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MRI studies on grey matter and periventricular white matter in MS Patients

MTR Gradient Image.

 

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Dr. Declan Chard

Multiple sclerosis (MS) has long been thought of as mainly a disease of brain white matter (WM), and its most obvious clinical feature (a relapse) has been closely linked with the formation of new WM lesions. However, it has become clear that there are abnormalities in brain grey matter (GM) too, albeit difficult to see with conventional MRI scans, and that in the longer-term these are significantly associated with disability.

MS Grey Matter Lesions

As with WM, lesions form in GM too. However, in contrast to WM, where conventional MRI scans show the majority of lesions, GM lesions are much more difficult to detect. Double inversion recovery is the most used method for detecting GM lesions, but prospectively about 10% of such lesions are seen. However, using a newer type of brain scan called Phase Sensitive Inversion Recovery (PSIR), compared with previous scans we were able to detect about three times as many GM lesions, and we were also able to assess their evolution over time showing that while GM lesions may extend into WM, the reverse is rarely seen (Sethi et al. 2016: https://www.ncbi.nlm.nih.gov/pubmed/26272028). This suggest that the mechanisms underlying GM lesion expansion are mainly from the outside rather than inside of the brain.

We also investigated whether or not GM lesions seen using PSIR could help with the diagnosis of MS, i.e. are they found mostly in people with MS and rarely in others, we also looked for such lesions in people with no known neurological problems. As with WM, we found that with increasing age some GM lesions were seen, but there were significantly fewer in people who did not have MS. This suggests that PSIR may, with further development, be able to help with the diagnosis of MS. We have published the first scientific paper from this work (Sethi et al. 2012: https://www.ncbi.nlm.nih.gov/pubmed/22807559 and Sethi et al. 2013: https://www.ncbi.nlm.nih.gov/pubmed/24244381).

Grey Matter Magnetisation Transfer Imaging

Using an MRI technique called Magnetisation Transfer Ratio (MTR) imaging, which is sensitive to amount of myelin in brain tissue, we can look for subtle changes in brain GM tissue structure.

Using MTR we found differences in the in the GM of people with MS compared with people with no known neurological problem, and in particular that GM MTR was more abnormal towards the outer surface of the brain (Samson et al. 2014 https://www.ncbi.nlm.nih.gov/pubmed/24552746). This gradient was more noticeable in people who had secondary progressive MS when compared with those who had progressive symptoms from the outset (primary progressive MS), and again suggests that mechanisms underlying GM pathology in MS may be influenced by processes arising close to the surface or outside the brain. This finding may be important when developing new treatments and tailoring this to individual people with MS.

Periventricular White Matter Magnetisation Transfer Imaging

Arising from our work on GM, which highlights the possibility that factors outside the brain (for example in the cerebrospinal fluid) may affect pathology within it, using MTR we have looked for evidence of similar gradients in WM. We found these in people with relapsing-remitting and secondary progressive MS and, as with GM MTR gradients, these were greater in people with secondary progressive MS (Liu et al. 2015: https://www.ncbi.nlm.nih.gov/pubmed/25823475). In more recent work, we have shown that these periventricular gradients may be found soon after the first clinical episode in people with MS, and that they predict the risk of having a further relapse (Brown et al. 2017: https://www.ncbi.nlm.nih.gov/pubmed/28043954). We have also shown that treatment with alemtuzumab, a potent MS disease modifying treatment, reduces abnormal periventricular MTR gradients and the steepness of the gradients before treatment in part predicts the clinical response (Brown et al. 2019: https://www.ncbi.nlm.nih.gov/pubmed/31169059). We continue to pursue this line of research.