As one layman to another, your "speculation" makes absolutely perfect sense. I agree with everything you said.
Instead of demyelination, the first pathological event would be some kind of damage in neurons or axons.
I definitely think this is entirely possible (maybe even probable). There’s certainly research indicating damage to both gray matter and axons happens early in the disease course.
I think Bromley originally posted this info about early gray matter involvement.
Gray Matter Damage in MS
a primarily GM-related process may be the earliest manifestation of MS
There’s also info about early axonal damage. Axonal Injury in Early MS
Irreversible brain damage associated with axonal dysfunction occurs at a very early stage in patients with clinically isolated syndromes
So, it seems to me that the first pathological events could indeed be some kind of damage in neurons or axons instead of the myelin. And, this new information you posted about axons producing glutamate is consistent with and seems to complement research Dunmann posted last year.
Unraveling Brain Damage in MS
The researchers showed myelin contains specialized receptors for glutamate
They discovered the surface of myelin has tiny open pores that provide a gateway for calcium to enter. If too much calcium enters, it can injure the myelin and affect our ability to walk, talk or see.
So, I would think these recently discovered pores in myelin present an opportunity for the glutamate produced by axons to exit and damage the myelin just as easily as they provide a gateway for glutamate to enter the myelin and damage axons, i.e., the pores on the surface of myelin provide a portal for the glutamate to go in either direction and cause damage and then the inflammation.
It’s definitely consistent with your speculation Finn where you wrote:
too much glutamate might be able to kill oligodendrocytes (myelin making cells),
and, to take it one step further, Dom wrote:
Overproduction of Glutamate to compensate for damage is a good candidate for continuing the cycle of destruction,
If I understand it correctly this would be something of a neuroprotective response, and when that fails and the myelin is damaged, inflammation follows in an attempt at remyelination(another neuroprotective response). Anyway it's my current understanding inflammation is needed for remyelination.
I think the plausibility of this sequence of events (neuronal and axonal damage initiate the process) is all reinforced by the research that men have thicker myelin and fewer lesions than women but a tendency for more severe disease progression. Could it be that it takes longer for the glutamate from axons to chew threw that thicker myelin men have and finally bring on the inflammation to try and repair it?
There’s also other MRI data that suggests an “inside out” initiation of pathology in MS. On slide 45 of this presentation Advanced Techniques in MRI Daniel Pelletier notes:
MTR changes in normal appearing white matter (NAWM) precede the appearance of new enhancing and T2 lesions—a challenging concept.
Finn—it’s just possible you found and developed an explanation for this challenging concept. Challenging it is, but the times they are a changin’
Overproduction of Glutamate to compensate for damage is a good candidate for continuing the cycle of destruction, though we still don't know how it begins
Did you miss that the stress hormone cortisol causes glutamate toxicity? Of course I think there are a lot of things that cause glutamate toxicity. Cortisol could be one of them though.
May the gathering of speculators carry on....I don't have a shred of scientific background either.
Take care all