Introduction L’amylose hATTR est une maladie rare, causant une polyneuropathie axonale invalidante et potentielle mortelle. Le monitoring de la progression de la neuropathie et de la réponse au traitement est crucial. Objectifs Déterminer si le NfL et GFAP sérique sont des biomarqueurs fiables de neuropathie dans l’amylose hATTR. Méthodes Quarante-huit patients hATTR inclus, 38 symptomatiques (S), 8 asymptomatiques (A) et 2 convertisseurs (C). Évaluation annuelle sur 4 ans : examen neurologique, scores fonctionnels/sévérité, Sudoscan®, ENMG et mesure du NfL et GFAP sérique, converti en Z-scores (zNfL et zGFAP) à l’aide d’une base de donnée de contrôles sains, corrigée à l’âge et IMC. Résultats zNfL médian −0,50 (A), 1,44 (C) et 2,46 (S). zNfL>1,42 distingue S vs A (se 88,9 %, sp 91,9 %, AUC 0,936), pas le zGFAP (AUC 0,588). zNfL corrèle (pas le zGFAP) aux échelles cliniques/électrophysiologiques de gravité de la neuropathie. Lors du suivi des asymptomatiques, zNfL reste stable<1 chez la plupart. Chez les symptomatiques, le zNfL diminue de 0,1/an. Chez 1/2 convertisseurs, augmentation significative du zNfL un an avant la transition symptomatique. Discussion Le zNfL est corrélé à la sévérité et transition symptomatique de la neuropathie. Un zNfL>1,42 distingue les symptomatiques des asymptomatiques. L’augmentation du NfL précède probablement la neuropathie clinique de plusieurs mois/années. Conclusion Le zNfL, pas le zGFAP, est un biomarqueur fiable de neuropathie dans l’amylose hATTR. L’utilisation de Z-score dérivée de large cohorte de contrôles sains doit être privilégiée.

Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising multiple sclerosis (MS) biomarkers, but biological confounding and inter-assay variability limit real-world use. We assessed whether Z score normalisation enables platform-agnostic monitoring in people with MS (pwMS) under ocrelizumab, and which early timepoint best stratifies subsequent biomarker trajectories. This pooled multicentre analysis of three German cohorts included pwMS treated with ocrelizumab for ≥ 12 months. Elecsys® or Simoa® assays were harmonised using covariate-adjusted Z scores. We evaluated biomarker 24-month trajectories and whether stratification and relative reductions predicted 24-month biomarker-status. 430 pwMS were included [78

IntroductionThere has been growing recognition of potential differences in disease course and presentation between men and women with MS. This study examined sex differences in MS using data collected at study entry in the Swiss Multiple Sclerosis Cohort (SMSC).MethodsA cross-sectional analysis of the data from 1541 SMSC participants (June 2012–February 2022) with persons with relapsing-remitting MS or Clinically Isolated Syndrome (named relapsing type) and progressive MS including persons with Primary Progressive Multiple Sclerosis (PPMS) and Secondary Progressive Multiple Sclerosis (SPMS) was performed. Sociodemographic and clinical characteristics, disease history, and severity indicators were examined, focusing on sex differences within progressive and relapsing MS types, and comparing these MS types. Statistical analyses included Mann-Whitney U tests and chi-squared tests for group comparisons. Multivariate linear regression models were constructed to examine the independent association of sex with Expanded Disability Status Scale (EDSS) scores, adjusting for age, disease duration, treatment category, recent relapse, and body mass index (BMI).ResultsWomen represented 65.8% of the cohort (1,014/1,541). BMI was significantly lower in women than in men in the relapsing type and SPMS (relapsing: p < 0.001; SPMS: p = 0.001; PPMS: p = 0.86). Age at first symptoms differed by sex depending on MS type: women were younger in the relapsing group (29.7 vs. 31.4 years, p = 0.036), while men were younger in PPMS (42.3 vs. 47.7 years, p < 0.001), with no difference in SPMS (p = 0.5). In univariate analysis, men showed a trend toward higher disability levels at study entry in the relapsing type (p = 0.058), but no significant sex differences in EDSS were observed in progressive forms. In multivariate analysis, female sex showed a trend toward lower EDSS scores in relapsing MS after adjusting for clinical factors (β = −0.13, 95% CI: −0.26 to 0.005, p = 0.059) but was not associated with EDSS in PPMS (β = −0.09, p = 0.802) or SPMS (β = + 0.09, p = 0.816).ConclusionThis study identified sex differences in disease distribution, BMI and EDSS at their entry in the SMSC. These findings underscore the complexity of sex differences in MS and highlight the importance of prospective longitudinal studies with standardized severity assessments to clarify sex-specific disease trajectories and inform personalized treatment strategies.

Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are biomarkers for neuroaxonal damage and astroglial injury, respectively. The present study aimed to quantify NfL and GFAP as well as investigate their association with psychiatric symptoms in a sample of recreational cannabis users. Blood samples from 331 individuals with regular recreational cannabis use were collected. Serum NfL (sNfL) and GFAP (sGFAP) levels were quantified in duplicate by an ultrasensitive single-molecule array (Simoa) technology. Reference populations were used to calculate age-, BMI-, and (for GFAP) sex-adjusted Z scores. Participants completed validated psychometric instruments assessing symptoms of cannabis use disorder, alcohol use disorder, psychosis, depression, and anxiety. Mean GFAP levels were significantly lower than those in the reference population (t(330) = −6.718, p < 0.001), whereas NfL levels did not differ (t(330) = 1.3, p = 0.19). Participants with hazardous cannabis use and those screening positive for psychotic symptoms showed higher NfL levels. Psychotic symptoms were additionally associated with lower GFAP levels. NfL correlated positively with total Cannabis Use Disorder Identification Test–Revised (CUDIT-R) scores (ρ(329) = 0.12, p = 0.03) and specifically with the items “memory/concentration problems” (ρ(329) = 0.11, p = 0.04) and “time spent buying/using/recovering” (ρ(329) = 0.13, p = 0.02). In multiple regression analysis, psychotic and cannabis use disorder symptoms independently predicted higher NfL levels. No variables predicted GFAP levels. There was no association between self-reported cannabis use amount or frequency in the past 30 days and GFAP or NfL. The results provide preliminary evidence of cannabis-related neuroaxonal alterations, warranting longitudinal studies to clarify the temporal relationship between these biomarkers and cannabis use.

Objective:The treatment of carotid artery stenosis (CAS) for stroke prevention is a matter of debate due to conflicting data, missing recent data, and advances in medical treatment options but also in interventional techniques and surgery. Therefore, the establishment of an easily available marker for brain damage might be a key tool in this patient group to guide treatment. Methods:A retrospective cross-sectional study was conducted leveraging a vascular surgery biobank of 95 patients aged 60 to 80 years. Serum neurofilament light chain (sNfL) and serum glial fibrillary acid protein (sGFAP) were evaluated using highly sensitive electrochemiluminescence immunoassays and z-scores. Discriminatory performance was assessed to differentiate between 19 symptomatic and 76 asymptomatic patients with CAS and their correlation with the degree of stenosis according to ultrasound-based North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria. Results:SNfL levels were markedly elevated in symptomatic compared with asymptomatic patients (median 17.4 vs 3.8 pg/mL; P < .001). sNfL robustly discriminated between these patients (area under the curve = 0.83; 95% confidence interval, 0.72-0.94), as did the NfL z-score (area under the curve = 0.83; 95% confidence interval, 0.71-0.95). Interestingly, within the asymptomatic cohort, sNfL levels demonstrated a significant, positive correlation with the degree of stenosis (Spearman's ρ = 0.24; P = .036). Serum levels of SGFAP were also associated with symptomatic status, albeit with a P-value >.05 (0.1 vs 0.1 pg/mL; (P = .057). Conclusions:The study provides evidence of increased sNfL in symptomatic vs asymptomatic CAS and, of note, of ongoing neuronal or glial damage in some patients with clinically asymptomatic CAS, with a positive correlation between sNfL and the degree of CAS. sNfL is a promising and already accessible blood biomarker that may guide therapeutic decisions in this patient population. The role of sGFAP remains elusive and must be evaluated in larger studies. Clinical Relevance:The CREST-2 trial has recently highlighted the high efficacy of intensive medical management in asymptomatic carotid artery stenosis (CAS), making the selection of patients for revascularization increasingly complex. Our study addresses this challenge by evaluating serum neurofilament light chain (sNfL) and serum glial fibrillary acid protein (sGFAP) as an objective biomarker for neuronal injury. Using individualized z-scores, we demonstrate that sNfL effectively differentiates symptomatic status (area under the curve = 0.828) and significantly correlates with the degree of stenosis in asymptomatic cohorts. These results suggest that sNfL can detect subclinical "silent" damage, providing a valuable biological tool to pinpoint high-risk patients who may require intervention beyond medical therapy alone. This represents a significant step toward personalized stroke prevention and refined risk stratification in the highly debated field of CAS management.

Background Whether surgical haematoma evacuation leads to reduced brain damage in patients with spontaneous supratentorial intracerebral haemorrhage (SSICH) remains unknown. Blood biomarkers reflecting brain damage could aid in prognosticating the clinical outcome and hence support quantifying the benefit of surgical interventions. Methods Blood samples from 10 patients with SSICH in the phase II early minimally invasive image-guided endoscopic evacuation of intracerebral hemorrhage (EMINENT-ICH) pilot study ( NCT04805177 , completed) were collected longitudinally (at baseline, 24 hours, 3 days, 1 week, 1 month and 6 months after surgical haematoma evacuation). Neurofilament light chain (NfL), glial fibrillar acidic protein (GFAP), calcium-binding protein S100B and the inflammatory markers interferon-gamma, interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-10 and tumour necrosis factor alpha were quantified. The perioperative and long-term course of concentrations and association with clinical outcome measures were assessed. A favourable outcome was defined as a modified ranking scale ≤3. Results Favourable outcome was observed in 60% (6/10) of patients (median age 72.5 years (IQR 67.5–79.8), 70% male), and in 70% (7/10) of patients, the preset goal of a postsurgery haematoma volume below 15 mL was achieved. On average, patients with unfavourable outcomes at 6 months had twofold higher NfL and sixfold higher GFAP concentrations compared with those with favourable outcomes (p NfL =0.127, p GFAP =0.017); concentrations of both markers were higher in patients with unsatisfactory haematoma evacuation (3.7-fold for NfL, p=0.0072 and 12.4-fold for GFAP, p=0.0122). Concentrations of other markers, especially ILs, were not indicative of functional outcomes. Conclusions Based on our results, we provide preliminary evidence that lower serum NfL and GFAP levels are associated with favourable clinical outcomes and successful haematoma evacuation in SSICH.

INTRODUCTION:Management of multiple sclerosis (MS) revolves around timely initiation of effective disease-modifying therapy. Here we investigate the additive predictive value of age-adjusted normalised neurofilament light chain (NfL) concentrations when combined with a clinicodemographic model of treatment response. METHODS:Data were obtained from three sources: the University Hospital Basel, the SET cohort in Prague, and EIMS and IMSE cohorts from Sweden. NfL samples were collected within 90 days of baseline, age-adjusted and normalised using a reference population. Principal component analysis reduced the dimensionality of clinicodemographic predictors. Cox proportional hazards models estimated cumulative hazards of relapse, 6-month confirmed disability worsening and 9-month confirmed disability improvement, with and without NfL. Uno's concordance index compared prediction accuracy across pooled and treatment-specific models. RESULTS:The study included 1716 individuals across three therapies: interferon β (n = 554), fingolimod (n = 307) and natalizumab (n = 369). Clinicodemographic characteristics were associated with relapse and disability outcomes. While NfL showed no association in the pooled cohort, in the natalizumab group, higher NfL predicted lower probability of disability improvement (HR = 0.819, 95% CI: 0.814-0.823). Pooled models predicted outcomes with moderate accuracy (relapse: 63.4%, disability worsening: 56.4%, improvement: 67.7%), with minimal contribution from NfL. In treatment-specific models, NfL-inclusive accuracy ranged from 51.3%-62.2% (relapse), 54.3%-60.3% (worsening) and 65%-67.9% (improvement), closely matching models without NfL. CONCLUSION:In well-characterised MS patients treated with interferon β, fingolimod or natalizumab, clinicodemographic information provides modest prognostic value; however, NfL adds minimal incremental utility.

Swiss cohort studies provide high-quality longitudinal data, but finding and comparing relevant studies across cohorts has historically been challenging. The Swiss Personalized Health Network Cohort Consortium (SPHN-CC) was established to address these limitations by creating the first coordinated network of Swiss cohort studies within the internationally recognized Maelstrom Research catalogue. Participating cohorts were invited in 2021-2022, including longitudinal and cross-sectional studies with 1010-21,993 participants. Data collected include questionnaires, physical and cognitive assessments, administrative records, and biological samples. Variables were classified into 18 domains and 134 subdomains, and an online metadata catalogue was implemented to document study designs, explore variable content, and assess harmonization potential. The catalogue enables researchers to identify study-specific and harmonized variables for co-analysis. Core variables, such as age, sex/gender, anthropometrics, and medication use, are widely available, while other variables vary across cohorts. Harmonization assessments demonstrate that several key variables can be co-analyzed across multiple studies, supporting collaborative research with over 37,000 participants. A use case illustrates the potential for harmonizing and co-analyzing data across studies. The SPHN-CC strengthens Swiss cohort research by enhancing data discoverability, supporting harmonization, and facilitating cross-cohort and international research, providing a model for more efficient use of high-value longitudinal data.

Importance:Capturing individual multiple sclerosis (MS) progression is difficult; few studies have evaluated glial fibrillary acidic protein (GFAP) in large longitudinal cohorts with independent validation. Objective:To investigate whether serum GFAP levels and treatment-related changes are associated with future progression independent of relapse activity (PIRA). Design, Setting, and Participants:This was a prospective observational study using 2 large MS cohorts: the Swiss MS Cohort (SMSC; initiated in June 2012; data extraction September 22, 2025) and the Expression, Proteomics, Imaging, Clinical study (EPIC; initiated in July 2004; data extraction February 21, 2024). The study took place at tertiary MS centers (8 for SMSC and 1 for EPIC). A total of 2329 persons with MS from both cohorts with at least 1 available time point with neurofilament light chain (NfL) and GFAP measurements were included (overall 18 629 measurements). Exposures:Clinical data and NfL and GFAP z scores, collected and calculated every 6 or 12 months. Main Outcomes and Measures:Risk of future PIRA, defined as Expanded Disability Status Scale score worsening confirmed after 6 or more months without relapses (in SMSC), or a composite additionally including greater than 20% worsening in the 9-hole peg test or timed 25-ft walk test (in EPIC). Results:The SMSC and EPIC cohorts consisted of 1709 (13 375 samples; median [IQR] follow-up, 6.9 [2.5-10.7] years and age, 40.6 [32.1-50.1] years; 1128 [66.0%] female) and 620 (5254 samples; median [IQR] follow-up, 13.1 [9.4-14.0] years and age, 42.0 [35.0-50.0] years; 432 [69.7%] female) persons with MS, respectively. Consistent with prior work, high NfL was associated with relapse risk within the next year, whereas high GFAP was associated with long-term PIRA risk. In addition, elevated GFAP (z score >1.0 [84th percentile]) was associated with an average 40% higher hazard of short-term PIRA in the subsequent visit interval (SMSC: median [IQR] 346 [190-375] days; hazard ratio [HR], 1.45, 95% CI, 1.21-1.75; P < .001; EPIC: 385 [355-518] days; HR, 1.36; 95% CI, 1.07-1.71; P = .01). GFAP-based cohort enrichment in clinical trials targeting PIRA as an end point could reduce sample size by approximately 20%. Further, in SMSC, every yearly GFAP z score unit reduction during the first 2 years receiving fingolimod or B-cell-depleting therapy was associated with a lower risk of subsequent PIRA (54% risk reduction; HR, 0.46; 95% CI, 0.26-0.84; P = .01 and 67% risk reduction; HR, 0.33; 95% CI, 0.18-0.61; P < .001), respectively. Conclusions and Relevance:In this cohort study, elevated GFAP was associated with a higher risk of PIRA, while treatment-associated reductions were associated with a lower PIRA risk. Together, these results suggest that serum GFAP may serve as a biomarker for personalized risk stratification and treatment monitoring and as a screening tool to reduce cohort size in clinical trials targeting MS progression.

Background and ObjectivesAccurate biomarkers that reflect disease activity, severity, and molecular pathophysiology in multiple sclerosis (MS) remain an unmet diagnostic need. We compared the performance of the established biomarkers, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), with emerging candidates in CSF and serum.MethodsWe measured 21 analytes using Olink proximity extension assay technology, NfL and GFAP using Simoa, and soluble triggering receptor expressed on myeloid cells (sTREM2) and neuronal pentraxin 2 (NPTX2) using Fujirebio platforms in paired CSF and serum/plasma samples from 293 participants. The cohort included patients with clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS), as well as individuals with inflammatory neurologic disease and symptomatic controls (SCs). CSF and serum biomarker levels were compared across diagnostic groups using multivariable Cox and linear regression models. Associations were assessed using CSF immunoglobulin profiles, time from first to second clinical event, and Expanded Disability Status Scale (EDSS) scores in CIS, as well as the Multiple Sclerosis Severity Score (MSSS) in patients with MS.ResultsEight biomarkers showed consistent differential expression. In CSF, CXCL13, CXCL9, IL-12b, and NfL were elevated in most CIS and MS subgroups compared with SCs. Osteopontin (OPN) levels were increased in RRMS and PPMS subgroups, whereas TNFRSF10A elevations were confined to patients with PPMS. In serum, NfL was elevated across all CIS and MS subgroups, GFAP was increased in RRMS and SPMS subgroups, and myelin oligodendrocyte glycoprotein (MOG) was increased in RRMS and PPMS subgroups. Higher CSF levels of CXCL13, CXCL9, and IL-12b predicted shorter intervals to a second clinical attack and correlated strongly with intrathecal IgM synthesis. Elevated EDSS scores at CIS onset were linked to higher CSF levels of CXCL13, IL-12b, TNFRSF10A, and OPN, and to NfL, GFAP, and MOG in serum. Prediction of future MSSS was limited to GFAP in CSF, whereas in serum, GFAP, MOG, OPN, and CXCL9 were significantly associated.DiscussionCSF CXCL13, CXCL9, and IL-12b are promising biomarkers for predicting relapse activity, while serum GFAP and MOG appear to be consistent candidates for prognosticating disease severity.

Granulocytes play a well-established role in the pathogenesis of brain tissue damage in neuromyelitis optica spectrum disorder (NMOSD). The release of granulocyte activation markers (GAM) into CSF has recently been shown to distinguish NMOSD from multiple sclerosis (MS) with high accuracy. However, their pathogenetic role in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is less clear, and their usefulness for diagnostic differentiation is unknown. This observational cohort study by eight tertiary centres in Europe and Japan included 244 CSF samples from patients with MOGAD (n = 71), NMOSD (n = 48), MS (n = 125) and control persons (n = 19). CSF levels of GAM [neutrophil elastase, myeloperoxidase, neutrophil gelatinase-associated lipocalin (NGAL), matrix metalloproteinase-8 and 9 (MMP-8, MMP-9)], astrocyte damage markers [ADM: glial fibrillary acidic protein (GFAP), S100B], and complement factors C5 and C5a were analysed by capillary ELISA (Ella™) or Luminex®. The primary outcome was the capacity of these markers to differentiate MOGAD, NMOSD and MS in the acute (≤21 days post-exacerbation) stage, and the correlation of GAM with C5 and C5a. Secondary analyses included the correlations of these markers with disability severity, measured by the Expanded Disability Status Scale (EDSS). GAM (except for MMP-9), ADM and C5/C5a levels peaked at onset of disease exacerbation of MOGAD and NMOSD (regardless of aquaporin-4 antibody status), and were significantly higher than in MS. MMP-9 levels were continuously increased in MS over MOGAD and NMOSD, both in acute and subacute/chronic stages. C5 and C5a were equally increased over MS in acute stages of MOGAD and NMOSD. A logistic model and receiver operating characteristics analyses incorporating GAM and C5 displayed high discriminatory power between MOGAD/NMOSD versus MS [area under the curve (AUC) = 0.880], NMOSD versus MS (AUC = 0.837) and MOGAD versus MS (AUC = 0.925) in acute stages. Accordingly, increased ADM levels in NMOSD differentiated NMOSD from MS and MOGAD (AUC = 0.897 and 0.843, respectively). GAM levels correlated with EDSS scores in MOGAD and NMOSD, but not in MS, while those of ADM correlated with disability in NMOSD, but not in MOGAD and MS. Determining CSF levels of GAM and C5/C5a, and of ADM provide a biology-driven approach to differentiate MOGAD, NMOSD and MS. Their measurement can be processed faster and with similar accuracy than with most autoantibody assays, enabling timely initiation of appropriate therapy in acute presentations. The correlation between GAM and C5/C5a levels with neurological impairment in MOGAD and NMOSD corroborates their role as effectors of neural damage, supporting the acute stage use of inhibitors of C5 activation.

In multiple sclerosis (MS) patients under therapy, the increase of serum glial fibrillary acidic protein (sGFAP) concentrations is associated with the course of 'progression in absence of relapse' (PIRA). While serum neurofilament light chain (sNfL) reflects both response as well as insufficient or lack of efficiency of disease-modifying therapies (DMT), the longitudinal course of sGFAP levels as a drug response marker for future PIRA in relation to specific types of DMT is less clear. We aimed to compare the predictive capacity of sGFAP and sNfL for PIRA and relapse activity and the longitudinal course in people with MS (PwMS) treated with fingolimod, based on Z scores derived from normative values. Overall, 420 PwMS under fingolimod treatment with follow-up of 9.1 years (interquartile range: 7.0-11.0) from the Swiss MS Cohort, contributing 2935 longitudinal serum samples, were included. A reference data set for sGFAP established from 4297 healthy controls across three European and North American cohorts was used to calculate Z scores. The longitudinal course and the predictive capacity of biomarkers for time to PIRA and relapse were assessed by Cox proportional hazards and linear mixed-effects models. In controls, sGFAP concentrations were 13.6% higher in females than males and increased exponentially with age. Altogether, 31.0% of PwMS experienced ≥1 PIRA event. Elevated sGFAP Z scores (>0.75) were associated with increased risk of PIRA [hazard ratio (HR): 1.64; 95% confidence interval (CI): 1.16-2.32; P = 0.006], while this was not the case for sNfL. Conversely, elevated sNfL predicted relapses (HR: 1.58; 95% CI: 1.13-2.23; P = 0.008), while sGFAP did not. Both biomarkers decreased under treatment: sGFAP by 0.19 Z score units (ZSU)/10 years (95% CI: -0.27 to -0.11; P < 0.001) and sNfL by 0.16 ZSU/10 years (95% CI: -0.27 to -0.06; P = 0.002). Serum GFAP remained elevated in PwMS with future PIRA events (estimate: 0.29; 95% CI: 0.07-0.50; P = 0.009); no such association was found for sNfL. Serum GFAP and sNfL Z scores provide complementary predictive capacity for PIRA and relapse risk. The decrease of sGFAP under fingolimod is a feature not observed with other types of DMT and may hint to a specific anti-neurodegenerative effect of Sphingosine-1-phosphate-receptor modulators on astrocytes.

The heterogeneity of multiple sclerosis (MS) pathology calls for robust biomarkers to predict disability and progression, particularly progression independent of relapse activity (PIRA). Here, we aimed to identify the most informative MRI and serum biomarkers for predicting clinical outcomes in people with MS (pwMS), including disability severity, cognitive impairment, disease phenotype, and risk of PIRA. We applied a machine learning-based feature selection approach to cross-sectional and longitudinal data from two independent pwMS cohorts. Cohort 1 (n = 120) included 57 MRI biomarkers, incorporating advanced quantitative MRI (qMRI). Cohort 2 (n = 279) included 35 MRI biomarkers derived from conventional MRI. Both cohorts obtained serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) measurements. Spinal cord atrophy consistently emerged as the strongest predictor of disability severity and predicted PIRA, along with cortical thinning and subcortical atrophy - particularly in deep gray matter. sNfL, sGFAP, and qMRI metrics independently contributed to the prediction of PIRA and progressive disease phenotype. In conclusion, our findings show that spinal cord atrophy and cortical degeneration are the most robust and consistent predictors of MS severity and progression. Serum biomarkers of neuroaxonal and astrocytic damage, together with qMRI-derived tissue metrics, provide independent and complementary value for outcome prediction.

BACKGROUND AND OBJECTIVES:In people with multiple sclerosis (pwMS), optical coherence tomography (OCT) quantifies loss of neurons (macular ganglion cell-inner plexiform layer [mGCIPL]) and axons (peripapillary retinal nerve fiber layer [pRNFL]) in the retina. Serum glial fibrillary acidic protein (sGFAP) is a promising astrocytic biomarker to capture disease progression in pwMS. We aimed to investigate the relationship between OCT markers and sGFAP in pwMS and explore their additive value in predicting disability progression. METHODS:PwMS and healthy controls underwent OCT at baseline (BL), excluding eyes with inter-eye asymmetry. Age, sex, and body mass index-adjusted Z scores of sGFAP were calculated. Cross-sectional and longitudinal associations between sGFAP and retinal layers were estimated using linear regression- and mixed-effects models (LMM). The additive effect of BL-OCT and BL-sGFAP on the trajectory of the Expanded Disability Status Scale (EDSS) was estimated using LMM, whereby pwMS were stratified into: group (1): low sGFAP Z score (<3rd quartile, Q1); group (2): high sGFAP Z score (≥Q3) and thick mGCIPL or low sGFAP Z Score and thin mGCIPL (≤Q1); and group (3): high sGFAP and thin mGCIPL. RESULTS:Two hundred and sixty-one pwMS (mean age: 48 years (y), female: 63%, on disease-modifying treatment: 80%, mean thickness of pRNFL: 94 μm and mGCIPL: 66 μm) and 52 controls (age: 52 years, female: 65%, pRNFL: 101 μm, mGCIPL: 72 μm) were included. At BL, pRNFL (β = -0.01, p = 0.042) and mGCIPL (β = -0.02, p = 0.013) were negatively associated with sGFAP Z scores in pwMS, but not in controls (p = 0.950, p = 0.386). BL-mGCIPL was also associated with sGFAP trajectories (β = -0.003, p = 0.044), over a median follow-up of 2.9 years. Compared with pwMS with good results in both markers (group 1), those with either high sGFAP or thin mGCIPL had a steeper EDSS increase (β = 0.030, p = 0.048), while pwMS with both high sGFAP and thin mGCIPL (group 3) showed the steepest trajectory of the EDSS (β = 0.101, p < 0.001). DISCUSSION:Our findings show a close relationship between astrocytic activation/injury and neurodegeneration in the CNS, measured at the retinal level. Moreover, they highlight an additive role of mGCIPL and sGFAP for identification of pwMS at higher risk of disability worsening.

Distinguishing posterior circulation stroke (PCS) from peripheral or other causes of acute vertigo can be challenging. Blood biomarkers, such as plasma neurofilament light chain (pNfL) and glial acidic fibrillary protein (pGFAP), have been associated with (even small) stroke lesions and could support patient selection for neuroimaging and inpatient evaluation in acute vertigo. This prospective study included consecutive patients presenting with acute vertigo to a neurological emergency department. All patients received neurological examination, laboratory testing and neuroimaging. pNfL and pGFAP were measured using Single Molecule Array (SIMOA) technique. pNfL and pGFAP levels were compared between PCS and patients with non-central vertigo. 102 patients were included (mean age 57.9 years, 57.8

BACKGROUND:Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia surface receptor that aids in tissue repair and debris clearance. The soluble form, sTREM2, found in both blood and cerebrospinal fluid, is considered a biomarker for microglial activation. Based on the central role of microglia in MS pathogenesis, we aimed to investigate whether serum sTREM2 levels could predict disability progression in patients with primary progressive MS. METHODS:Serum levels of sTREM2 were measured at baseline using a single-molecule array assay in a multicenter cohort of 137 primary progressive multiple sclerosis (PPMS) patients. Univariable and multivariable linear models evaluated the association between sTREM2 levels and EDSS change at 2 years, 6 years, and last follow-up. RESULTS:While an association was observed at 2 years only in non-inflammatory PPMS patients, no consistent relationship was found between sTREM2 levels and disability progression over longer follow-up. CONCLUSIONS:These findings suggest that serum sTREM2 may have limited value as a biomarker of disability progression in PPMS.

BACKGROUND AND OBJECTIVES:Accurate biomarkers that reflect disease activity, severity, and molecular pathophysiology in multiple sclerosis (MS) remain an unmet diagnostic need. We compared the performance of the established biomarkers, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), with emerging candidates in CSF and serum. METHODS:We measured 21 analytes using Olink proximity extension assay technology, NfL and GFAP using Simoa, and soluble triggering receptor expressed on myeloid cells (sTREM2) and neuronal pentraxin 2 (NPTX2) using Fujirebio platforms in paired CSF and serum/plasma samples from 293 participants. The cohort included patients with clinically isolated syndrome (CIS), relapsing-remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS), as well as individuals with inflammatory neurologic disease and symptomatic controls (SCs). CSF and serum biomarker levels were compared across diagnostic groups using multivariable Cox and linear regression models. Associations were assessed using CSF immunoglobulin profiles, time from first to second clinical event, and Expanded Disability Status Scale (EDSS) scores in CIS, as well as the Multiple Sclerosis Severity Score (MSSS) in patients with MS. RESULTS:Eight biomarkers showed consistent differential expression. In CSF, CXCL13, CXCL9, IL-12b, and NfL were elevated in most CIS and MS subgroups compared with SCs. Osteopontin (OPN) levels were increased in RRMS and PPMS subgroups, whereas TNFRSF10A elevations were confined to patients with PPMS. In serum, NfL was elevated across all CIS and MS subgroups, GFAP was increased in RRMS and SPMS subgroups, and myelin oligodendrocyte glycoprotein (MOG) was increased in RRMS and PPMS subgroups. Higher CSF levels of CXCL13, CXCL9, and IL-12b predicted shorter intervals to a second clinical attack and correlated strongly with intrathecal IgM synthesis. Elevated EDSS scores at CIS onset were linked to higher CSF levels of CXCL13, IL-12b, TNFRSF10A, and OPN, and to NfL, GFAP, and MOG in serum. Prediction of future MSSS was limited to GFAP in CSF, whereas in serum, GFAP, MOG, OPN, and CXCL9 were significantly associated. DISCUSSION:CSF CXCL13, CXCL9, and IL-12b are promising biomarkers for predicting relapse activity, while serum GFAP and MOG appear to be consistent candidates for prognosticating disease severity.

Abstract Serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (GFAP) are biomarkers of neuroaxonal and astrocytic damage but remain understudied in adolescent psychiatric populations. This study investigated sNfL and GFAP levels in 412 adolescents diagnosed with anorexia nervosa (AN) ( n = 52), depression ( n = 237), and other psychiatric disorders ( n = 123). We assessed their diagnostic utility, correlation with disease severity, and longitudinal changes during AN treatment. Biomarkers were measured using Single Molecule Array technology, with Z-scores derived from reference datasets. Compared to population norms, both biomarkers were elevated in AN (sNfL: 1.15 ± 1.17; GFAP: 1.50 ± 0.84) and in depression (sNfL: 0.34 ± 1.10; GFAP: 0.58 ± 1.00). Patients with AN showed significantly higher biomarker levels than those with depression or other psychiatric disorders; importantly, this distinction remained evident in sensitivity analyses restricted to underweight individuals with depression. In AN, sNfL levels correlated with baseline weight loss (β = −0.45, R² = 0.20) and declined significantly during treatment, while GFAP changes were less pronounced. Neither marker correlated with depressive symptom severity. Bootstrapped ROC analyses showed moderate-to-good discriminatory power (AUCs 0.70–0.84) for distinguishing AN from depression. These findings suggest that neuroaxonal and astrocytic stress is a component of adolescent psychopathology, particularly in AN. sNfL appears sensitive to starvation-related neurobiological changes, with levels normalizing alongside weight restoration. GFAP showed similar but less robust trends. Accordingly, the observed biomarker changes reflect more than underweight alone, supporting a potential role in differential diagnosis and treatment monitoring.

BACKGROUND:We aimed to conduct an individual patient data meta-analysis on blood neurofilament light chain (NfL) in ischemic stroke (IS) to enhance its clinical applicability. METHODS:We performed a systematic literature search of studies on blood NfL measured in adult patients within 30 days after IS onset and derived age- and BMI-adjusted Z-scores based on a previously published reference population of healthy controls. We collected clinical, radiological and biochemical parameters of IS patients and tested associations of NfL at defined timepoints after IS onset (D1: < 24 h; D2: 24-48 h; D3: 48-72 h; D4-5: 72-120 h; D6-7: 120-168 h; D8-30: > 168 h) with baseline characteristics and 3-month follow-up outcomes (modified Rankin Scale, mRS; survival). RESULTS:We included 4081 blood NfL values from 2872 participants (IS n = 1985, transient ischemic attack n = 88, healthy controls n = 799) of 18 published studies and 3 unpublished cohorts. In patients with IS, NfL Z-score progressively increased from D1 [median: 2.0 (IQR: 0.9-2.9)] to D6-7 [median: 3.5 (IQR: 3.0-3.8)], with discriminative ability being high for IS vs. controls (AUC: 0.79-0.97) and fair for IS vs. TIA (AUC: 0.64-0.80). Higher NfL Z-score at D1 was associated with greater risk of symptomatic intracranial hemorrhage (aOR = 1.33, p = 0.014) and, from D2 onwards, with larger infarct lesion volume (highest Spearman's rho: 0.795 at D6-7). NfL independently predicted a mRS > 2 (aOR = 1.31, p < 0.001) and mortality (aOR = 1.67, p < 0.001) at 3 months. CONCLUSIONS:Blood NfL level was progressively elevated after IS, could discriminate IS from healthy controls with high accuracy and had prognostic value for intra-hospital complications and 3-month clinical outcomes in IS.

BACKGROUND AND AIMS:In individuals with hereditary transthyretin amyloidosis (ATTRv) polyneuropathy, monitoring of disease progression and treatment response is crucial. The objective is to determine if serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) are reliable biomarkers of ATTRv polyneuropathy. METHODS:We included 48 ATTRv individuals (38 symptomatic, 10 asymptomatic). Yearly assessments (over 4 years) included a full clinical examination with disease severity and functional scores, electrochemical skin conductance, nerve conduction studies, and measurement of sNfL and sGFAP levels. Using a reference database, sNfL and sGFAP were converted to Z-scores (zNfL and zGFAP). RESULTS:Median zNfL was -0.50 in asymptomatic, 1.44 in converters, and 2.46 in symptomatic subjects. zNfL > 1.42 discriminated symptomatic from asymptomatic subjects (AUC 0.936), not zGFAP (AUC 0.588). zNfL, not zGFAP, correlated with most clinical and electrophysiological neuropathy severity scales. Two asymptomatic carriers became symptomatic during follow-up. In one of them, a significant rise in zNfL occurred 1 year before symptomatic transition. INTERPRETATION:In ATTRv, zNfL correlates with neuropathy severity and symptomatic transition. A zNfL > 1.42 may discriminate symptomatic from asymptomatic subjects. zGFAP is not a reliable biomarker of polyneuropathy in ATTRv. Routine use of NfL should be based on deviation measure such as Z-score.