You want some non-COVID stuff reported…ProfG has been doing this on his MS-selfie site and we can only report what people are publishing, so maybe this week we can do the “Real MS” for a change
One school of thought thinks that MS starts in the central nervous system and then lesions form, this is the “inside-out” brigade, in this study they use scans from trials and then find where lesions arise and look what happens before. They suggest that something happens before the lesions form. So evidence for inside-out.
Elliott C, Momayyezsiahkal P, Arnold DL, Liu D, Ke J, Zhu L, Zhu B, George IC, Bradley DP, Fisher E, Cahir-McFarland E, Stys PK, Geurts JJG, Franchimont N, Gafson A, Belachew S. Abnormalities in normal-appearing white matter from which multiple sclerosis lesions arise. Brain Commun. 2021 Aug 10;3(3):fcab176. doi: 10.1093/braincomms/fcab176.
Brain MRIs of pre-lesion normal-appearing white matter were analysed in participants with new T2 lesions, pooled from three clinical trials: SYNERGY (NCT01864148; n = 85 with relapsing multiple sclerosis) was the test data set; ASCEND (NCT01416181; n = 154 with secondary progressive multiple sclerosis) and ADVANCE (NCT00906399; n = 261 with relapsing-remitting multiple sclerosis) were used as validation data sets. Focal normal-appearing white matter tissue state was analysed prior to lesion formation in areas where new T2 lesions later formed (pre-lesion normal-appearing white matter) using normalized magnetization transfer ratio and T2-weighted (nT2) intensities, and compared with overall normal-appearing white matter and spatially matched contralateral normal-appearing white matter. Each outcome was analysed using linear mixed-effects models. Follow-up time (as a categorical variable), patient-level characteristics (including treatment group) and other baseline variables were treated as fixed effects. In SYNERGY, nT2 intensity was significantly higher, and normalized magnetization transfer ratio was lower in pre-lesion normal-appearing white matter versus overall and contralateral normal-appearing white matter at all time points up to 24 weeks before new T2 lesion onset. In ASCEND and ADVANCE (for which normalized magnetization transfer ratio was not available), nT2 intensity in pre-lesion normal-appearing white matter was significantly higher compared to both overall and contralateral normal-appearing white matter at all pre-lesion time points extending up to 2 years prior to lesion formation. In all trials, nT2 intensity in the contralateral normal-appearing white matter was also significantly higher at all pre-lesion time points compared to overall normal-appearing white matter. Brain atlases of normal-appearing white matter abnormalities were generated using measures of voxel-wise differences in normalized magnetization transfer ratio of normal-appearing white matter in persons with multiple sclerosis compared to scanner-matched healthy controls. We observed that overall spatial distribution of normal-appearing white matter abnormalities in persons with multiple sclerosis largely recapitulated the anatomical distribution of probabilities of T2 hyperintense lesions. Overall, these findings suggest that intrinsic spatial properties and/or longstanding precursory abnormalities of normal-appearing white matter tissue may contribute to the risk of autoimmune acute demyelination in multiple sclerosis.
Personally I don’t care too much if it is “inside out” or “outside-in” as the inside is connected to the out and the out has a route to an inside. I think the scientists made this construct to try and explain why so many MS drugs do not work in progressive MS but I am not sure you need to create such a polarised view. By the time you try to approach treatment both processess are at work in an MS brain
In terms of MS DMT the relapse problem are on balance the “outside-in”. I think the clinical trial is the ultimate experiment and response to therapy tells us this is part of the problem.
If this were not the case, things like natalizumab would do nothing.
Likewise in terms of progression, it is pretty obvious to me that there is an problem inside that needs dealing with. Yes I know we keep on targeting the “outside-in” in progressive MS. That is not my fault so don’t shoot the messenger.
Now the question is. Is the “outside-in” important as it is not targeting the “real MS”. However targeting the “outside-in” early in disease course, i.e. with a few years of onset, it does seem impact disability accumulation. However, there are elements in MS that are not going to response well/quickly to these approaches.
We need something to deal with the inside-out biology.
Now this study may support the concept of some biology occuring some time before you see the lesions form, we know this happens. This is what the MRI study suggests. However, MRI is not a microscope and the problem of using MRI is that maybe the problem is in “Birmingham” but the Magnet tells you something is happening in “Western Europe”. It is not high powered enough, Pathologically we can see the pre-active lesions that may be precursors for subsequent lesions and they are not going to seen in conventonal MRI.
It may indeed be the case that oligodendrocytes go first and it is inside out. However. MRI is never going to be able to exclude the possibility that cells enter the brain from the outside and cause damage inside. This damage may be caused by an immune cell that is nowhere near the damage because it does the damage elsewhere and by an invisible mechanism. e.g. you see an effect, which is interpreted to be “Ouch”, in the brain where you are looking because you have had your toe chopped off.
So you need other stuff to back this up. One of the key features that created the “outside in” was the case report of someone dying shortly (about 17 hours) after an attack.
In these areas of damage there were areas of cell suicide of oligodendrocytes with condensation of the nuclear material (e.g. the two blobs in the crazy frog ghost on the far right hand cell below).
This was reported in Barnett MH, Prineas JW. Relapsing and remitting multiple sclerosis: pathology of the newly forming lesion. Ann Neurol. 2004 Apr;55(4):458-68. A few years later we had brain biopsies reporting the same thing
Remember the murderer seldom hangs round the body to be caught by the police. The histologist is like the police they come to the scence after the carnage and they try to work out what happened
However, this week Prof Prineas(histologist) is back. The original artical came out in 2004 BB BB=before the Blog. What would be have made of this?
However this case has surfaced again (case 9. Figure 30-32) and you can even see the caspar the friendly ghost oligodendrocyte (far right above. It is turned on its side)
Prineas JW, Parratt JD. Multiple Sclerosis: Microglia, Monocytes, and Macrophage-Mediated Demyelination. J Neuropathol Exp Neurol pp. 1–22 doi: 10.1093/jnen/nlab083
The original case was in 14 year old girl who had disease for 9 months. She had had 4 attacks in that time certainly time for the preverbial toe to have been affected. There was so called remyelination in the sections looked (so there had been demyelination and repar) at and there was myelin loss (looks white compared to the Blue. Had this really happened in 17 hours).
First question, was this case multiple sclerosis or something else like neuromyelitis optica?
Hopefully one of the pathology gang will explain this….The conclusion is that the target is astrocytes and oligodendrocytes and not myelin…..Maybe we can get the “Autoimmunity to myelin basic protein is MS” brigade to defend their position. I would say response to therapy tells us that MS is not simply a problem of targeting “myelin basic protein”..this is a concept made up by lazy T cell immunologists who found it easy to purified myelin basic protein..
Anyway something to look forward to…………
Disclaimer: Please note that the opinions expressed here are those of the author and do not reflect the positions of the Barts and The London School of Medicine and Dentistry nor Barts Health NHS Trust or Queen Mary Univeristy of London.