The CSF Profile Linked to Cortical Damage Predicts Multiple Sclerosis Activity

Abstract

Objective Intrathecal inflammation correlates with the grey matter damage since the early stages of multiple sclerosis (MS), but whether the cerebrospinal fluid (CSF) profile can help to identify patients at risk of disease activity is still unclear. Methods We evaluated the association between CSF levels of 18 cytokines, previously found to be associated to grey matter damage, and the disease activity, among 99 patients with relapsing‐remitting MS, who underwent blinded clinical and 3 T magnetic resonance imaging (MRI) evaluations for 4 years. Groups with evidence of disease activity (EDA) or no evidence of disease activity (NEDA; occurrence of relapses, new white matter lesions, and Expanded Disability Status Scale [EDSS] change) were identified. Cortical lesions and the annualized cortical thinning were also evaluated. Results Forty‐one patients experienced EDA and, compared to the NEDA group, had at diagnosis higher CSF levels of CXCL13, CXCL12, IFNγ, TNF, sCD163, LIGHT, and APRIL (p < 0.001). In the multivariate analysis, CXCL13 (hazard ratio [HR] = 1.35; p = 0.0002), LIGHT (HR = 1.22; p = 0.005) and APRIL (HR = 1.78; p = 0.0001) were the CSF molecules more strongly associated with the risk of EDA. The model, including CSF variables, predicted more accurately the occurrence of disease activity than the model with only clinical/MRI parameters (C‐index at 4 years = 71% vs 44%). Finally, higher CSF levels of CXCL13 (β = 4.7*10−4; p < 0.001), TNF (β = 3.1*10−3; p = 0.004), LIGHT (β = 2.6*10−4; p = 0.003), sCD163 (β = 4.3*10−3; p = 0.009), and TWEAK (β = 3.4*10−3; p = 0.024) were associated with more severe cortical thinning. Interpretation A specific CSF profile, mainly characterized by elevated levels of B‐cell related cytokines, distinguishes patients at high risk of disease activity and severe cortical damage. The CSF analysis may allow stratifications of patients at diagnosis for optimizing therapeutic approaches. ANN NEUROL 2020;88:562–573

Meningeal inflammation in multiple sclerosis induces phenotypic changes in cortical microglia that differentially associate with neurodegeneration

“…As B cells are most prominent in the meninges of both MS2 patients and 2 month CMI animals, this would suggest that at first T cells and myeloid cells populate the MS meninges, with the amount of meningeal B cells rising over time. This also fits with the finding that the amount of B cells in meninges and B-cell related cytokines in the CSF associate with disease progression 17,28,33 . Furthermore, the extent of meningeal inflammation in MS patients, and more specifically the amount of meningeal B cells, has been strongly linked to the presence of tertiary lymphoid-like follicles 15,28 .…”

“…Meningeal inflammation in SPMS is characterized by accumulation of immune cells like B-, T-and myeloid cells, either diffusely present or in aggregates resembling tertiary lymphoid follicles 14,15 . The degree of inflammation and the presence of follicles both associate with the severity of cortical pathology, possibly by production and subsequent diffusion of pro-inflammatory cytokines into the cortex 16,17 . Indeed, in a recently developed animal model for chronic meningeal inflammation, chronic overexpression of two of these cytokines, TNFα and IFNγ, in the leptomeninges of rats was recently shown to induce meningeal inflammation, cortical demyelination and neuronal loss, thereby closely mimicking SPMS 18 .…”

Re-Examining the Role of TNF in MS Pathogenesis and Therapy

“…Recent technical progress in terms of test sensitivity has made possible the detection of the levels of cytokines and other molecules in the CSF, which is more informative of the brain activity than the blood ( Table 2 ). Thus, in the last years the identification of a specific intrathecal inflammatory signature has greatly enhanced [ 170 , 171 ]. In line with the idea that the CSF better mirrors CNS neuropathology, a positive correlation between TNF liquoral level and neurological deterioration was shown in a cohort of PMS, while serum TNF levels of the same subjects did not correlate with disease progression [ 155 ].…”

Cerebrospinal Fluid IgM Levels in Association With Inflammatory Pathways in Multiple Sclerosis Patients

“…The chemokines CXCL13 and CCL21 are particularly known to regulate B-cell migration into the CNS and to favor the intrathecal accumulation of B cells (Kowarik et al, 2012). In particular, CXCL13 has recently been suggested as a prognostic marker for CIS and MS (Brettschneider et al, 2010;Ferraro et al, 2015;Magliozzi et al, 2020) and seems to play a role in the formation of ectopic lymphoid tissues within the CNS in MS (Magliozzi et al, 2007). In addition, CSF CXCL13 levels were found incremented in MS patients (Khademi et al, 2011), in which they are correlated with a high number of CSF CD5 + B cells and with intrathecal IgM production (Krumbholz et al, 2006;Villar et al, 2010;Ferraro et al, 2015).…”