Module 8 Extra

Question 1

M8Extra - The various clinical courses of MS and related diseases

Answer 1

Types of MS is relapse remission, primary progressive and secondary progressive.
Primary progressive MS develops with increasing neurological deficits and there is no remission. Disease onset is in your 50s.
Relapse remission MS has episodes followed by remission and generally turns in to secondary MS. Onset is in 30s but conversion to secondary progressive is in the 50s.
In primary/secondary there is similar speed of progression and the disease activity (lesions) can be seen in MRIs.
Genetics: for relapse remission, there is 1/3 more females but primary progressive it’s not as common. If you carry risk genes but don’t have it, the mother can pass it on but the men can’t  might indicate that mitochondria genes are implicated

Related disease:
MOGAD: antibodies towards MOG  demyelination. Targets eyes more than MS and steroids helps recover functions
NMOSD – autoantibodies against AQP4 channels in the astrocytes  astrocyte and neuronal damage (demyelination). Has a relapse-remission profile. Cognitive changes are often not seen in NMOSD but in MS.

Question 2

M8Extra - The immunological biomarkers associated with MS

Answer 2

MS in MS, we see T cells (CD8 more than CD4), B cells and macrophages.
More than 90% of MS patients have intrathecal oligoclonal bands (IgG) in cerebrospinal fluid
Markers for neurodegeneration
- Neurofilaments in the serum and CSF (you can measure neurodegeneration but it’s not MS specific)
- Measure astrocytic activation (marker for active disease in the relapse remission cases – where we have inflammation)

Question 3

M8Extra - Grey matter and white matter disease, focal lesions and diffuse injury

Answer 3

You have focal white matter lesions and there are different types: active (BBB injury associated), chronic active, slowly expanding lesions and inactive lesions.
The active focal ones are in the early stages (in relapse remission) and the chronic active and slowly expanding lesions are associated the progressive stages (both)

De-myelination in the gray matter
Cortical demyelination increase with disease progression and the active lesions are associated with meningeal inflammation.
Demyelination in the gray matter in the spinal cord is seen in the early stages and active lesions are associated with perivascular inflammation.

Diffuse neurodegeneration
Both in white and gray matter (can’t be seen morphologically), but does lead to brain atrophy. You can observe it in progressive stages. It’s the diffuse myelin abnormalities and alterations in phospholipids.

Question 4

M8Extra - Leptomeningeal inflammation and its relation to cortical pathology

Answer 4

An inflammation of the meninges can also sometimes be observed in MS. This correlates with a worse cortical pathology. This is because the cytokines released by the immune cells will damage the pia mater, allowing cytokines to flow into the brain and making the inflammation even worse.

Question 5

M8Extra - Animal models for MS and related diseases

Answer 5

MS animal models:
- Autoimmune inflammatory ones (e.g. EAE: experimental autoimmune encephalomyelitis). They’re induced with immunization with myelin protein or by adoptive transfer of myelin specific t-cells.

Pathology in EAE: inflammation in spinal cord and brain. You can see demyelination, axonal damage – have remission and relapses.

Symptoms in EAE: tail and limb weakness and if severe, you see paralysis
EAE is a spinal cord disease in mice (primarily brain in humans) and has more CD4+ cells than CD8+ (opposite in humans)
- Viral inflammatory (e.g. PMEV).
- Inflammatory demyelinating (some EAE models)
- Non-inflammatory demyelinating (e.g. Cuprizone)

Related diseases:
- A model for NMOSD can be made by harvesting AQP4 anti-bodies and injecting them into a mouse