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Persistent organic pollutants often co-occur in human exposure environments, yet their combined effects on disease risk remain poorly understood. This study examined associations between serum concentrations of 14 per- and polyfluorinated substances (PFAS) and three hydroxylated polychlorinated biphenyls (OH-PCBs) and the onset of multiple sclerosis (MS), utilizing data from the Swedish population-based Epidemiological Investigation of Multiple Sclerosis (EIMS) cohort, comprising 907 MS cases and 907 matched controls. We employed single-substance logistic regression and quantile g-computation to evaluate cumulative and individual compound associations. We considered linear and non-linear risk patterns while adjusting for lifestyle factors and MS-associated HLA alleles.

Our analysis revealed non-linear associations for several individual compounds, particularly perfluorooctane sulfonic acid (PFOS), perfluorononanoic acid, 2,2′,3,4′,5,5′,6-heptachloro-4-biphenylol (4-OH-CB187), and 2,2′,4,4′,5,5′-, Hexachloro-3-biphenylol (3-OH-CB153), with increased odds of MS. Interaction analyses further indicated that the association between PFOS and MS odds was modified by the presence of the HLA-B*44:02 allele, known for its protective effect on MS risk. Mixture modeling highlighted that combined exposures to PFAS and OH-PCBs significantly increased MS odds, even when associations for individual compounds were weak or absent.

These findings emphasize the complexity of associations between environmental contaminants, lifestyle and genetic risk factors, and the odds of MS. They underscore the importance of addressing co-exposure in environmental health research and call for further studies to elucidate underlying biological mechanisms.

Advances in ultrasensitive immunoassays have enabled reliable quantification of neuroglial biomarkers in blood, providing valuable insights into neurological disorders. However, cross-platform evaluations are necessary to ensure comparability and standardization. This study aimed to compare the analytical performance of a Single Molecule Array (Simoa) and an ultrasensitive electrochemiluminescence (ECL) assay for quantifying neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in human serum. Baseline serum samples from 174 participants in the RIFUND trial were analyzed in parallel on both platforms. Concentrations of NfL and GFAP were compared using Spearman correlation, Bland–Altman analyses, reproducibility assessments, dilution linearity, and cross-platform recovery. All samples were quantifiable on both platforms. NfL concentrations correlated strongly between methods (Spearman correlation r = 0.88, p < 0.0001), whereas GFAP correlated moderately (r = 0.77, p < 0.0001). Inter- and intra-assay coefficients of variation were comparable between platforms for both analytes. The relationship between the two assays could be described with the following equations: NfLECL = 7.63 × NfLSIMOA + 1.71 and GFAPECL = 0.332 × GFAPSIMOA + 4.22. Dilution linearity was excellent on both platforms (R2 > 0.99), although cross-platform recovery varied systematically across the analytical range. Both Simoa and ECL demonstrated strong analytical performance for neuroglial biomarker quantification in serum. Despite systematic differences in absolute concentrations, relative agreement was high, particularly for NfL. These findings highlight the need for platform harmonization and provide empirically derived conversion factors to support analytical comparability in research and clinical applications.

In the treatment of relapsing-remitting multiple sclerosis, autologous haematopoietic stem cell transplant (AHSCT) and immune-reconstitution therapies show several similarities. These treatment strategies have not yet been compared head-to-head. This study emulated pairwise trials of comparative effectiveness of stem cell transplant versus immune-reconstitution therapies cladribine and alemtuzumab. This cohort/registry study of comparative treatment effectiveness included data from seven specialist multiple sclerosis centres with AHSCT programmes (RESCUE-MS) and international MSBase registry during 2006-2023. The study included patients with relapsing-remitting multiple sclerosis treated with AHSCT, cladribine or alemtuzumab, with a minimum of 2-months follow-up before commencing study therapy and ≥2 disability assessments after commencing the study therapy. Patients were matched on a propensity score derived from their clinical and demographic characteristics. The matched groups were compared according to annualized relapse rates, freedom from relapses and 6-month confirmed disability worsening and improvement (measured with the Expanded Disability Status Scale). The matching of 143 (stem cell) to 283 cladribine-treated patients and 134 (stem cell) to 562 alemtuzumab-treated patients reduced the measured differences between the groups by 98% and 96%, respectively. The matched patients had high mean disease activity (>0.8 relapses in the prior 2 years), mean Expanded Disability Status Scale scores of 3-4, and were followed-up for a mean of 3.8-3.9 (stem cell), 1.9 (cladribine) or 4.5 years (alemtuzumab). Compared with cladribine, stem cell transplant was associated with a lower risk of relapse [mean annualized relapse rate ± standard deviation (SD): 0.05 ± 0.28 versus 0.16 ± 0.39, respectively; hazard ratio: 0.24; 95% confidence interval (CI): 0.15-0.41], similar risk of disability worsening (hazard ratio: 0.70; 95% CI: 0.34-1.43) and higher probability of disability improvement (hazard ratio: 2.19; 95% CI: 1.31-3.66). Compared with alemtuzumab, stem cell transplant was associated with a lower risk of relapses (mean annualized relapse rate ± SD: 0.04 ± 0.23 versus 0.09 ± 0.21, respectively; hazard ratio: 0.52; 95% CI: 0.29-0.93), similar risk of disability worsening (hazard ratio: 0.95; 95% CI: 0.53-1.72) and higher probability of disability improvement (hazard ratio: 2.03; 95% CI: 1.23-3.34). Thirty-four per cent of patients treated with stem cell transplant experienced delayed complications, mainly infections. No treatment-associated deaths were reported. Among patients with active relapsing-remitting multiple sclerosis and moderate disability, AHSCT is superior to cladribine and alemtuzumab at suppressing relapses and enabling recovery of neurological function. The high effectiveness of stem cell transplant is likely attributable to a complex interplay between immune suppression and reconstitution.

The PET radioligand [¹¹C]L-deprenyl-D2 binds to monoamine oxidase B (MAO-B), enabling studies of neuroinflammation in various neurological disorders. This study aimed to evaluate non-invasive and parametric methods for quantifying [¹¹C]L-deprenyl-D2 PET. Twenty-eight subjects underwent 60 min dynamic [¹¹C]L-deprenyl-D2 PET. The irreversible binding parameter λk₃ and the net influx rate relative to the non-displaceable volume of distribution K_ND were estimated with an irreversible two-tissue plasma-input compartment model (2T3k). Non-invasive quantification of K_ND was performed using cerebellum corrected for specific binding with previously suggested corrections as reference tissue. These corrections were further optimised by comparison to the 2T3k non-displaceable signal in cerebellum. Parametric images were computed using a basis function implementation of the 2T3k model, reference Patlak methods and the reduced reference tissue model. Additionally, a semi-quantitative specific binding index (SBI) was calculated as the ratio of the mean activity concentration at 30-40 or 50-60 min p.i. in target tissues to the peak cerebellum uptake. Parametric λk₃ images agreed well with VOI-based nonlinear regression. Modified cerebellar reference models and SBI demonstrated poor-to-moderate correlations with arterial input-based analysis and yielded false positive differences in voxel-wise group comparisons. Full kinetic analysis with arterial input is required for accurate assessment of MAO-B activity with [¹¹C]L-deprenyl-D2.

Background and Aim: Brain-derived tau (BD-tau) is a predominantly CNS-derived form of tau protein detectable in blood that reflects brain injury and has emerged as a potential biomarker in ischemic stroke for assessing neuronal damage, monitoring infarct progression, and predicting functional outcome. However, its temporal profile and the optimal timing for correlation with infarct volume remain unclear.

Methods: This prospective cohort study included patients with ischemic stroke, with venous blood samples collected daily during the first week and at 3 months after symptom onset. Infarct volume was assessed by MRI at 48-72 h. Plasma BD-tau concentrations were measured using a Simoa assay. Linear mixed-effects models were used to analyze changes in biomarker levels. The optimal time point for correlation between BD-tau and infarct volume was identified using a 24-h moving-window Pearson correlation analysis.

Results: Fifty-four patients (median age 78 years, 50% female) contributed 285 plasma samples. Plasma levels of BD-tau followed a parabolic trajectory reaching a peak approximately 5 days after symptom onset. After 90 days, the concentration of BD-tau was lower than in the last measurement of the first week. The strongest correlation between BD-tau and infarct volume occurred at 105 h (4.4 days) (r = 0.89, 95% CI: 0.78-0.95) after symptom onset.

Conclusions: Plasma BD-tau exhibits a distinct temporal profile after ischemic stroke, with peak levels and maximal correlation with infarct volume occurring around Day 4-5. These findings have important implications for interpreting BD-tau levels and optimizing sampling strategies in clinical studies.

Background and Purpose: Recent MRI developments have allowed for in vivo myelin imaging in clinically feasible time frames. This retrospective study aimed to evaluate the ability of the Rapid Estimation of Myelin for Diagnostic Imaging (REMyDI) technique in monitoring longitudinal myelin changes and brain atrophy in persons with multiple sclerosis (pwMS) undergoing treatment with rituximab or autologous hematopoietic stem cell transplantation (aHSCT).

Methods: Between May 2017 and January 2022, 62 pwMS treated with either rituximab (n = 25) or aHSCT (n = 37) underwent brain MRI scans at three time points. A 3 Tesla brain MRI was performed, including 3D T1-weighted imaging, 3D T2-weighted fluid-attenuated inversion recovery imaging, and 2D multi-dynamic multi-echo imaging for REMyDI and brain volumetrics. Longitudinal changes in imaging parameters and associations with the Expanded Disability Status Scale and Symbol Digit Modalities Test were analyzed using mixed-effects models.

Results: The rituximab group exhibited increases in whole-brain myelin (+0.25 mL per year), cortical myelin (+0.11 mL per year), and myelin in normal-appearing deep gray matter (NADGM) (+0.02 mL per year). In contrast, these measures were stable or declined in the aHSCT group. Brain parenchymal fraction showed a larger reduction in the rituximab group (-0.68% per year) compared to the aHSCT group (-0.24% per year). Myelin-related imaging measures showed positive but nonsignificant associations with clinical parameters.

Conclusions: REMyDI enables longitudinal assessment of myelin-related metrics in vivo, which complements conventional brain volumetrics and is suitable for monitoring treatment responses in MS.

Anti-NMDA receptor (NMDAR) encephalitis is an autoimmune disorder of the central nervous system involving both B- and T-cell activation. In this exploratory study, targeted proteomics was used to characterize protein expression profiles in serum and cerebrospinal fluid (CSF) from patients with anti-NMDAR encephalitis. Samples from eight patients and 16 age- and sex-matched symptomatic controls were analyzed in a retrospective case-control design. Protein concentrations in serum and CSF were quantified using Proximity Extension Assay (PEA) technology targeting 182 proteins related to immunity, synaptic regulation, and neuronal maintenance. Linear regression identified seven significantly altered proteins in CSF and three in serum after Bonferroni correction (p < 0.00027). In CSF, six proteins associated with immune signaling and neuronal support (ADA, CCL19, CXCL5, BMP-4, FGF-5, CDH3) were decreased, while the protease CASP-8 was elevated. In serum, proteases CTSC and CASP-8 were increased, whereas ADA, a key regulator of purine metabolism and immune signaling, was decreased. Strong to moderate correlations between CSF and serum levels were observed for ADA (r = 0.606, p = 0.013) and CASP-8 (r = 0.526, p = 0.037). Longitudinal CSF data from two patients revealed dynamic changes in CXCL5, CCL19, and CASP-8 corresponding to disease activity and treatment response. Overall, these findings revealed distinct yet related proteomic signatures in serum and CSF, suggesting compartment-specific immune responses involving both innate and adaptive pathways. The consistent elevation of CASP-8 highlights its potential as a biomarker of disease activity and warrants further investigation.

Objectives

To evaluate the utility of cerebrospinal fluid (CSF) biomarkers—matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinases-1 (TIMP-1), the MMP-9/TIMP-1 ratio, and osteopontin (OPN)—as indicators of blood–brain barrier (BBB) integrity and disease activity in people with relapsing–remitting multiple sclerosis (pwMS), and to assess their changes following autologous hematopoietic stem cell transplantation (aHSCT).

Methods

CSF samples from pwMS treated with aHSCT (n = 43) and healthy controls (n = 32) were analyzed for MMP-9, TIMP-1, and OPN concentrations using ELISA and electrochemiluminescence assays. Lumbar punctures were performed at baseline and at 1, 2, and 3–5 years post-aHSCT. Biomarker findings were compared with standard CSF parameters, prior treatments, and MRI data.

Results

MMP-9/TIMP-1 ratios and OPN levels were significantly elevated in pwMS compared to controls, particularly in those with gadolinium-enhancing lesions or on first-line therapies. Both biomarkers declined significantly after aHSCT and remained low during follow-up. The MMP-9/TIMP-1 ratio showed superior discriminatory capacity and correlated with inflammatory CSF markers.

Interpretation

CSF MMP-9/TIMP-1 ratio and OPN are elevated in MS and decrease following aHSCT, reflecting reduced inflammation and restored BBB integrity. These biomarkers may support disease monitoring and therapeutic evaluation.

Exposure to per- and polyfluorinated substances (PFAS) and hydroxylated polychlorinated biphenyls (OH-PCBs) is associated with adverse human health effects, including immunosuppression. It is unknown if these substances can affect the course of autoimmune diseases. This study was based on 907 individuals with multiple sclerosis (MS) and 907 matched controls, where the MS cases were followed longitudinally using the Swedish MS register. We demonstrate sex- and disease-specific differences in serum PFAS concentrations between individuals with MS and controls. Moreover, two OH-PCBs (4-OH-CB187 and 3-OH-CB153) are associated with an increased risk of developing multiple sclerosis, regardless of sex and immigration status. With a clinical follow-up time of up to 18 years, an increase in serum concentrations of perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), and perfluorodecanoic acid (PFDA) decreases the risk of confirmed disability worsening in both sexes, as well as perfluoroheptanesulfonic acid (PFHpS) and perfluorononanoic acid (PFNA), only in males with MS. These results show previously unknown associations between OH-PCBs and the risk of developing MS, as well as the inverse associations between PFAS exposure and the risk of disability worsening in MS.

Autologous haematopoietic stem cell transplantation (AHSCT) is a treatment option for relapsing forms of multiple sclerosis (MS) that are refractory to disease-modifying therapy (DMT). AHSCT after failure of high-efficacy DMT in aggressive forms of relapsing-remitting MS is a generally accepted indication, yet the optimal placement of this approach in the treatment sequence is not universally agreed upon. Uncertainties also remain with respect to other indications, such as in rapidly evolving, severe, treatment-naive MS, progressive MS, and neuromyelitis optica spectrum disorder (NMOSD). Furthermore, treatment and monitoring protocols, rehabilitation and other supportive care before and after AHSCT need to be optimized. To address these issues, we convened a European Committee for Treatment and Research in Multiple Sclerosis Focused Workshop in partnership with the European Society for Blood and Marrow Transplantation Autoimmune Diseases Working Party, in which evidence and key questions were presented and discussed by experts in these diseases and in AHSCT. Based on the workshop output and subsequent written interactions, this Consensus Statement provides practical guidance and recommendations on the use of AHSCT in MS and NMOSD. Recommendations are based on the available evidence, or on consensus when evidence was insufficient. We summarize the key evidence, report the final recommendations, and identify areas for further research.