Serum biomarkers at disease onset for personalized therapy in multiple sclerosis.

The potential of combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict disability worsening in multiple sclerosis (MS) remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across thirteen European hospitals, spanned from July 15, 1994, to August 18, 2022, with follow-up until September 26, 2023. We enrolled MS patients who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, median age was 34.2 years (IQR, 27.6-42.4), and 509 patients (70.2%) were female. Median follow-up duration was 6.43 years (IQR, 4.65-9.81). Higher sNfL values associated with an elevated risk of RAW (HR of 1.45; 95% CI 1.19-1.76; P < 0.001), PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003), and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We further examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values (NLGL) exhibited a low risk of all outcomes and served as reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA, and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values (NLGH) showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in MS may identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response.

Serum biomarker levels predict disability progression in patients with primary progressive multiple sclerosis.

BACKGROUND: We aimed to investigate the potential of serum biomarker levels to predict disability progression in a multicentric real-world cohort of patients with primary progressive multiple sclerosis (PPMS). METHODS: A total of 141 patients with PPMS from 18 European MS centres were included. Disability progression was investigated using change in Expanded Disability Status Scale (EDSS) score over three time intervals: baseline to 2 years, 6 years and to the last follow-up. Serum levels of neurofilament light chain (sNfL), glial fibrillar acidic protein (sGFAP) and chitinase 3-like 1 (sCHI3L1) were measured using single-molecule array assays at baseline. Correlations between biomarker levels, and between biomarkers and age were quantified using Spearman's r. Univariable and multivariable linear models were performed to assess associations between biomarker levels and EDSS change over the different time periods. RESULTS: Median (IQR) age of patients was 52.9 (46.4-58.5) years, and 58 (41.1%) were men. Median follow-up time was 9.1 (7.0-12.6) years. Only 8 (5.7%) patients received treatment during follow-up. sNfL and sGFAP levels were moderately correlated (r=0.43) and both weakly correlated with sCHI3L1 levels (r=0.19 and r=0.17, respectively). In multivariable analyses, levels of the three biomarkers were associated with EDSS changes across all time periods. However, when analysis was restricted to non-inflammatory patients according to clinical and radiological parameters (n=64), only sCHI3L1 levels remained associated with future EDSS change. CONCLUSIONS: Levels of sNfL, sGFAP and sCHI3L1 are prognostic biomarkers associated with disability progression in patients with PPMS, being CHI3L1 findings less dependent on the inflammatory component associated with disease progression.

Deeply 3D-T1-TFE hypointense voxels are characteristic of phase-rim lesions in multiple sclerosis.

OBJECTIVES: The development of new drugs for the treatment of progressive multiple sclerosis (MS) highlights the need for new prognostic biomarkers. Phase-rim lesions (PRLs) have been proposed as markers of progressive disease but are difficult to identify and quantify. Previous studies have identified T1-hypointensity in PRLs. The aim of this study was to compare the intensity profiles of PRLs and non-PRL white-matter lesions (nPR-WMLs) on three-dimensional T1-weighted turbo field echo (3DT1TFE) MRI. We then evaluated the performance of a derived metric as a surrogate for PRLs as potential markers for risk of disease progression. METHODS: This study enrolled a cohort of relapsing-remitting (n = 10) and secondary progressive MS (n = 10) patients for whom 3 T MRI was available. PRLs and nPR-WMLs were segmented, and voxel-wise normalized T1-intensity histograms were analyzed. The lesions were divided equally into training and test datasets, and the fifth-percentile (p5)-normalized T1-intensity of each lesion was compared between groups and used for classification prediction. RESULTS: Voxel-wise histogram analysis showed a unimodal histogram for nPR-WMLs and a bimodal histogram for PRLs with a large peak in the hypointense limit. Lesion-wise analysis included 1075 nPR-WMLs and 39 PRLs. The p5 intensity of PRLs was significantly lower than that of nPR-WMLs. The T1 intensity-based PRL classifier had a sensitivity of 0.526 and specificity of 0.959. CONCLUSIONS: Profound hypointensity on 3DT1TFE MRI is characteristic of PRLs and rare in other white-matter lesions. Given the widespread availability of T1-weighted imaging, this feature might serve as a surrogate biomarker for smoldering inflammation. CLINICAL RELEVANCE STATEMENT: Quantitative analysis of 3DT1TFE may detect deeply hypointense voxels in multiple sclerosis lesions, which are highly specific to PRLs. This could serve as a specific indicator of smoldering inflammation in MS, aiding in early detection of disease progression. KEY POINTS: • Phase-rim lesions (PRLs) in multiple sclerosis present a characteristic T1-hypointensity on 3DT1TFE MRI. • Intensity-normalized 3DT1TFE can be used to systematically identify and quantify these deeply hypointense foci. • Deep T1-hypointensity may act as an easily detectable, surrogate marker for PRLs.

Oral lacosamide for the treatment of refractory trigeminal neuralgia: A retrospective analysis of 86 cases.

BACKGROUND AND OBJECTIVES: First-line treatment for trigeminal neuralgia (TN) is limited to carbamazepine and oxcarbazepine, and in refractory cases, alternatives are scarce. Lacosamide has been suggested as a valid option. In this study, we describe a series of patients who received oral lacosamide as treatment for TN after first-line drug failure. METHODS: In this retrospective descriptive cohort study, we included patients with refractory TN who attended a tertiary center between 2015 and 2021 and were prescribed oral lacosamide after first-line treatment failure. The primary endpoints were pain relief and adverse effects. We secondarily analyzed clinical outcomes and compared responders versus nonresponders in the search for potential predictors of response. RESULTS: Eighty-six patients were included (mean age: 62 [SD 15.6] years; 54/86 [63%] female). The TN etiology was secondary in 16/86 (19%) patients. Concomitant continuous pain was present in 29/86 (34%) patients. The mean number of previous treatments was 2.7 [SD 1.5]. Pain relief was achieved in 57/86 (66%) cases, with 28/86 (33%) patients presenting adverse effects, all of which were mild. No statistically significant differences were observed between responders and nonresponders, but subtle clinical differences suggested potential predictors of response. CONCLUSION: Lacosamide may be an effective and relatively safe treatment for refractory pain in TN patients after first-line treatment failure.

Influence of Cardiovascular Risk Factors in Early Relapsing-Remitting Multiple Sclerosis: A Retrospective Analysis.

INTRODUCTION: Prior studies have suggested that cardiovascular risk factors (CVRFs) can affect the prognosis of multiple sclerosis (MS). The aim of this study was to assess if CVRFs affect the early course of MS. METHODS: A retrospective observational study was performed, including patients diagnosed with relapsing-remitting MS (RRMS) from 2010 to 2020, with at least 2 years of disease and 6 months follow-up. Age at onset, disease duration, number of relapses, time to confirmed Expanded Disability Status Scale (EDSS) 3.0 and 6.0, and time to secondary progressive MS (SPMS) were collected. Presence and date at onset of hypertension (HT), diabetes mellitus (DM), high low-density lipoprotein cholesterol (LDLc), and smoking during the study period were collected. The primary objective was to assess if CVRFs at the onset of MS are associated with lower time to EDSS 3.0, time to EDSS 6.0, and time to SPMS, using bivariate and multivariate analysis. RESULTS: 281 RRMS patients were included; median age at onset was 33 (IQR 26-39); 69.4% were female. Median EDSS at onset was 1.5 (IQR 1-2.5). Nine patients reached SPMS; 24 patients were diagnosed with HT, 9 with DM, 109 with high LDLc, and 123 were smokers during follow-up. No statistically significant association was found between the presence of CVRF at MS onset and the mentioned clinical outcomes during the MS course. CONCLUSION: No association was found between CVRFs and the early course of MS in our cohort.

Effectiveness of Fingolimod versus Natalizumab as Second-Line Therapy for Relapsing-Remitting Multiple Sclerosis in Spain: Second-Line GATE Study.

BACKGROUND: There is a lack of head-to-head studies comparing the efficacy of fingolimod (FIN) and natalizumab (NTZ) as second-line therapy for relapsing-remitting multiple sclerosis (RRMS). METHODS: Multicenter, observational study, in which, information of 388 patients randomly selected and treated with FIN or NTZ in routine clinical practice was retrospectively collected with the main objective of comparing the annualized relapse rate (ARR) over the first year, after FIN or NTZ treatment initiation. RESULTS: Mean ARR during the first year of treatment was 0.28 in FIN group and 0.12 in NTZ group (p = 0.0064); nevertheless, the difference between groups lost statistical significance when the propensity score analysis was performed. Time to disability -progression was similar in both treatment groups (12.3 ± 6.7 months in FIN, and 12.8 ± 0.1 months in NTZ; p = 0.4654). Treatment persistence after the first year of treatment was higher in patients treated with FIN (95%) than in those treated with NTZ (84%; p = 0.0014). CONCLUSIONS: After 12 months of treatment, both FIN and NTZ reduced the ARR, but ARR percent reduction was significantly higher with NTZ. Treatment persistence was higher in patients receiving FIN.

Increased C-X-C Motif Chemokine Ligand 12 Levels in Cerebrospinal Fluid as a Candidate Biomarker in Sporadic Amyotrophic Lateral Sclerosis.

Sporadic amyotrophic lateral sclerosis (sALS) is a fatal progressive neurodegenerative disease affecting upper and lower motor neurons. Biomarkers are useful to facilitate the diagnosis and/or prognosis of patients and to reveal possible mechanistic clues about the disease. This study aimed to identify and validate selected putative biomarkers in the cerebrospinal fluid (CSF) of sALS patients at early disease stages compared with age-matched controls and with other neurodegenerative diseases including Alzheimer disease (AD), spinal muscular atrophy type III (SMA), frontotemporal dementia behavioral variant (FTD), and multiple sclerosis (MS). SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC-MS/MS) for protein quantitation, and ELISA for validation, were used in CSF samples of sALS cases at early stages of the disease. Analysis of mRNA and protein expression was carried out in the anterior horn of the lumbar spinal cord in post-mortem tissue of sALS cases (terminal stage) and controls using RTq-PCR, and Western blotting, and immunohistochemistry, respectively. SWATH acquisition on liquid chromatography-tandem mass spectrometry (LC-MS/MS) revealed 51 differentially expressed proteins in the CSF in sALS. Receiver operating characteristic (ROC) curves showed CXCL12 to be the most valuable candidate biomarker. We validated the values of CXCL12 in CSF with ELISA in two different cohorts. Besides sALS, increased CXCL12 levels were found in MS but were not altered in AD, SMA, and FTD. Therefore, increased CXCL12 levels in the CSF can be useful in the diagnoses of MS and sALS in the context of the clinical settings. CXCL12 immunoreactivity was localized in motor neurons in control and sALS, and in a few glial cells in sALS at the terminal stage; CXCR4 was in a subset of oligodendroglial-like cells and axonal ballooning of motor neurons in sALS; and CXCR7 in motor neurons in control and sALS, and reactive astrocytes in the pyramidal tracts in terminal sALS. CXCL12/CXCR4/CXCR7 axis in the spinal cord probably plays a complex role in inflammation, oligodendroglial and astrocyte signaling, and neuronal and axonal preservation in sALS.

Epidemiology of NMOSD in Catalonia: Influence of the new 2015 criteria in incidence and prevalence estimates.

BACKGROUND: Population-based studies on neuromyelitis optica spectrum disorders (NMOSD) are limited, and it is unclear whether the rates have changed with the implementation of the new 2015 criteria. OBJECTIVES: To estimate the incidence and prevalence of NMOSD in Catalonia (Spain), using both the 2006 and the 2015 criteria. METHODS: In this clinic-based retrospective study, patients diagnosed with NMOSD between 2006 and 2015 were identified using multiple sources, including direct contact to all Catalan hospitals, identification of cases through the Catalan Health Surveillance System, and registry of antibodies to aquaporin-4 (AQP4-IgG) and myelin oligodendrocyte glycoprotein (MOG-IgG) in a reference laboratory. The incidence rate was calculated for the period 1 January 2006-1 January 2016 and prevalence for the date 1 January 2016. RESULTS: We identified 74 patients (by the 2015 criteria). Most patients were Caucasian (81%), and female (76%) with a median age at disease onset of 42 years (range, 10-76 years). In total, 54 (73%) patients were positive for AQP4-IgG, 11 (15%) double-seronegative, and 9 (12%) MOG-IgG-positive. Rates of incidence and prevalence (0.63/1,000,000 person-years and 0.89/100,000, respectively) were 1.5-fold higher than those reported by the 2006 criteria. Lowest rates were seen in children and elder people and highest in women and middle-aged people (40-59 years). The female predominance was lost in incident AQP4-IgG-seronegative children and AQP4-IgG-positive elder people. MOG-IgG and double-seronegativity contributed similarly but did not influence the long-term outcome. CONCLUSION: The new criteria increase the estimates, but NMOSD remains as a rare disease. The differences in age- and sex-specific estimates highlight the importance of the serologic classification.

Feasibility and Effects of Structured Physical Exercise Interventions in Adults with Relapsing-Remitting Multiple Sclerosis: A Pilot Study.

Multiple sclerosis (MS) is a chronic neurological disease which affects young adults at a time of maximum personal, professional and social growth. Recent guidelines on physical activity have established that exercise is an essential component of the clinical management of people with MS with mild or moderate degree of disability. The main purpose of this study was to test the feasibility and the effects of two different 40-week structured physical exercise interventions (a supervised high intensity interval training plus home exercise program and a self-applied home-based exercise program) on clinical evolution, psychological wellbeing, quality of life, fatigue, cardiorespiratory fitness, strength and balance of people with MS. Twenty-nine participants with relapsing-remitting MS (RRMS) participated in this study. All of them were fully ambulatory and with minimal disability (Expanded Disability Status Scale <3), for at least the last six months. Participants selected to be part of a combined face-to-face plus home exercise group (CFTFG; n = 8); a self-applied home-based exercise group (HG; n = 11) or a control group (CG; n = 10). A total of 23 participants completed the protocol (79.3%), of which 8 participants (100%) from the CFTFG, 7 (63.6%) from the HG and 8 (80%) from the CG. During the first 20-weeks of training, adherence from the CFTFG reached 77.5% and from the HG reached 50 %. During the second 20-weeks of training, adherence from the CFTFG reached 62.5% and from the HG reached 45.4%. After 20-weeks of training, a significant improvement in the absolute VO2 peak and in the 30-second sit to stand test was observed in the CFTFG (all p < .05). This study confirms that offering a 40-week structured exercise programme to a group of fully ambulatory and minimally disabled persons with RRMS is feasible and safe. Any adverse event related to the trial was reported by the participants.

Leukocyte adhesion molecule dynamics after Natalizumab withdrawal in Multiple Sclerosis.

Cell-adhesion molecules (CAMs) dynamics in Multiple Sclerosis (MS) patients have been widely studied after Natalizumab (NTZ) introduction. However, their temporal dynamics after NTZ withdrawal (NTZ-W) has not been described. We prospectively evaluate changes in the expression levels of CAMs (CD49d, CD29, L-Selectin and CD11a) involved in T cell migration of 22 MS patients after NTZ-W. CD49d, CD29 and CD11a expression experienced a continuous increase expression two months after NTZ-W and Cd49d expression at month six after NTZ-W correlated to NTZ treatment duration, both in CD45+CD4+ and CD45+CD8+. CD49d expression up to month three after NTZ-W was related to MS activity in CD45+CD8+ at the end of the study. Results from this study suggest that patients with a longer NTZ treatment are more susceptible to present a "molecular rebound" after NTZ-W. CD49d determination may be a useful tool to closely monitor MS activity in patients who interrupt NTZ.

Antibodies to myelin oligodendrocyte glycoprotein in aquaporin 4 antibody seronegative longitudinally extensive transverse myelitis: Clinical and prognostic implications.

OBJECTIVE: We aimed to investigate the frequency and clinical significance of antibodies to myelin oligodendrocyte glycoprotein (MOG-abs) in patients who presented with a first episode of seronegative aquaporin 4 antibody (AQP4-ab) longitudinally extensive transverse myelitis (LETM). METHODS: Epidemiological, clinical, and paraclinical data of 56 patients from three European centres were analysed. Patients were retrospectively tested for MOG-abs and AQP4-abs, by cell-based assays. FINDINGS: Thirteen (23.2%) patients were MOG-ab positive. Among the 56 patients, six (10.7%) converted to neuromyelitis optica (NMO), one (1.8%) to multiple sclerosis (MS), nine (16.1%) had recurrent LETM, and 40 (71.4%) remained as monophasic LETM. Compared with seronegative patients, those with MOG-abs were younger (median: 32.5 vs 44 years; p=0.007), had cerebrospinal fluid pleocytosis more frequently (94% vs 45%, p=0.003) and had better outcome (median Expanded Disability Status Scale (EDSS) 2.0 vs 3.0, p=0.027). MOG-ab positive patients also showed an increase risk of optic neuritis relapse and NMO conversion (p=0.010). CONCLUSION: Patients with MOG-abs in AQP4-ab seronegative LETM have clinical distinctive features, higher risk of optic neuritis relapses, and better outcome than patients seronegative.

Adaptive natural killer cell response to cytomegalovirus and disability progression in multiple sclerosis.

BACKGROUND: Human cytomegalovirus (HCMV) causes a highly prevalent infection which may have a multifaceted impact on chronic inflammatory disorders. However, its potential influence in multiple sclerosis (MS) remains controversial. The HCMV-host interaction may induce an adaptive reconfiguration of the natural killer (NK) cell compartment, whose hallmark is a persistent expansion of peripheral NKG2C+ NK-cells. OBJECTIVE: The purpose of this study was to evaluate whether the HCMV-driven NKG2C+ NK-cell expansion is related to the MS clinical course. METHODS: Multicentre analysis of NKG2C expression and genotype according to HCMV serostatus and time of assignment of irreversible disability scores in 246 MS patients prospectively followed up in our institutions. RESULTS: NKG2C expression was unrelated to disease-modifying drugs, remained stable under steady-state conditions, and was higher in HCMV(+) NKG2C(+/+) homozygous individuals. NKG2C+ NK-cell expansion in HCMV(+) patients, as compared to HCMV(+) or HCMV(-) patients with lower NKG2C+ NK-cells proportions, conferred a lower risk of progression in Cox regression analysis (Expanded Disability Status Scale (EDSS)>3.0, hazard ratio (HR)=0.33, 95% confidence interval (CI) 0.15-0.71, p=0.005; EDSS>5.5, HR=0.23, 95% CI 0.07-0.74, p=0.014). Neither HCMV serostatus nor NKG2C genotype appeared to be related to disability progression. CONCLUSIONS: HCMV may exert a beneficial influence on MS, decreasing the risk of disability progression in those patients displaying a virus-driven NKG2C+ NK-cell expansion.

Glial and neuronal markers in cerebrospinal fluid predict progression in multiple sclerosis.

OBJECTIVE: To investigate glial and neuronal biomarkers in cerebrospinal fluid (CSF) samples from patients with relapsing-remitting multiple sclerosis (RRMS) and clinically isolated syndrome (CIS) suggestive of multiple sclerosis (MS), and to evaluate their ability to predict conversion from CIS to clinically definite MS (CDMS) and also disability progression in MS. METHODS: CSF levels of neurofilament light protein (NFL), t-tau, p-tau, glial fibrillary acidic protein (GFAP), S-100B, human chitinase 3-like 1 protein (YKL-40), monocyte chemoattractant protein-1 (MCP-1), α-sAPP and ß-sAPP; and Aß38, Aß40 and Aß42, were analyzed in 109 CIS patients and 192 RRMS patients. The mean follow-up time of these 301 patients was 11.7 ± 6.4 years. RESULTS: High levels of NFL were associated with early conversion from CIS to CDMS (hazard ratio (HR) with 95% confidence interval (CI): 2.69 (1.75 - 4.15); p < 0.0001). High levels of YKL-40 and GFAP were associated with earlier progression in the Expanded Disability Status Scale (EDSS), score 3: YKL-40 (HR (95% CI): 2.78 (1.48 - 5.23); p = 0.001) and GFAP (HR (95% CI): 1.83 (1.01 - 3.35); p = 0.04). High levels of YKL-40 were associated with earlier progression to EDSS 6 (HR (95% CI): 4.57 (1.01 - 20.83); p = 0.05). CONCLUSIONS: CSF levels of NFL in CIS patients are an independent prognostic marker for conversion to CDMS. Whereas, CSF levels of YKL-40 and GFAP are independent prognostic markers for disability progression in MS.

Effectiveness of natalizumab in patients with highly active relapsing remitting multiple sclerosis.

INTRODUCTION: We evaluated the effectiveness of natalizumab in patients with highly active, relapsing-remitting multiple sclerosis (HA-RRMS) to identify baseline predictors associated with freedom from disease activity. METHODS: We analyzed 70 patients treated with natalizumab and followed for at least 1 year with progression of disability of ≥1 point on the EDSS before starting therapy. We recorded freedom from clinical activity, radiological activity, and disease activity (clinical and radiological). RESULTS: The median (IQR) follow-up was 2.3 (2.0-3.8) years. Of the 52 patients who completed 2 years of treatment, 25 were free of disease activity (48.1%). The ARR decreased from a mean ± SD of 2.49 ± 0.86 at baseline to 0.47 ± 0.83 at the end of the first year (p < 0.001) and 0.34 ± 0.69 at the end of the second year (p < 0.001). The percentage of patients with gadolinium-enhanced lesions decreased from 21 at baseline to 5.7 at the end of the first year (p < 0.001) and to 5.8 during the second year (p < 0.005). Baseline EDSS ≤3.0 was significantly associated with freedom from disease activity (OR, 2.49; 95% CI, 1.24-4.99; p = 0.010). CONCLUSIONS: Natalizumab is effective in patients with HA-RRMS. Baseline EDSS ≤3.0 increases the probability of remaining disease-free in HA-RRMS treated with natalizumab.

Etiologic spectrum and prognosis of longitudinally extensive transverse myelopathies.

BACKGROUND: Patients with a first episode of longitudinal extensive transverse myelopathy (LETM) were reviewed with two objectives: to evaluate the clinical spectrum of LETM and to analyze the related clinical and laboratory variables that can be used as functional prognostic markers. METHODS: A retrospective review was conducted of clinical, radiologic and biochemical data of patients admitted for LETM between 1993 and 2011. RESULTS: Our cohort included 72 patients [median age 41 years, interquartile range (IQR) 29-61.5]. Median follow-up was 34 months (IQR 17.2-63). The modified Rankin Scale (mRS) score was ≥2 at the end of follow-up in 72.2%. The final diagnosis was idiopathic LETM in 22 patients, multiple sclerosis in 18, parainfectious disease in 11, systemic disease in 9, spinal cord infarction and neuromyelitis optica spectrum disorders in 3 patients each, and acute demyelinating encephalomyelitis, dural fistula, and tumor-related LETM in 2 patients each. Unfavorable outcome was associated with mRS ≥2 at admission [odds ratio (OR) 1.39, 95% confidence interval (CI) 1.16-1.66] and older age (OR 1.06, 95% CI 1.01-1.11). CONCLUSION: Idiopathic LETM was the most frequent diagnosis at the end of follow-up. Older age and clinically severe disease at onset were independent prognostic factors of poorer functional recovery.

The T1-dark-rim: A novel imaging sign for detecting smoldering inflammation in multiple sclerosis.

PURPOSE: Paramagnetic rim lesions (PRLs), usually identified in susceptibility-weighted imaging (SWI), are a promising prognostic biomarker of disability progression in multiple sclerosis (MS). However, SWI is not routinely performed in clinical practice. The objective of this study is to define a novel imaging sign, the T1-dark rim, identifiable in a standard 3DT1 gradient-echo inversion-recovery sequence, such as 3D T1 turbo field echo (3DT1FE) and explore its performance as a SWI surrogate to define PRLs. METHODS: This observational cross-sectional study analyzed MS patients who underwent 3T magnetic resonance imaging (MRI) including 3DT1TFE and SWI. Rim lesions were evaluated in 3DT1TFE, processed SWI, and SWI phase and categorized as true positive, false positive, or false negative based on the value of the T1-dark rim in predicting SWI phase PRLs. Sensitivity and positive predictive values of the T1-dark rim for detecting PRLs were calculated. RESULTS: Overall, 80 rim lesions were identified in 63 patients (60 in the SWI phase and 78 in 3DT1TFE; 58 true positives, 20 false positives, and two false negatives). The T1-dark rim demonstrated 97% sensitivity and 74% positive predictive value for detecting PRLs. More PRLs were detected in the SWI phase than in processed SWI (60 and 57, respectively). CONCLUSION: The T1-dark rim sign is a promising and accessible novel imaging marker to detect PRLs whose high sensitivity may enable earlier detection of chronic active lesions to guide MS treatment escalation. The relevance of T1-dark rim lesions that are negative on SWI opens up a new field for analysis.

Does serum neurofilament light chain measurement influence therapeutic decisions in multiple sclerosis?

BACKGROUND: The assessment of serum neurofilament light chain (sNfL) concentration in multiple sclerosis (MS) is a useful tool for predicting clinical outcomes and assessing treatment response. However, its use in clinical practice is still limited. We aimed to assess how measurement of sNfL influences neurologists' treatment decisions in MS. METHODS: We conducted a cross-sectional, web-based study in collaboration with the Spanish Society of Neurology. Neurologists involved in MS care were presented with different simulated case scenarios of patients experiencing either their first demyelinating MS event or a relapsing-remitting MS. The primary outcome was therapeutic inertia (TI), defined as the absence of treatment initiation or intensification despite elevated sNfL levels. Nine cases were included to estimate the TI score (range 0-9, where higher values represented a higher degree of TI). RESULTS: A total of 116 participants were studied. Mean age (standard deviation-SD) was 41.9 (10.1) years, 53.4 % male. Seventy-eight (67.2 %) were neurologists fully dedicated to the care of demyelinating disorders. Mean (SD) TI score was 3.65 (1.01). Overall, 92.2 % of participants (n = 107) presented TI in at least 2/9 case scenarios. The lack of full dedication to MS care (p = 0.014), preference for taking risks (p = 0.008), and low willingness to adopt evidence-based innovations (p = 0.009) were associated with higher TI scores in the multivariate analysis after adjustment for confounders. CONCLUSION: TI was a common phenomenon among neurologists managing MS patients when faced with the decision to initiate or escalate treatment based on elevated sNfL levels. Identifying factors associated with this phenomenon may help optimize treatment decisions in MS care.

Baseline serum neurofilament light chain levels differentiate aggressive from benign forms of relapsing-remitting multiple sclerosis: a 20-year follow-up cohort.

BACKGROUND AND OBJECTIVES: Serum biomarkers are emerging as useful prognostic tools for multiple sclerosis (MS); however, long-term studies are lacking. We aimed to evaluate the long-term prognostic value of the serum levels of neurofilament light chain (NfL), total tau, glial fibrillary acidic protein (GFAP), and chitinase 3-like-1 (CHI3L1) measured close to the time of MS onset. METHODS: In this retrospective, exploratory, observational, case and controls study, patients with relapsing-remitting MS (RRMS) with available baseline serum samples and prospectively follow-up in our MS unit for a long time were selected based on their clinical evolution to form two groups: (1) a benign RRMS (bRRMS) group, defined as patients with an Expanded Disability Status Scale (EDSS) score of ≤ 3 at ≥ 10 years of follow-up; (2) an aggressive RRMS (aRRMS) group, defined as patients with an EDSS score of ≥ 6 at ≤ 15 years of follow-up. An age-matched healthy control (HC) group was selected. NfL, total tau, and GFAP serum levels were quantified using a single-molecule array (SIMOA), and CHI3L1 was quantified using ELISA. RESULTS: Thirty-one patients with bRRMS, 19 with aRRMS, and 10 HC were included. The median follow-up time from sample collection was 17.74 years (interquartile range, 14.60-20.37). Bivariate and multivariate analyses revealed significantly higher NfL and GFAP levels in the aRRMS group than in the bRRMS group. A receiver operating characteristic curve analysis identified serum NfL level as the most efficient marker for distinguishing aRRMS from bRRMS. DISCUSSION: This proof-of-concept study comparing benign and aggressive RRMS groups reinforces the potential role of baseline NfL serum levels as a promising long-term disability prognostic marker. In contrast, serum GFAP, total tau, and CHI3L1 levels demonstrated a lower or no ability to differentiate between the long-term outcomes of RRMS.

Increased CXCL12, a potential CSF biomarker for differential diagnosis of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a debilitating and lethal neurodegenerative disorder marked by the gradual deterioration of motor neurons. Diagnosing amyotrophic lateral sclerosis is challenging due to the lack of reliable diagnostic tools, with clinical assessment being the primary criterion. Recently, increased levels of neurofilament light chain in CSF have been considered a useful biomarker in disease, correlating with disease progression but not specific for diagnosis. This study utilized enzyme-linked immunosorbent assay to measure CSF C-X-C motif chemokine ligand 12 levels in healthy controls, amyotrophic lateral sclerosis patients and patients with amyotrophic lateral sclerosis-mimic disorders, assessing its potential as a diagnostic biomarker and comparing it with neurofilament light chain levels. Our results confirmed previous findings, showing increased C-X-C motif chemokine ligand 12 levels in amyotrophic lateral sclerosis patients compared to healthy control (797.07 ± 31.84 pg/mL versus 316.15 ± 16.6 pg/mL; P = 0.000) and increased CSF neurofilament light chain levels in amyotrophic lateral sclerosis (4565.63 ± 263.77 pg/mL) compared to healthy control (847.86 ± 214.37 pg/mL; P = 0.000). Increased C-X-C motif chemokine ligand levels were specific to amyotrophic lateral sclerosis, not seen in amyotrophic lateral sclerosis-mimic conditions like myelopathies (252.20 ± 23.16 pg/mL; P = 0.000), inflammatory polyneuropathies (270.24 ± 32.23 pg/mL; P = 0.000) and other mimic diseases (228.91 ± 29.20 pg/mL; P = 0.000). In contrast, CSF neurofilament light chain levels in amyotrophic lateral sclerosis overlapped with those in myelopathies (2900.11 ± 872.20 pg/mL; P = 0.821) and other mimic diseases (3169.75 ± 1096.65 pg/mL; P = 0.63), but not with inflammatory polyneuropathies (1156.4 ± 356.6 pg/mL; P = 0.000). Receiver operating characteristic curve analysis indicated significant differences between the area under the curve values of C-X-C motif chemokine ligand and neurofilament light chain in their diagnostic capacities. C-X-C motif chemokine ligand could differentiate between amyotrophic lateral sclerosis and myelopathies (area under the curve 0.99 ± 0.005), inflammatory polyneuropathies (area under the curve 0.962 ± 0.027) and other mimic diseases (area under the curve 1.00 ± 0.00), whereas neurofilament light chain was only effective in inflammatory polyneuropathies cases (area under the curve 0.92 ± 0.048), not in myelopathies (area under the curve 0.71 ± 0.09) or other mimic diseases (area under the curve 0.69 ± 0.14). We also evaluated C-X-C motif chemokine ligand levels in plasma [amyotrophic lateral sclerosis (2022 ± 81.8 pg/mL) versus healthy control (1739.43 ± 77.3 pg/mL; P = 0.015)] but found CSF determination (area under the curve 0.97 ± 0.012) to be more accurate than plasma determination (area under the curve 0.65 ± 0.063). In plasma, single molecule array (SIMOA) neurofilament light chain determination [amyotrophic lateral sclerosis (86.00 ± 12.23 pg/mL) versus healthy control (12.69 ± 1.15 pg/mL); P = 0.000] was more accurate than plasma C-X-C motif chemokine ligand 12 (area under the curve 0.98 ± 0.01405). These findings suggest that CSF C-X-C motif chemokine ligand 12 levels can enhance diagnostic specificity in distinguishing amyotrophic lateral sclerosis from amyotrophic lateral sclerosis-mimic disorders, compared to neurofilament light chain. Larger studies are needed to validate these results, but C-X-C motif chemokine ligand 12 determination shows promising diagnostic potential.

Association of Complement Factors With Disability Progression in Primary Progressive Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study investigated the role of the complement system in disability progression of patients with primary progressive MS (PPMS). METHODS: Sixty-eight patients with PPMS from 12 European MS centers were included in the study. Serum and CSF levels of a panel of complement components (CCs) were measured by multiplex enzyme-linked immunosorbent assay at a baseline time point (i.e., sampling). Mean (SD) follow-up time from baseline was 9.6 (4.8) years. Only one patient (1.5%) was treated during follow-up. Univariable and multivariable logistic regressions adjusted for age, sex, and albumin quotient were performed to assess the association between baseline CC levels and disability progression in short term (2 years), medium term (6 years), and long term (at the time of the last follow-up). RESULTS: In short term, CC played little or no role in disability progression. In medium term, an elevated serum C3a/C3 ratio was associated with a higher risk of disability progression (adjusted OR 2.30; 95% CI 1.17-6.03; p = 0.040). By contrast, increased CSF C1q levels were associated with a trend toward reduced risk of disability progression (adjusted OR 0.43; 95% CI 0.17-0.98; p = 0.054). Similarly, in long term, an elevated serum C3a/C3 ratio was associated with higher risk of disability progression (adjusted OR 1.81; 95% CI 1.09-3.40; p = 0.037), and increased CSF C1q levels predicted lower disability progression (adjusted OR 0.41; 95% CI 0.17-0.86; p = 0.025). DISCUSSION: Proteins involved in the activation of early complement cascades play a role in disability progression as risk (elevated serum C3a/C3 ratio) or protective (elevated CSF C1q) factors after 6 or more years of follow-up in patients with PPMS. The protective effects associated with C1q levels in CSF may be related to its neuroprotective and anti-inflammatory properties.