstable distribution of sodium and potassium in the neuron.
The increased demand of glucose from the mitochondria to the ATP pump to clear the increase is not maintainable and glucose is depleted, therefore the ATP pump cannot maintain the chemical balance of sodium and potassium which eventually leads to neuronal death
What are the types and effects of animal model demyelination
Toxic - Cuprizone, ethidium bromide
(Oligodendrocyte death, remyelination days after withdrawal)
Inflammatory - experimental autoimmune encephalomyelitis
(Monophasic or relapsing remitting lesion formation)
Viral - theilers mouse virus encephalomyelitis
( chronic encephalomyelitis)
What is remyelination and what are the processes of remyelination
The development of myelin sheath after loss
- it can be complete in some models
- varies between people with MS
- varies between lesions
Normal
Demyelination
- loss of some myelin sheath
Remyelination
Remyelination failure/ axonal loss
What is the evidence of remyelination?
G ratio
Circumference of the axon / circumference of myelin
What are the molecular processes of remyelination
- Proliferation of OPCs (oligodendrocyte progenitor cells)
( + BDNF (brain derived neurotrophic factor)
( - notch-1) - Migration
(+ FGF2 ( fibroblast growth factor)
(- CSPG (chondroitin sulfate proteoglycan) - Differentiation
- Generation
- Wrapping and compaction
(+ HGF ( hepatocyte growth factor)
(- LINGO1)
Each step is controlled by signalling pathways that can be supportive of inhibitory.
What are the treatment agent trials?
Olexosine
(promotes remyelination in vitro an mouse models)
Anti- LINGO-1
(LINGO-1 expressed by oligodendrocytes inhibited differentiation)
Histamine receptor antagonist
(H3 antagonist enhanced remyelination in cuprizone model)
What ate the drugs, mechanisms and their effect on MS patients in trials
GSK239512 (histamine h3 receptor antagonist)
- trialled on RRMS
- small effect on MTR (magnetisation transfer ratio)
Opicinumab (Anti- LINGO1 antibody)
- trialled on RMS
^ negative for clinical outcomes
- trialled on acute optic neuritis
^ reduced VEP (visual evoked potentials) in PP population
What is Neuro protection and what are the current investigations?
4-AP
Reduces axonal loss in experimental AON (anterior olfactory nucleus)
- VGKC blocker, enhances conduction, reduces Neuro axonal vulnerability to demyelination, promotes remyelination
Clemastine (1st generation antihistamine, can induce OPC differention)
- full field, pattern reversal VEP P100 latency shortening as outcome
- shows remyelination/ repair to be promising and achievable in MS
High dose Biotin
- no significant differences
Anti-LINGO-1 (opicinumab) review
-possible remyelinating effect
What are the optimal outcome measures for phase 2 trials
Treatment trial
- people at risk of progression
- does the treatment work?
Clinical practice
- is this person likely to progress?
- is this treatment effective for them?
MRI
- T2 weighted lesion
- magnetisation transfer ratio
- quantitative MT
- myelin water fraction
- diffusion tensor imaging (radial diffusivity)
PET
- [11C] PIB
What is pathological specificity in MS
Histopathological features
- myelin density
- axonal density
- glial density
MRI features
- MTR
- DTI : FA
- DTI : MD
What is MTR
MTR is magnetisation transfer ratio
It is contrast mechanism that is used extensively to investigate tissue microstructure in the brain.
What are the key concepts of remyelination in demyelinating diseases
- high capacity in the CNS to remyelinate
- remyelination is variable in MS
- remyelination may be promoted or inhibited by endogenous factors
- factors involved in remyelination may be amenable to modification by drugs
