Cerebrospinal Fluid Biomarkers of Myeloid and Glial Cell Activation Are Correlated With Multiple Sclerosis Lesional Inflammatory Activity

Abstract

Multiple sclerosis (MS)-related inflammation can be divided into lesional activity, mediated by immune cells migrating from the periphery to the central nervous system (CNS) and non-lesional activity, mediated by inflammation compartmentalized to CNS tissue. Lesional inflammatory activity, reflected by contrast-enhancing lesions (CELs) on the magnetic resonance imaging (MRI), is effectively inhibited by current disease modifying therapies (DMTs). While, the effect of DMTs on non-lesional inflammatory activity is currently unknown. Reliable and simultaneous measurements of both lesional and non-lesional MS activity is necessary to understand their contribution to CNS tissue destruction in individual patients. We previously demonstrated that CNS compartmentalized inflammation can be measured by combined quantification of cerebrospinal fluid (CSF) immune cells and cell-specific soluble markers. The goal of this study is to develop and validate a CSF-biomarker-based molecular surrogate of MS lesional activity. The training cohort was dichotomized into active (CELs > 1 or clinical relapse) and inactive lesional activity (no CELs or relapse) groups. Matched CSF and serum samples were analyzed for 20 inflammatory and axonal damage biomarkers in a blinded fashion. Only the findings from the training cohort with less than 0.1% probability of false positive (i.e., p < 0.001) were validated in an independent validation cohort. MS patients with lesional activity have elevated IL-12p40, CHI3L1, TNFα, TNFβ, and IL-10, with the first two having the strongest effects and validated statistically-significant association with lesional activity in an independent validation cohort. Marker of axonal damage, neurofilament light (NfL), measured in CSF (cNfL) was also significantly elevated in MS patients with active lesions. NfL measured in serum (sNfL) did not differentiate the two MS subgroups with pre-determined significance, (p = 0.0690) even though cCSF and sNfL correlated (Rho = 0.66, p < 0.0001). Finally, the additive model of IL12p40 and CHI3L1 outperforms any biomarker discretely. IL12p40 and CHI3L1, released predominantly by immune cells of myeloid lineage are reproducibly the best CSF biomarkers of MS lesional activity. The residuals from the IL12p40/CHI3L1-cNfL correlations may identify MS patients with more destructive inflammation or contributing neurodegeneration.

Prognostic Value of Serum/Plasma Neurofilament Light Chain for COVID-19 Associated Mortality

“…As serum/plasma NfL levels increase with physiological aging (Disanto et al, 2017), the measured NfL concentrations were adjusted for effect of healthy aging as described previously (Masvekar R et al, 2021). Following age vs serum-or plasma-NfL equations from HC cohorts were used: ln(serum NfL) = 0.0177*Age + 0.9696 and ln(plasma NfL) = 0.0158*Age + 1.247.…”

“…Serum and plasma samples from healthy controls (HC) and multiple sclerosis (MS) subjects were collected at Neuroimmunological Diseases Section (NDS), NIAID after informed consent under IRB-approved protocol (ClinicalTrials.gov: NCT00794352). The NfL levels measured in HC and MS subgroups were previously reported (Masvekar R et al, 2021) and are used in the current study only as a positive control of neuronal injury; the measurements of other COVID-19 prognostic biomarkers in these control samples were not reported previously. 378 serum or plasma samples were collected from 338 COVID-19 patients grouped into 3 independent cohorts (Figure 1, Table 1, and Supplementary Data File 1).…”

“…). The NfL levels measured in HC and MS subgroups were previously reported (Masvekar R et al, 2021) and are used in the current study only as a positive control of neuronal injury; the measurements of other COVID-19 prognostic biomarkers in these control samples were not reported previously. 378 serum or plasma samples were collected from 338 COVID-19 patients grouped into 3 independent cohorts (Figure 1, Table 1, and Supplementary Data File 1).…”

Emerging Biomarkers of Multiple Sclerosis in the Blood and the CSF: A Focus on Neurofilaments and Therapeutic Considerations

“…Interestingly, another study found no correlation between baseline serum NfL levels and baseline EDSS. Interestingly, high baseline serum NfL concentrations predicted high EDSS levels at follow-up and at study end [ 318 ]. Not just flat concentrations, but the change in serum NfL levels has also been associated with a change in EDSS [ 306 , 310 ] scores.…”

Navigating the ventricles: Novel insights into the pathogenesis of hydrocephalus

“… 13 CSF biomarkers have also been identified for multiple sclerosis, Parkinson's disease and Alzheimers disease (AD). 14 , 15 AD is probably the most extensively studied, and in AD, the ratio of the content of amyloid beta peptide Aβ 42/ Aβ 40 has been used to predict cortical amyloid deposition. 16 Idiopathic normal pressure hydrocephalus (iNPH) may also show changes in Aβ 42 levels compared with age-matched controls.…”