Background: Neurofilament light chain protein (NFL) and chitinase3-like1 (CHI3L1) have gained importance recently as prognostic biomarkers in multiple sclerosis (MS).Objectives: We aimed to investigate NFL and CHI3L1 cerebrospinal fluid (CSF) profiles in multiple sclerosis and the informative and prognostic potential of the individual and combined measures.Methods: CSF NFL and CHI3L1 levels were measured in a cross-sectional cohort of 157 MS patients [99 relapsing-remitting (RRMS), 35 secondary progressive (SPMS), and 23 primary progressive (PPMS)]. Clinical relapse and/or gadolinium-enhanced lesions (GEL) in MRI within 90 days from CSF collection by lumbar puncture (LP) were registered and considered as indicators of disease activity. Longitudinal treatment and disability data were evaluated during medical visits with a median follow-up of 50 months.Results: CSF levels of NFL and CHI3L1 were higher in MS patients compared to non-MS controls. In RRMS and SPMS patients, increased NFL levels were associated with clinical relapse, and gadolinium-enhanced lesions in MRI (p < 0.001), while high CHI3L1 levels were characteristic of progressive disease (p = 0.01). In RRMS patients, CSF NFL, and CHI3L1 levels correlated with each other (r = 0.58), and with IgM-oligoclonal bands (p = 0.02 and p = 0.004, respectively). In addition, CSF CHI3L1 concentration was a predictor for 1-point EDSS worsening {HR = 2.99 [95% CI (1.27, 7.07)]} and progression during follow-up {HR = 18 [95% CI (2.31, 141.3)]}. The pattern of combined measure of biomarkers was useful to discriminate MS phenotypes and to anticipate clinical progression: RRMS more frequently presented high NFL combined with low CHI3L1 levels, compared to SPMS (HR 0.41 [0.18–0.82]), and PPMS (HR 0.46 [0.19–0.87]), while elevation of both biomarkers preceded diagnosis of clinical progression in RRMS patients (log rank = 0.02).Conclusions: Individual measures of CSF NFL and CHI3L1 are biomarkers of disease activity and progression, respectively. The pattern of combined measure discriminates MS phenotypes. It also predicts the subset of RRMS patients that will progress clinically allowing early intervention.
ObjectiveNeurofilament light protein (NfL) and chitinase 3–like 1 (CHI3L1) are biomarkers for acute neuroaxonal damage and local inflammation, respectively. Thus, we set out to evaluate how these biomarkers were associated with clinical features of demyelinating diseases in parallel with the expression in brain autopsies from patients with similar disease stages, assuming their comparability.MethodsNfL and CHI3L1 in CSF and serum CHI3L1 were assessed retrospectively in a cross-sectional cohort of controls (n = 17) and patients diagnosed with MS (n = 224), relapsing (n = 163) or progressive (n = 61); neuromyelitis optica (NMO, n = 7); and acute disseminated encephalomyelitis (ADEM, n = 15). Inflammatory activity was evaluated at the time of sampling, and CSF biomarker levels were related to the degree of inflammation in 22 brain autopsy tissues.ResultsDuring a clinical attack, the CSF NfL increased in MS, NMO, and ADEM, whereas CHI3L1 was only elevated in patients with NMO and ADEM and in outlier MS patients with extensive radiologic activity. Outside relapses, CHI3L1 levels only remained elevated in patients with progressive MS. CHI3L1 was detected in macrophages and astrocytes, predominantly in areas of active demyelination, and its expression by astrocytes in chronic lesions was independent of lymphocyte infiltrates and associated with active neurodegeneration.ConclusionsBoth CSF NfL and CHI3L1 augment during acute inflammation in demyelinating diseases. In MS, CHI3L1 may be associated with low-grade nonlymphocytic inflammation and active neurodegeneration and therefore linked to progressive disease.Classification of EvidenceThis study provides Class III evidence that CSF NfL and CHI3L1 levels increase in inflammatory brain diseases during acute inflammation.
Cerebrospinal kappa free light chain (KFLC)-index is a marker of intrathecal immunoglobulin synthesis that aids in the diagnosis of multiple sclerosis (MS). However, little evidence exists on its prognostic role. Our aim is to analyze the relationship between KFLC-index and other MS biomarkers and to explore its prognostic role. This is a monocentric observational study in a cohort of 52 people with relapsing MS (pwRMS) performed on prospectively acquired clinical data and with retrospective evaluation of biomarkers. We measured KFLC-index, immunoglobulin intrathecal synthesis, cerebrospinal fluid (CSF) chitinase 3-like 1 (CHI3L1), and neurofilament light protein (NFL) and reviewed MRI to detect leptomeningeal contrast enhancement (LMCE). We compared time to Expanded Disability Status Scale (EDSS) 3 and to initiation of high-efficacy disease-modifying therapies (heDMTs) by multivariate Cox regression analysis. Median KFLC-index correlated with IgG/IgM indexes (p < 0.0001/p < 0.05) and IgG-oligoclonal bands (OCGBs) (p < 0.001). Patients with IgM-oligoclonal bands (OCMBs) had a higher KFLC-index (p = 0.049). KFLC-index was higher in patients with LMCE (p = 0.008) and correlated with CHI3L1 (p = 0.007), but disease activity had no effect on its value. Bivariate and multivariate analyses confirmed KFLC-index > 58 as an independent risk factor for reaching an EDSS of 3 (hazard ratio (HR) = 12.4; 95% CI = 1.1–147; p = 0.047) and for the need of treatment with heDMTs (HR = 3.0; 95% CI = 1.2–7.1; p = 0.0013). To conclude, our data suggest a potential prognostic role of the KFLC-index during the MS course.
Background and ObjectivesPrimary progressive multiple sclerosis (PPMS) displays a highly variable disease progression with a characteristic accumulation of disability, what makes difficult its diagnosis and efficient treatment. The identification of microRNAs (miRNAs)-based signature for the early detection in biological fluids could reveal promising biomarkers to provide new insights into defining MS clinical subtypes and potential therapeutic strategies. The objective of this cross-sectional study was to describe PPMS miRNA profiles in CSF and serum samples compared with other neurologic disease individuals (OND) and relapsing-remitting MS (RRMS).MethodsFirst, a screening stage analyzing multiple miRNAs in few samples using OpenArray plates was performed. Second, individual quantitative polymerase chain reactions (qPCRs) were used to validate specific miRNAs in a greater number of samples.ResultsA specific profile of dysregulated circulating miRNAs (let-7b-5p and miR-143-3p) was found downregulated in PPMS CSF samples compared with OND. In addition, in serum samples, miR-20a-5p and miR-320b were dysregulated in PPMS against RRMS and OND, miR-26a-5p and miR-485-3p were downregulated in PPMS vs RRMS, and miR-142-5p was upregulated in RRMS compared with OND.DiscussionWe described a 2-miRNA signature in CSF of PPMS individuals and several dysregulated miRNAs in serum from patients with MS, which could be considered valuable candidates to be further studied to unravel their actual role in MS.Classification of EvidenceThis study provides Class II evidence that specific miRNA profiles accurately distinguish PPMS from RRMS and other neurologic disorders.
The clinical diagnosis of patients with autoantibodies directed to conformational myelin oligodendrocyte glycoprotein MOG-IgG, can be challenging because of atypical clinical presentation. MOG-IgG seropositivity has been reported in several demyelinating diseases, including relapsing opticospinal syndromes [in the neuromyelitis optica spectrum disorders (NMOSD) and less frequently, in multiple sclerosis (MS)], but it has rarely been associated with the progressive course of disease. To contribute to the characterization of MOG-related demyelination, we describe the case of a patient with progressive demyelinating opticospinal disease, IgG-oligoclonal bands (OCB), and serum MOG-IgG.
In situ RT-PCR detects and amplifies mRNA (cDNA) while obtaining spatial information of gene expression. When the intended use is an ultrastructural analysis of morphology, the procedure may be technically challenging and quality of tissue dramatically altered by proteolytic digestion and extreme astringency and temperature conditions. We describe a low-damaging protocol of in situ RT-PCR combined to conventional electron microscopy that preserves fine morphology, increases sensitivity, and decreases costs and complexity associated to RNA probes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.