Several neuropathological and imaging studies demonstrated that cortical and deep grey matter damage follows a ‘surface in’ gradient, suggesting the possibility that soluble inflammatory factors released in the cerebrospinal fluid (CSF) might play a pathogenetic role.
To verify whether soluble factors released from meningeal and CSF inflammation are considered the most probably triggers of superficial grey matter damage.
We evaluated the association, at diagnosis, between, among 110 relapsing remitting naïve MS patients, who underwent blinded clinical, CSF and 3T-MRI evaluations at time of diagnosis. The CSF protein levels of 32 inflammatory mediators were correlated, by using multivariate regression analysis, with the volume loss in hippocampus, insula, cerebellum and thalamus.
Significant correlations were found between: hippocampus volume loss and the CSF protein levels of CXCL13 (β=-5.65x10-3;p<0.0001), CXCL10 (β=-1.46x10-4;p<0.05) and sCD163 (β=-3.20x10-6; p<0.0001); thalamic volume loss and the CSF protein levels of CXCL13 (β=-12.5;p<0.0001), sTNF-R1 (β=-6.00x10-2; p<0.05), sCD163 (β=-1.33x10-2; p<0.0001) and fibrinogen (β=-31.48; p<0.05); cerebellum volume loss and the CSF protein levels of sCD163 (β=-6.78x10-2; p<0.001) and chitinase-3-like1(β=-3.20x10-2;p<0.05); finally, insula volume loss and the CSF protein levels of CXCL13 (β=-5.92x10-3; p<0.001), CCL20 (β=-1.14x10-1; p<0.001) and osteopontin (β=1.71x10-6; p<0.05).
At time of diagnosis, elevated CSF levels of the mayor B-cell chemoattractant molecule CXCL13 is substantially linked to grey matter atrophy in all the deep and cortical grey matter examined areas. In addition, elevated levels of markers of glia activity, such as sCD163, osteopontin, chitinase-3-like1 and sTNFR1 have also a key role in grey matter volume loss. These data represent the first demonstration of a direct link between intrathecal CSF inflammatory myelin and the surface in grey matter damage since early disease stages.