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Jan Hillert,1 Helmut Butzkueven,2,3 Melinda Magyari,4 Stig Wergeland,5,6 Nicholas Moore,7 Merja Soilu-Hänninen,8 Tjalf Ziemssen,9 Jens Kuhle,10 Luigi Pontieri,11 Lars Forsberg,1 Jan Harald Aarseth,5 Chao Zhu,2 Nicholas Sicignano,12 Vasili Mushnikov,13 Irene Bezemer,14 Meritxell Sabidó15 1Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden; 2Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia; 3The Alfred Hospital, Melbourne, Victoria, Australia; 4Danish Multiple Sclerosis Center and Danish Multiple Sclerosis Registry, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 5Norwegian MS Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway; 6Department of Clinical Medicine, University of Bergen, Bergen, Norway; 7Bordeaux PharmacoEpi (BPE), Université de Bordeaux, Bordeaux, France; 8Turku University Hospital Neurocenter and Division of Clinical Neurosciences, University of Turku, Turku, Finland; 9Center of Clinical Neuroscience, Department of Neurology, University Clinic Carl Gustav Carus, Dresden University of Technology, Dresden, Germany; 10MS Centre and Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB), Departments of Neurology, Biomedicine and Clinical Research, University Hospital Basel, University of Basel, Basel, Switzerland; 11Danish Multiple Sclerosis Registry, Department of Neurology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; 12Health ResearchTx LLC, Trevose, PA, USA; 13IQVIA, Helsinki, Finland; 14IQVIA, Amsterdam, the Netherlands; 15Merck Healthcare KGaA, Darmstadt, GermanyCorrespondence: Meritxell Sabidó, Merck Healthcare KGaA, Frankfurter Str. 250, Darmstadt, 64293, Germany, Email meritxell.sabido-espin@merckgroup.comPurpose: Understanding the long-term safety of disease-modifying therapies for multiple sclerosis (MS) in routine clinical practice can be undertaken through registry-based studies. However, variability of data quality across such sources poses the challenge of data fit for regulatory decision-making. CLARION, a non-interventional cohort safety study of cladribine tablets, combines aggregated data from MS registries/data sources, except in Germany (which utilizes primary data collection). We describe the application of key data quality indicators (DQIs) within CLARION to evaluate data quality over time, as recommended by the European Medicines Agency (EMA) guideline on registry-based studies.Methods: DQIs were defined with participating registries/sources; they were used to assess data quality according to the EMA Data Quality Framework, addressing consistency, accuracy, completeness, and study representativeness. DQIs were associated with potential remedial measures if data quality was not met. DQIs were summarized overall and for individual MS registries/data sources to November 1, 2022.Results: A total of 28 DQIs were analyzed using data from 5069 patients arising from eight MS registries/data sources and 14 countries. The Representativeness DQIs showed that 72.0% of patients were female, median age at MS diagnosis was 29.0 to 43.3 years, and 93.5% had relapsing-remitting MS. Consistency DQIs showed a total of 2899 patients had achieved at least two years of follow-up; 6.9% did not have any recorded visits during this timeframe. Discrepant values were assessed as part of Accuracy DQIs, and improvements over time were noted for recorded dates of MS onset and diagnosis. Regarding Completeness DQIs, 191/5069 (3.8%) patients were lost to follow-up.Conclusion: The application of 28 DQIs within the CLARION study has helped with understanding, not only intrinsic and question-specific determinants of data quality, but also tracking the quality of post-authorization safety data obtained from MS registries/data sources, thereby providing a foundation for the regulatory decision-making process.Keywords: cladribine tablets, multiple sclerosis, safety, fingolimod

BackgroundHIV-associated cardiovascular disease (CVD) risk in combination antiretroviral therapy (cART)-treated perinatally HIV-infected patients (PHIV+) remains unknown due to the young age of this population. Lipoprotein(a) (Lp(a)) has been established as an independent causal risk factor for CVD in the general population but has not been well established in the population of PHIV+.MethodsWe cross-sectionally compared lipid profiles, including nonfasting Lp(a), together with total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides between 35 cART-treated PHIV+ children aged 8-18 years and 37 controls who were matched for age, sex, ethnicity, and socioeconomic status. We explored associations between Lp(a) and disease- and treatment-related factors (inflammation, monocyte activation, and vascular), biomarkers, and neuroimaging outcomes using linear regression models.ResultsPHIV+ children had significantly higher levels of Lp(a) compared with controls (median, 43.6 [21.6-82.4] vs 21.8 [16.8-46.6] mg/dL; P = .033). Other lipid levels were comparable between groups. Additional assessment of apolipoprotein B, apolipoprotein CIII, apolipoprotein E, and APOE genotype revealed no significant differences. Higher Lp(a) levels were associated with higher plasma apoB levels and with lower monocyte chemoattractant protein-1 and TG levels in PHIV+ children. Lp(a) was not associated with HIV- or cART-related variables or with neuroimaging outcomes.ConclusionscART-treated PHIV+ children appear to have higher levels of Lp(a) compared with ethnicity-matched controls, which may implicate higher CVD risk in this population. Future research should focus on the association between Lp(a) and (sub)clinical CVD measurements in cART-treated PHIV+ patients.Dutch trial register numberNRT4074.

Background: A randomized trial of phenytoin in acute optic neuritis (ON) demonstrated a 30% reduction in retinal nerve fiber layer (RNFL) loss with phenytoin versus placebo. Here we present the corresponding serum neurofilament analyses. Methods: Eighty‐six acute ON cases were randomized to receive phenytoin (4–6 mg/kg/day) or placebo for 3 months, and followed up for 6 months. Serum was collected at baseline, 3 and 6 months for analysis of neurofilament heavy chain (NfH) and neurofilament light chain (NfL). Results: Sixty‐four patients had blood sampling. Of these, 58 and 56 were available at 3 months, and 55 and 54 were available at 6 months for NfH and NfL, respectively. There was no significant correlation between serum NfH and NfL at the time points tested. For NfH, the difference in mean placebo – phenytoin was −44 pg/ml at 3 months (P = 0.019) and −27 pg/ml at 6 months (P = 0.234). For NfL, the difference was 1.4 pg/ml at 3 months (P = 0.726) and −1.6 pg/ml at 6 months (P = 0.766). Conclusions: At 3 months, there was a reduction in NfH, but not NFL, in the phenytoin versus placebo group, while differences at 6 months were not statistically significant. This suggests a potential neuroprotective role for phenytoin in acute ON, with the lower NfH at 3 months, when levels secondary to degeneration of the anterior visual pathway are still elevated, but not at 6 months, when levels have normalized. [ABSTRACT FROM AUTHOR]

Objective: To validate kappa free light chain (KFLC) and lambda free light chain (LFLC) indices as a diagnostic biomarker in multiple sclerosis (MS). Methods: We performed a multicenter study including 745 patients from 18 centers (219 controls and 526 clinically isolated syndrome (CIS)/MS patients) with a known oligoclonal IgG band (OCB) status. KFLC and LFLC were measured in paired cerebrospinal fluid (CSF) and serum samples. Gaussian mixture modeling was used to define a cut-off for KFLC and LFLC indexes. Results: The cut-off for the KFLC index was 6.6 (95% confidence interval (CI) = 5.2–138.1). The cut-off for the LFLC index was 6.9 (95% CI = 4.5–22.2). For CIS/MS patients, sensitivity of the KFLC index (0.88; 95% CI = 0.85–0.90) was higher than OCB (0.82; 95%CI = 0.79–0.85; p < 0.001), but specificity (0.83; 95% CI = 0.78–0.88) was lower (OCB = 0.92; 95% CI = 0.89–0.96; p < 0.001). Both sensitivity and specificity for the LFLC index were lower than OCB. Conclusion: Compared with OCB, the KFLC index is more sensitive but less specific for diagnosing CIS/MS. Lacking an elevated KFLC index is more powerful for excluding MS compared with OCB but the latter is more important for ruling in a diagnosis of CIS/MS. [ABSTRACT FROM AUTHOR]

Background and purpose: To investigate the relation of age at disease onset and clinical outcomes across the lifespan from adolescence in patients with multiple sclerosis (MS) on disease‐modifying therapy (DMT). Methods: We analysed data from the Swiss Association for Joint Tasks of Health Insurers database containing data from 14 718 patients with MS. Patients were included in this analysis when they were on DMT for at least 1 year. The influence of age at disease onset on future relapses and disability worsening was explored using multivariable Cox proportional hazard regression models. Results: Data from 9705 patients with MS were analysed. Pediatric‐onset MS patients (n = 236) had higher relapse rates and marginally slower disability worsening rates compared with adult‐onset MS (n = 9469). The risk of relapses was highest in childhood and decreased continuously to about 35 years of age. It remained stable for about a decade and then again continuously decreased. In contrast, disability worsening hazards remained stable from childhood to about 32 years of age and then increased sharply around the age of 45 years. Conclusions: Age is an important factor independently affecting clinical outcomes in MS. This should be considered when designing clinical trials or choosing DMT. [ABSTRACT FROM AUTHOR]

Background and purpose: Neurofilament light chain is a cytoskeletal protein of neurons. Its levels are increasingly recognized as measures of neuroaxonal damage. The aim of this study was to explore serum neurofilament light chain (sNfL) levels in multiple sclerosis (MS) patients and healthy controls during pregnancy and puerperium. Methods: This was a prospective, longitudinal, single‐center study. sNfL concentration was assessed using a highly sensitive single‐molecule array during pregnancy and in puerperium, in a cohort of 39 pregnant patients with relapsing multiple sclerosis (P‐MS). Twenty‐one healthy pregnant women (HPW) served as a control group. Eight P‐MS suffered relapses during pregnancy (P‐MS‐R) in the first or second trimesters. Results: No differences in pregnancy and delivery data were observed between P‐MS and HPW. P‐MS showed higher sNfL values than HPW in the first trimester, independently of the presence (P = 0.002) or not (P = 0.02) of relapses during pregnancy. However, in the third trimester, only P‐MS‐R showed higher sNfL values than HPW (P = 0.001). These differences extended to the puerperium, where P‐MS‐R showed higher sNfL values than those with no relapses during gestation (P = 0.02). Conclusion: These data strongly suggest that sNfL levels reflect MS activity during pregnancy. Additionally, the absence of relapses during pregnancy may have a beneficial effect on neurodegeneration during puerperium. [ABSTRACT FROM AUTHOR]

Background and purpose: Treatment options in primary progressive multiple sclerosis (PPMS) are scarce and, with the exception of ocrelizumab, anti‐inflammatory agents have failed to show efficacy in ameliorating disability progression. The aim of this study was to investigate a potential effect of anti‐inflammatory disease‐modifying treatment on disability outcomes in PPMS. Methods: Using MSBase, a large, international, observational database, we identified patients with PPMS who were either never treated or treated with a disease‐modifying agent. Propensity score matching was used to select subpopulations with similar baseline characteristics. Expanded Disability Status Scale (EDSS) outcomes were compared with an intention‐to‐treat and an as‐treated approach in paired, pairwise‐censored analyses. Results: Of the 1284 included patients, 533 were matched (treated, n = 195; untreated n = 338). Median on‐study pairwise‐censored follow‐up was 3.4 years (quartiles 1.2–5.5). No difference in the hazard of experiencing 3‐month confirmed EDSS progression events was observed between the groups [hazard ratio (HR), 1.0; 95% confidence interval (CI), 0.6–1.7, P = 0.87]. We did not find significant differences in the hazards of confirmed EDSS improvement (HR, 1.0; 95% CI, 0.6–1.6, P = 0.91) or reaching a confirmed EDSS step ≥7 (HR, 1.1; 95% CI, 0.7–1.6, P = 0.69). Conclusion: Our pooled analysis of disease‐modifying agents suggests that these therapies have no substantial effect on short‐ to medium‐term disability outcomes in PPMS. [ABSTRACT FROM AUTHOR]

Aims: Cell matrix modulating protein SPARCL-1 is highly expressed by astrocytes during CNS development and following acute CNS damage. Applying NanoLC-MS/MS to CSF of RRMS and SPMS patients, we identified SPARCL-1 as differentially expressed between these two stages of MS, suggesting a potential as CSF biomarker to differentiate RRMS from SPMS and a role in MS pathogenesis. Methods: This study examines the potential of SPARCL-1 as CSF biomarker discriminating RRMS from SPMS in three independent cohorts (n = 249), analyses its expression pattern in MS lesions (n = 26), and studies its regulation in cultured human brain microvasculature endothelial cells (BEC) after exposure to MS-relevant inflammatory mediators. Results: SPARCL-1 expression in CSF was significantly higher in SPMS compared to RRMS in a Dutch cohort of 76 patients. This finding was not replicated in 2 additional cohorts of MS patients from Sweden (n = 81) and Switzerland (n = 92). In chronic MS lesions, but not active lesions or NAWM, a vessel expression pattern of SPARCL-1 was observed in addition to the expression by astrocytes. EC were found to express SPARCL-1 in chronic MS lesions, and SPARCL-1 expression was regulated by MS-relevant inflammatory mediators in cultured human BEC. Conclusions: Conflicting results of SPARCL-10s differential expression in CSF of three independent cohorts of RRMS and SPMS patients precludes its use as biomarker for disease progression. The expression of SPARCL-1 by BEC in chronic MS lesions together with its regulation by inflammatory mediators in vitro suggest a role for SPARCL-1 in MS neuropathology, possibly at the brain vascular level. [ABSTRACT FROM AUTHOR]

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Background and purpose N-acetyl aspartate ( NAA) assessed using proton magnetic resonance spectroscopy (1H MRS) has a high pathological specificity for axonal density. Retinal nerve fibre layer thickness ( RNFLT) measured by using optical coherence tomography is increasingly used as a surrogate marker of neurodegeneration in multiple sclerosis ( MS). Our aim was to investigate the relation between RNFLT and NAA/creatine in brain normal-appearing white matter ( NAWM), their dynamics over time and the association with clinical outcome measures in relapsing MS. T2 WM lesions served as control tissue. Methods Forty-three MS patients underwent standardized neurological examination including the Expanded Disability Status Scale ( EDSS), Multiple Sclerosis Functional Composite ( MSFC) score, optical coherence tomography and magnetic resonance imaging including 1H MRS at baseline and after 1 year. Results At baseline, NAA/creatine level was lower in T2 WM lesions than in NAWM (1.64 ± 0.16 vs. 1.88 ± 0.24, P < 0.001). Lowest levels were found in secondary progressive MS ( SPMS). Mean RNFLT was higher in clinically isolated syndrome than in the combined group of relapsing−remitting MS and SPMS (99.8 ± 12.3 μm vs. 92.4 ± 12.8 μm, P = 0.038). In all patients, mean RNFLT decreased by 1.4% during follow-up. At baseline, MSFC z-scores correlated with NAA/creatine levels both in NAWM ( r = 0.42; P = 0.008) and T2 WM lesions ( r = 0.52, P = 0.004). NAWM NAA/creatine variation correlated with the RNFLT change over 1 year ( ρ = 0.43, P = 0.046). Conclusions N-acetyl aspartate/creatine level reduction correlated with RNFLT thinning over 1 year in an EDSS stable MS cohort suggesting that these techniques might be sensitive to detect subclinical disease progression. [ABSTRACT FROM AUTHOR]

Objectives: To explore long-term effects of treatment and prognostic relevance of variables assessed at baseline and during the European secondary progressive multiple sclerosis (SPMS) trial of interferon beta 1b (IFNB-1b). Methods: We assessed 362 patients (60% female; median age 41 years; Expanded Disability Status Scale (EDSS): 5.5; 51% randomized to IFNB-1b) for their EDSS and treatment history after 10 years. Non-parametric analysis of covariance (ANCOVA) and multivariate linear regression models were applied. Results: Median EDSS was 6.0 at the end of the randomized controlled trial (RCT), in the IFNB-1b and placebo groups, and 7.0 in long-term follow-up patients (those receiving IFNB-1b in the RCT were 6.5 and those receiving placebo in the RCT were 7.0; p = 0.086). 24 patients (6.6%) were deceased. The EDSS at baseline and the EDSS change during the RCT were the most important predictors of the EDSS 10 years later (partial R2: 0.47). The ability to predict changes in EDSS 10 years after the RCT was limited (R2: 0.12). Magnetic resonance imaging (MRI) measures remained in the predictive models, but explained < 5% of the variability. Conclusions: The results from this analysis did not provide convincing evidence to support a favorable long-term outcome in those patients allocated IFNB-1b during the RCT, in our SPMS cohort. The progressive stage of the disease remains largely unpredictable by clinical and conventional MRI measures, so better prognostic markers are needed. [ABSTRACT FROM AUTHOR]

Background and objective: We explored which clinical and biochemical variables predict conversion from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) in a large international cohort. Methods: Thirty-three centres provided serum samples from 1047 CIS cases with at least two years' follow-up. Age, sex, clinical presentation, T2-hyperintense lesions, cerebrospinal fluid (CSF) oligoclonal bands (OCBs), CSF IgG index, CSF cell count, serum 25-hydroxyvitamin D3 (25-OH-D), cotinine and IgG titres against Epstein-Barr nuclear antigen 1 (EBNA-1) and cytomegalovirus were tested for association with risk of CDMS. Results: At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres. Conclusions: We validated MRI lesion load, OCB and age at CIS as the strongest independent predictors of conversion to CDMS in this multicentre setting. A role for vitamin D is suggested but requires further investigation. [ABSTRACT FROM AUTHOR]

Recently, the disappearance of oligoclonal bands (OCBs) from the cerebrospinal fluid (CSF) of a few natalizumab-treated patients with multiple sclerosis (MS) has been reported. This is interesting since CSF-restricted OCB are believed to persist in MS. We pooled CSF data from 14 MS centers to obtain an adequate sample size for investigating the suspected changes in central nervous system (CNS)-restricted humoral immune activities in the context of natalizumab therapy. In a retrospective chart analysis, CSF parameters of blood–CSF barrier integrity and intrathecal IgG production from 73 natalizumab-treated MS patients requiring a diagnostic puncture for exclusion of progressive multifocal leukoencephalopathy were compared with CSF data obtained earlier in the course of disease before natalizumab therapy. At the time of repeat lumbar puncture, local IgG production (according to Reibergram) was significantly reduced (p < 0.0001) and OCB had disappeared in 16% of the patients. We therefore conclude that natalizumab therapy interferes with intrathecal antibody production at least in a significant number of patients. [ABSTRACT FROM PUBLISHER]

Purpose: We evaluated the performance of the placental alpha-microglobulin-1 immunoassay (AmniSure(®), AT) in cervicovaginal secretions in patients with uncertain rupture of membranes (ROM) and investigated the influence of the examiners experience. Methods: This prospective cohort study was performed in pregnant women (17-42 weeks of gestation) with signs of possible ROM. Evaluation included clinical assessment, examination for cervical leakage, Nitrazine test and measurement of the amniotic fluid index by ultrasound and AT. ROM occurrence was based on review of the medical records after delivery. Results: 199 women were included. AT had a sensitivity of 94.4%; specificity of 98.6%; positive predictive value, 96.2%; negative predictive value, 98.0%. Clinical assessment showed a sensitivity of 72.2%; specificity of 97.8%; positive predictive value, 92.9%; negative predictive value, 90.6%. AT was more sensitive for diagnosing ROM (p = 0.00596) compared to clinical assessment, independent of the examiners experience. Furthermore, the sole use of AT reduced costs by 58.4% compared to clinical assessment. Conclusions: AT was more sensitive compared to clinical assessment, independent of the examiners experience and gestational age. Our data extend its use in patients with uncertain ROM. Moreover, AT seems to be a cost-effective approach in the assessment of these patients. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to measure Aβ1–42, T-tau and P-tau181 in the cerebrospinal fluid (CSF) of patients with posterior cortical atrophy (PCA), a presenile dementia likely to represent a variant of Alzheimer’s disease (AD). Methods: CSF samples from 34 subjects including 9 patients with PCA, 11 age-matched patients with AD and 14 age-matched cognitively healthy controls were analyzed using commercially available ELISA kits. Results: The Aβ1–42, T-tau and P-tau181 levels in PCA patients differed significantly (p < 0.02) from those in healthy controls but were indistinguishable from subjects with a clinical diagnosis of AD. Conclusion: High T-tau and P-tau181 and low Aβ1–42 levels in PCA – typically observed in AD – indicate that the underlying pathology of PCA is usually AD. If these findings are replicated in PCA patients with autopsy-confirmed AD neuropathology, PCA patients may be eligible for disease-modifying AD treatments. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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The article presents a reprint of the article "Short commentary on 'a consensus protocol for the standardization of cerebrospinal fluid collection and biobanking', " by C. E. Teunissen and colleagues, which appeared in the previous issue of the journal. It discusses a study about a standardization protocol for biobanking and cerebrospinal fluid (CSF) collection. It provides tables that depict guidelines for CSF withdrawal and information requirements of patients with multiple sclerosis (MS).

Background: Patients with a single episode of neurologic dysfunction and brain magnetic resonance imaging (MRI) scans suggestive of multiple sclerosis are at high risk for clinically definite multiple sclerosis, but the outcome for individual patients is unpredictable. An increased risk of progression to clinically definite multiple sclerosis in patients with serum antibodies against myelin oligodendrocyte glycoprotein (MOG) and myelin basic protein (MBP) has been reported.Methods: We measured serum anti-MOG and anti-MBP IgG and IgM antibodies in 462 patients with a first clinical event suggestive of multiple sclerosis and at least two clinically silent lesions on brain MRI. The patients were participating in a multicenter trial of treatment with interferon beta-1b. Antibodies were assessed by Western blot analysis at baseline, and the results compared with the time and rate of progression to clinically definite multiple sclerosis or a diagnosis of multiple sclerosis as defined by an international panel (the McDonald criteria). Regular visits were scheduled for the assessment of neurologic impairment and for MRI before treatment and at months 3, 6, 9, 12, 18, and 24.Results: No associations were found between the presence of anti-MOG and anti-MBP IgM and IgG antibodies and progression to clinically definite multiple sclerosis or a diagnosis of multiple sclerosis according to the McDonald criteria, either in the entire cohort or in any subgroups of the study population.Conclusions: Serum antibodies against MOG and MBP, as detected by Western blot analysis, are not associated with an increased risk of progression to clinically definite multiple sclerosis in patients who have had a clinically isolated syndrome suggestive of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Copyright of Deutsche Zeitschrift fur Chirurgie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

• Combination of motor EP (MEP) from upper and lower limbs and somatosensory EP (SEP) after tibial nerve stimulation carries the main prognostic information predicting 32% of EDSS-change over two years in primary progressive multiple sclerosis (PPMS). • Current results replicate and corroborate the previously reported prognostic value of multimodal EP in PPMS. • Quantitative scoring outperforms ordinal scoring to prognosticate EDSS-change. To validate the prognostic value of multimodal evoked potentials (mmEP) in primary progressive multiple sclerosis (PPMS) and to determine the most predictive EP-modalities. Thirty-nine patients with PPMS (expanded disability status scale (EDSS): 2.0–6.5; mean clinical follow-up: 2.8 years) had visual (VEP), upper and lower limb somatosensory (SEP) and motor EP (MEP) at baseline. Quantitative EP-scores for single (qVEP, qSEP, qMEP) and combined modalities were correlated to EDSS and compared to previously published data of 21 PPMS patients. Predictors of EDSS-change were analyzed in pooled data by linear regression. Samples were comparable. Except qVEP, all EP-scores were correlated to EDSS at baseline (Rho: 0.45–0.69; p < 0.01) and follow-up (Rho: 0.59–0.80; p < 0.001). Combined EP-modalities significantly predicted EDSS-change (R2 adj : 0.24), while EDSS and age did not. Tibial qSEP (R2 adj : 0.22) and qMEP (R2 adj : 0.26) were the best single modality predictors, outperformed by their combination (R2 adj : 0.32). Quantitative EP-scores predict up to 32% of EDSS-change over three years. Modalities representing motor and long tract function carry the main prognostic information. Replication of previous results corroborates the use of mmEP as a prognostic biomarker candidate in PPMS. [ABSTRACT FROM AUTHOR]

Background and Objectives: Disentangling brain aging from disease-related neurodegeneration in patients with multiple sclerosis (PwMS) is increasingly topical. The brain-age paradigm offers a window into this problem but may miss disease-specific effects. In this study, we investigated whether a disease-specific model might complement the brain-age gap (BAG) by capturing aspects unique to MS., Methods: In this retrospective study, we collected 3D T1-weighted brain MRI scans of PwMS to build (1) a cross-sectional multicentric cohort for age and disease duration (DD) modeling and (2) a longitudinal single-center cohort of patients with early MS as a clinical use case. We trained and evaluated a 3D DenseNet architecture to predict DD from minimally preprocessed images while age predictions were obtained with the DeepBrainNet model. The brain-predicted DD gap (the difference between predicted and actual duration) was proposed as a DD-adjusted global measure of MS-specific brain damage. Model predictions were scrutinized to assess the influence of lesions and brain volumes while the DD gap was biologically and clinically validated within a linear model framework assessing its relationship with BAG and physical disability measured with the Expanded Disability Status Scale (EDSS)., Results: We gathered MRI scans of 4,392 PwMS (69.7% female, age: 42.8 ± 10.6 years, DD: 11.4 ± 9.3 years) from 15 centers while the early MS cohort included 749 sessions from 252 patients (64.7% female, age: 34.5 ± 8.3 years, DD: 0.7 ± 1.2 years). Our model predicted DD better than chance (mean absolute error = 5.63 years, R 2 = 0.34) and was nearly orthogonal to the brain-age model (correlation between DD and BAGs: r = 0.06 [0.00-0.13], p = 0.07). Predictions were influenced by distributed variations in brain volume and, unlike brain-predicted age, were sensitive to MS lesions (difference between unfilled and filled scans: 0.55 years [0.51-0.59], p < 0.001). DD gap significantly explained EDSS changes ( B = 0.060 [0.038-0.082], p < 0.001), adding to BAG (Δ R 2 = 0.012, p < 0.001). Longitudinally, increasing DD gap was associated with greater annualized EDSS change ( r = 0.50 [0.39-0.60], p < 0.001), with an incremental contribution in explaining disability worsening compared with changes in BAG alone (Δ R 2 = 0.064, p < 0.001)., Discussion: The brain-predicted DD gap is sensitive to MS-related lesions and brain atrophy, adds to the brain-age paradigm in explaining physical disability both cross-sectionally and longitudinally, and may be used as an MS-specific biomarker of disease severity and progression.

Introduction: Understanding the prevalence of multiple sclerosis (MS) provides information for healthcare planning and helps identify trends and patterns of disease occurrence. For Switzerland, the number of persons with MS (pwMS) was last estimated at approximately 15,000 in 2016. The study's objectives are to update estimates of MS prevalence and characterise the change in MS prevalence in Switzerland between 2016 and 2021, the last year with complete administrative data., Methods: The Swiss MS Registry (SMSR) is an ongoing, longitudinal study in Switzerland. It has previously established a methodology to assess the epidemiology of MS in Switzerland by integrating SMSR data with administrative data on reimbursement approvals for disease-modifying therapies (DMTs). Subsequently, the benchmark-multiplier method is applied to the combined data. Using the same methodology, we calculated overall and sex- and age-specific prevalence rates for 2021. Furthermore, we descriptively analysed changes since 2016 by comparing the prevalence figures and demographic and clinical characteristics of pwMS in both years., Results: We estimated the population of pwMS in Switzerland at 18,140 [95% simulation interval 17,550-18,750], corresponding to a period prevalence of 200.8-214.5/100,000 inhabitants. Peak prevalence was observed in the 50 to 55-year age group. Compared to 2016, the 2021 estimate corresponds to a 20% increase (n=3,000). Extrapolating from Swiss population growth, we estimated that one-fifth of the observed prevalence increase may be attributed to a rising population. The proportion of pwMS in the age range from 50 to 64 (32.5% vs. 35.9%) and above 65 (8.0% vs. 11.1%) years increased. Consequently, the median [interquartile range] age increased from 47 [37-55] to 49 [38-57] years. The median age at diagnosis (36 [28-45] years) and the female-to-male ratio (2.7:1) remained stable since 2016. The proportion of pwMS treated with DMTs increased from 62.1% to 69.0%, with the largest change observed in infusion therapies (15.7% vs. 23.3%)., Conclusion: The estimated MS prevalence in Switzerland has increased since the previous estimate in 2016, with a shift in peak prevalence towards older ages. Population growth explained around one-fifth of this increase, thus leaving room for contributions by additional factors, which require further investigation. The rising MS prevalence has several implications for healthcare, research and society., (The Author(s). Published by S. Karger AG, Basel.)

Background and Objectives: In patients with multiple sclerosis (PwMS), thalamic atrophy occurs during the disease course. However, there is little understanding of the mechanisms leading to volume loss and of the relationship between microstructural thalamic pathology and disease progression. This cross-sectional and longitudinal study aimed to comprehensively characterize in vivo pathologic changes within thalamic microstructure in PwMS using advanced multiparametric quantitative MRI (qMRI)., Methods: Thalamic microstructural integrity was evaluated using quantitative T1, magnetization transfer saturation, multishell diffusion, and quantitative susceptibility mapping (QSM) in 183 PwMS and 105 healthy controls (HCs). The same qMRI protocol was available for 127 PwMS and 73 HCs after a 2-year follow-up period. Inclusion criteria for PwMS encompassed either an active relapsing-remitting MS (RRMS) or inactive progressive MS (PMS) disease course. Thalamic alterations were compared between PwMS and HCs and among disease phenotypes. In addition, the study investigated the relationship between thalamic damage and clinical and conventional MRI measures of disease severity., Results: Compared with HCs, PwMS exhibited substantial thalamic alterations, indicative of microstructural and macrostructural damage, demyelination, and disruption in iron homeostasis. These alterations extended beyond focal thalamic lesions, affecting normal-appearing thalamic tissue diffusely. Over the follow-up period, PwMS displayed an accelerated decrease in myelin volume fraction [mean difference in annualized percentage change ( MD-ApC ) = -1.50; p = 0.041] and increase in quantitative T1 ( MD-ApC = 0.92; p < 0.0001) values, indicating heightened demyelinating and neurodegenerative processes. The observed differences between PwMS and HCs were substantially driven by the subgroup with PMS, wherein thalamic degeneration was significantly accelerated, even in comparison with patients with RRMS. Thalamic qMRI alterations showed extensive correlations with conventional MRI, clinical, and cognitive disease burden measures. Disability progression over follow-up was associated with accelerated thalamic degeneration, as reflected by enhanced diffusion ( β = -0.067; p = 0.039) and QSM ( β = -0.077; p = 0.027) changes. Thalamic qMRI metrics emerged as significant predictors of neurologic and cognitive disability even when accounting for other established markers including white matter lesion load and brain and thalamic atrophy., Discussion: These findings offer deeper insights into thalamic pathology in PwMS, emphasizing the clinical relevance of thalamic damage and its link to disease progression. Advanced qMRI biomarkers show promising potential in guiding interventions aimed at mitigating thalamic neurodegenerative processes.

Prolonged treatment with anti-CD20 antibodies can lead to hypogammaglobulinemia and increased infection risk in multiple sclerosis (MS). We investigated switch from anti-CD20 to cladribine as a strategy to prevent immunoglobulin reduction while preserving efficacy. We prospectively analysed serum IgG, IgM, neurofilament light (NfL) and glial fibrillary acidic protein (GFAP) in 44 patients, 14 who were switched from anti-CD20 to cladribine and 30 continuing anti-CD20. Over 1 year, serum IgG, IgM, NfL and GFAP remained stable after switch and similar to patients continuing anti-CD20. More than 90 % of patients remained free of disease activity. Cladribine should be further explored as de-escalating agent from anti-CD20 in MS., Competing Interests: Declaration of competing interest The employer (Department of Neurology, Regional Hospital Lugano (EOC), Lugano, Switzerland) receives financial support from Abbvie, Biogen Idec, Lundbeck, Merck, Novartis Roche, Sanofi, Teva. The submitted work is not related to these agreements., (Copyright © 2024. Published by Elsevier B.V.)

Background: Spontaneous supratentorial intracerebral hemorrhage is the deadliest form of stroke with mortality rates over 50%. Currently, no sufficiently effective treatment to improve both mortality and functional outcome rates exists. However, it seems that minimally invasive surgery, especially endoscopic surgery, might be beneficial in improving survival and functional outcome rates, yet large confirmatory studies thereof are lacking. The aim of this trial is to compare whether early minimally invasive endoscopic surgery leads to improved functional outcome rates compared to the best medical treatment., Methods: This is a prospective, parallel-arm, outcome assessor blinded multicenter trial across Switzerland. Endoscopic surgery will be compared to the best medical treatment in a 1:1 randomization over a total time of 12 months. The primary outcome is defined as improved functional outcome (mRS < 3) after 6 months; secondary outcomes include mortality and morbidity rates as well as patient reported outcomes and the temporal evolution of serum biomarkers for brain damage., Discussion: Currently, large, randomized trials assessing the role and potential effect of early endoscopic surgery in intracerebral hemorrhage are lacking. Potential practical and methodological issues faced in this trial are patient enrollment, adherence to the hematoma evacuation technique used, potential patient cross-over, and the adaptive Bayesian statistical design. Nonetheless, this trial would be among the first to research the effects of early minimally invasive endoscopic surgery for SSICH and can provide class I evidence for future treatment options in intracerebral hemorrhage., Trial Registration: ClinicalTrials.gov NCT05681988. Registered on January 3, 2023., (© 2024. The Author(s).)

Objective: To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B-cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events., Methods: A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores., Results: Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17-2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95-2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow-up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (-0.92 [-1.23, -0.60], p < 0.0001), whereas levels in patients with PIRA remained high., Interpretation: Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: Pathological studies suggest that multiple sclerosis (MS) lesions endure multiple waves of damage and repair; however, the dynamics and characteristics of these processes are poorly understood in patients living with MS., Methods: We studied 128 MS patients (75 relapsing-remitting, 53 progressive) and 72 healthy controls who underwent advanced magnetic resonance imaging and clinical examination at baseline and 2 years later. Magnetization transfer saturation and multi-shell diffusion imaging were used to quantify longitudinal changes in myelin and axon volumes within MS lesions. Lesions were grouped into 4 classes (repair, damage, mixed repair damage, and stable). The frequency of each class was correlated to clinical measures, demographic characteristics, and levels of serum neurofilament light chain (sNfL)., Results: Stable lesions were the most frequent (n = 2,276; 44%), followed by lesions with patterns of "repair" (n = 1,352; 26.2%) and damage (n = 1,214; 23.5%). The frequency of "repair" lesion was negatively associated with disability (β = -0.04; p < 0.001) and sNfL (β = -0.16; p < 0.001) at follow-up. The frequency of the "damage" class was higher in progressive than relapsing-remitting patients (p < 0.05) and was related to disability (baseline: β = -0.078; follow-up: β = -0.076; p < 0.001) and age (baseline: β = -0.078; p < 0.001). Stable lesions were more frequent in relapsing-remitting than in progressive patients (p < 0.05), and in younger patients versus older (β = -0.07; p < 0.001) at baseline. Further, "mixed" lesions were most frequent in older patients (β = 0.004; p < 0.001) at baseline., Interpretation: These findings show that repair and damage processes within MS lesions occur across the entire disease spectrum and that their frequency correlates with patients disability, age, disease duration, and extent of neuroaxonal damage. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

The grey matter of the brain develops and declines in coordinated patterns during the lifespan. Such covariation patterns of grey matter structure can be quantified as grey matter networks, which can be measured with magnetic resonance imaging. In Alzheimer's disease, the global organization of grey matter networks becomes more random, which is captured by a decline in the small-world coefficient. Such decline in the small-world value has been robustly associated with cognitive decline across clinical stages of Alzheimer's disease. The biological mechanisms causing this decline in small-world values remain unknown. Cerebrospinal fluid (CSF) protein biomarkers are available for studying diverse pathological mechanisms in humans and can provide insight into decline. We investigated the relationships between 10 CSF proteins and small-world coefficient in mutation carriers ( N = 219) and non-carriers ( N = 136) of the Dominantly Inherited Alzheimer Network Observational study. Abnormalities in Amyloid beta, Tau, synaptic (Synaptosome associated protein-25, Neurogranin) and neuronal calcium-sensor protein (Visinin-like protein-1) preceded loss of small-world coefficient by several years, while increased levels in CSF markers for inflammation (Chitinase-3-like protein 1) and axonal injury (Neurofilament light) co-occurred with decreasing small-world values. This suggests that axonal loss and inflammation play a role in structural grey matter network changes., Competing Interests: C.C.: receives research support from: Biogen, EISAI, Alector and Parabon. The funders of the study had no role in the collection, analysis, interpretation of data; or in the writing of the report; or in the decision to submit the paper for publication. C.C. is a member of the advisory board of ADx Healthcare and Vivid Genomics Marty Farlow: Grant/Research Support from AbbVie, ADCS Posiphen, AstraZeneca, Biogen, Eisai, Eli Lilly, Genentech, Novartis, Suven Life Sciences, Ltd., vTv Therapeutics; Consultant/Advisory Boards/DSMB Boards for Allergan, Avanir, AZTherapies, Biogen MA Inc., Cerecin (formerly Accera), Chemigen, Cognition Therapeutics, Cortexyme, Danone, Eisai Inc., Eli Lilly, Longeveron, Green Valley, Medavante, Otsuka Pharmaceutical, Proclara, Neurotrope Bioscience, Samumed, Takeda, vTv Therapeutics, Zhejian Hisun Pharmaceuticals; patent Elan Johannes Levin reports speaker’s fees from Bayer Vital, speaker’s fees from Willi Gross Foundation, consulting fees from Axon Neuroscience, consulting fees from Ionis Pharmaceuticals, non-financial support from Abbvie, MODAG compensation for part time CMO, Thieme medical publishers and W. Kohlhammer GmbH medical publishers author fees, outside the submitted work. E.M.: NIA (research Funding); Eli Lilly-DSMB; ESAI—CMS; Alzamend—scientific advisory board. P.S. is partner at LSP Invester fund and has acquired grant support (for the institution) from GE Healthcare, Danone Research, Piramal and Merck. In the past 2 years, he has received consultancy/speaker fees (paid to the institution) from Lilly, GE Healthcare, Novartis, Sanofi, Nutricia, Probiodrug, Biogen, Roche, Avraham and EIP Pharma. Outside of this manuscript, R.J.B. reports grant/research/clinical trial support: NIH, Alzheimer's Association, BrightFocus Foundation, Rainwater Foundation Tau Consortium, Association for Frontotemporal Degeneration, Cure Alzheimer's Fund, the Tau SILK Consortium (AbbVie, Biogen and Eli Lilly), Janssen, and an anonymous foundation. R.J.B. reports consulting fees/honoraria from Janssen, Pfizer, Roche, Eisai, and Merck. R.J.B. reports equity ownership interest/advisory board income from C2N Diagnostics. All other authors report no disclosures., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Obstructive sleep apnea is associated with cognitive impairment and increased risk for neurodegenerative diseases. Obstructive sleep apnea treatment with positive airway pressure therapy helps to improve cognitive symptoms and reduces long-term dementia risk. To test whether these treatment effects are due to a reduction in neuronal damage, we examined longitudinal changes in the neurodegenerative serum neurofilament light chain and cognitive performance of patients with obstructive sleep apnea. In this study, 17 patients with obstructive sleep apnea completed baseline and follow-up (9 month after starting PAP treatment) investigation of sleep, daytime symptoms, cognitive testing and serum neurofilament light chain measurements. Depending on treatment adherence and efficacy, participants were assigned either to the effective treatment (n = 10) or non-effective treatment group (n = 7). As results at baseline lower mean oxygen saturation during sleep was associated with higher serum neurofilament light chain. Patients in the non-effective treatment group showed a significant increase of age-adjusted percentile of serum neurofilament light chain levels at follow-up, whereas serum neurofilament light chain values remained constant in the effective treatment group. At a functional level, effective treatment leads to an improvement in processing speed, which was not the case in the non-effective treatment group. Longitudinal changes of age-adjusted serum neurofilament light chain levels were associated with changes in cognitive performance. To conclude, this longitudinal observational study showed that effective obstructive sleep apnea treatment positively affects the amount of neuronal damage as well as working memory performance. As cognitive symptoms might not only be attributed to obstructive sleep apnea-related sleep deficiency, but also neurodegeneration, our results underline the importance of treatment adherence and efficacy for the prevention of neuronal damage and cognitive consequences., (© 2024 The Authors. Journal of Sleep Research published by John Wiley & Sons Ltd on behalf of European Sleep Research Society.)

Background and Objectives: Myelin and iron play essential roles in remyelination processes of multiple sclerosis (MS) lesions. χ-separation, a novel biophysical model applied to multiecho T2*-data and T2-data, estimates the contribution of myelin and iron to the obtained susceptibility signal. We used this method to investigate myelin and iron levels in lesion and nonlesion brain areas in patients with MS and healthy individuals., Methods: This prospective MS cohort study included patients with MS fulfilling the McDonald Criteria 2017 and healthy individuals, aged 18 years or older, with no other neurologic comorbidities. Participants underwent MRI at baseline and after 2 years, including multiecho GRE-(T2*) and FAST-(T2) sequences. Using χ-separation, we generated myelin-sensitive and iron-sensitive susceptibility maps. White matter lesions (WMLs), cortical lesions (CLs), surrounding normal-appearing white matter (NAWM), and normal-appearing gray matter were segmented on fluid-attenuated inversion recovery and magnetization-prepared 2 rapid gradient echo images, respectively. Cross-sectional group comparisons used Wilcoxon rank-sum tests, longitudinal analyses applied Wilcoxon signed-rank tests. Associations with clinical outcomes (disease phenotype, age, sex, disease duration, disability measured by Expanded Disability Status Scale [EDSS], neurofilament light chain levels, and T2-lesion number and volume) were assessed using linear regression models., Results: Of 168 patients with MS (median [interquartile range (IQR)] age 47.0 [21.7] years; 101 women; 6,898 WMLs, 775 CLs) and 103 healthy individuals (age 33.0 [10.5] years, 57 women), 108 and 62 were followed for a median of 2 years, respectively (IQR 0.1; 5,030 WMLs, 485 CLs). At baseline, WMLs had lower myelin (median 0.025 [IQR 0.015] parts per million [ppm]) and iron (0.017 [0.015] ppm) than the corresponding NAWM (myelin 0.030 [0.012]; iron 0.019 [0.011] ppm; both p < 0.001). After 2 years, both myelin (0.027 [0.014] ppm) and iron had increased (0.018 [0.015] ppm; both p < 0.001). Younger age ( p < 0.001, b = -5.111 × 10 -5 ), lower disability ( p = 0.04, b = -2.352 × 10 -5 ), and relapsing-remitting phenotype (RRMS, 0.003 [0.01] vs primary progressive 0.002 [IQR 0.01], p < 0.001; vs secondary progressive 0.0004 [IQR 0.01], p < 0.001) at baseline were associated with remyelination. Increment of myelin correlated with clinical improvement measured by EDSS ( p = 0.015, b = -6.686 × 10 -4 )., Discussion: χ-separation, a novel mathematical model applied to multiecho T2*-images and T2-images shows that young RRMS patients with low disability exhibit higher remyelination capacity, which correlated with clinical disability over a 2-year follow-up.

Inflammation of the brain is called encephalitis and may result in acute and chronic brain damage. Encephalitis can be caused by various pathogens, especially neurotropic viruses, or can occur in the context of autoimmune diseases. Encephalitis is often difficult to diagnose and to monitor precisely during the course of the disease. Thanks to highly specific detection technology, components of the neuron skeleton, such as neurofilaments, can now be reliably quantified in the peripheral blood besides cerebrospinal fluid (CSF). Among them, neurofilament light chain (NfL) has demonstrated wide utility due to high preanalytical stability, robust diagnostic technology, and excellent reproducibility. We provide an overview of how NfL has advanced diagnostics in encephalitis and outline future avenues in research needs and possible clinical applicability of NfL in adults and children.