Abstract
ObjectiveIntrathecal inflammation, compartmentalized in cerebrospinal fluid (CSF) and in meningeal infiltrates, has fundamental role in inflammation, demyelination, and neuronal injury in cerebral cortex in multiple sclerosis (MS). Since the exact link between intrathecal inflammation and mechanisms of cortical pathology remains unknown, we aimed to investigate a detailed proteomic CSF profiling which is able to reflect cortical damage in early MS.MethodsWe combined new proteomic method, TRIDENT, CSF analysis, and advanced 3T magnetic resonance imaging (MRI), in 64 MS patients at the time of diagnosis and 26 controls with other neurological disorders. MS patients were stratified according to cortical lesion (CL) load.ResultsWe identified 227 proteins differently expressed between the patients with high and low CL load. These were mainly related to complement and coagulation cascade as well as to iron homeostasis pathway (30 and 6% of all identified proteins, respectively). Accordingly, in the CSF of MS patients with high CL load at diagnosis, significantly higher levels of sCD163 (P < 0.0001), free hemoglobin (Hb) (P < 0.05), haptoglobin (P < 0.0001), and fibrinogen (P < 0.01) were detected. By contrast, CSF levels of sCD14 were significantly (P < 0.05) higher in MS patients with low CL load. Furthermore, CSF levels of sCD163 positively correlated (P < 0.01) with CSF levels of neurofilament, fibrinogen, and B cell‐related molecules, such as CXCL13, CXCL12, IL10, and BAFF.InterpretationIntrathecal dysregulation of iron homeostasis and coagulation pathway as well as B‐cell and monocyte activity are strictly correlated with cortical damage at early disease stages.
Highlights
Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association
Upon stratification of multiple sclerosis (MS) population according to median value of cortical lesion (CL) number, the MShigh group (56%, mean CL number = 15.7 Æ 6.7; CL volume = 1620 Æ 728 mm3) was characterized by about 12-fold higher numbers and volume of CLs compared to MSlow group (44%, mean CL number = 1.2 Æ 1.7; CL volume = 132 Æ 186 mm3) (Table 1)
The present study, besides confirming our previous findings of a strong association between severe cortical pathology and a distinctive cerebrospinal fluid (CSF) inflammatory profile[7] in an independent MS subgroup, enabled us to detect previously unexpected or unknown candidate molecules involved in altered CSF profiles and associated cortical pathology since early disease stages
Summary
Compartmentalized inflammation within the meninges of MS patients is spatially related to subpial demyelination, which accounts for about 70% of GM demyelination in progressive MS,[5] and neuronal/glial alterations in the adjacent GM, following a “surface-in" gradient[6] from the pial surface toward the WM. In a recent combined ex vivo and in vivo study, compartmentalized inflammation in meningeal infiltrates a 2019 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.
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