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Background and Objectives:Cognitive impairment is a common and impactful symptom of relapsing-remitting multiple sclerosis (RRMS). Cognitive outcome measures are often used in cross-sectional studies, but their performance as longitudinal outcome measures in clinical trials is not widely researched. In this study, we used data from a large clinical trial to describe change on the Symbol Digit Modalities Test (SDMT) and the Paced Auditory Serial Addition Test (PASAT) over up to 144 weeks of follow-up.Methods:We used the dataset from DECIDE (clinicaltrials.gov identifierNCT01064401), a large randomized controlled RRMS trial to describe change on the SDMT and PASAT over 144 weeks of follow-up. We compared change on these cognitive outcomes with change on the timed 25-foot walk (T25FW), a well-established physical outcome measure. We investigated several definitions for clinically meaningful change: any change, 4-point change, 8-point change, and 20% change for the SDMT, any change, 4-point change and 20% change for the PASAT, and 20% change for the T25FW.Results:DECIDE included 1,814 trial participants. SDMT and PASAT scores steadily improved throughout follow-up: the SDMT from a mean 48.2 (standard deviation, SD, 16.1) points at baseline to 52.6 (SD 15.2) at 144 weeks, and the PASAT from 47.0 (SD 11.3) at baseline to 50.0 (SD 10.8) at 144 weeks. This improvement in scores is most likely due to a practice effect. Throughout the trial, participants were more likely to experience improvement than worsening of their SDMT and PASAT performance, while the number of worsening events on the T25FW steadily increased. Changing the definition of clinically meaningful change for the SDMT and PASAT, or using a 6-month confirmation changed the overall number of worsening or improvement events, but did not affect the overall behaviour of these measures.Discussion:Our findings suggests that the SDMT and PASAT scores do not accurately reflect the steady cognitive decline that people with RRMS experience. Both outcomes show post baseline increases in scores, which complicates the interpretation of these outcome measures in clinical trials. More research into the size of these changes is needed before recommending a general threshold for clinically meaningful longitudinal change.

Background and ObjectivesThe specificity of novel blood biomarkers for multiple sclerosis (MS)–related neurodegeneration is unclear because neurodegeneration also occurs during normal aging. To understand which aspects of neurodegeneration the serum biomarkers neurofilament light (sNfL), serum glial fibrillary acidic protein (sGFAP), and serum contactin-1 (sCNTN1) reflect, we here explore their cross-sectional association with disability outcome measures and MRI volumes in a unique cohort of people with MS (PwMS) of the same age.MethodssNfL, sGFAP (both singe-molecule array technology) and sCNTN1 (Luminex) were measured in serum samples of 288 PwMS and 125 healthy controls (HCs) of the Project Y cohort, a population-based cross-sectional study of PwMS born in the Netherlands in 1966 and age-matched HC.ResultssNfL (9.83 pg/mL [interquartile range {IQR}: 7.8–12.0]) and sGFAP (63.7 pg/mL [IQR: 48.5–84.5]) were higher in PwMS compared with HC (sNfL: 8.8 pg/mL [IQR: 7.0–10.5]; sGFAP: 51.7 pg/mL [IQR: 40.1–68.3]) (p< 0.001), whereas contactin-1 (7,461.3 pg/mL [IQR: 5,951.8–9,488.6]) did not significantly differ between PwMS compared with HC (7,891.2 pg/mL [IQR: 6,120.0–10,265.8]) (p= 0.068). sNfL and sGFAP levels were 1.2-fold higher in secondary progressive patients (SPMS) compared with relapsing remitting patients (p= 0.009 andp= 0.043). Stratified by MS subtype, no relations were seen for CNTN1, whereas sNfL and sGFAP correlated with the Expanded Disability Status Scale (ρ = 0.43 and ρ = 0.39), Nine-Hole Peg Test, Timed 25-Foot Walk Test, and Symbol Digit Modalities Test (average ρ = 0.38) only in patients with SPMS. Parallel to these clinical findings, correlations were only found for sNfL and sGFAP with MRI volumes. The strongest correlations were observed between sNfL and thalamic volume (ρ = −0.52) and between sGFAP with deep gray matter volume (ρ = − 0.56) in primary progressive patients.DiscussionIn our cohort of patients of the same age, we report consistent correlations of sNfL and sGFAP with a range of metrics, especially in progressive MS, whereas contactin-1 was not related to clinical or MRI measures. This demonstrates the potential of sNfL and sGFAP as complementary biomarkers of neurodegeneration, reflected by disability, in progressive MS.

In this observational study, 159 patients with multiple sclerosis received personalized dosing of ocrelizumab incentivized by the COVID-19 pandemic. Re-dosing was scheduled when CD19 B-cell count was ⩾10 cells/µL (starting 24 weeks after the previous dose, repeated 4-weekly). Median interval until re-dosing or last B-cell count was 34 [30–38] weeks. No clinical relapses were reported and a minority of patients showed Expanded Disability Status Scale (EDSS) progression. Monthly serum neurofilament light levels remained stable during extended intervals. Two (1.9%) of 107 patients with a follow-up magnetic resonance imaging (MRI) scan showed radiological disease activity. Personalized dosing of ocrelizumab could significantly extend intervals with low short-term disease activity incidence, encouraging future research on long-term safety and efficacy.

Autopsy cases show that cortical lesions (CLs) in multiple sclerosis (MS) lack lymphocyte/macrophage influx, blood-brain barrier breakdown, and complement activation. However, some CLs were demonstrated to harbor activated microglia. Here, we assessed the clinical significance of microglia activation in CLs in a large autopsy sample, and we investigated possible interrelationships with other pathologic characteristics.We cross-sectionally investigated the clinicopathologic characteristics of 22 patients with MS with extensive subpial demyelination (CL group) and 19 patients with MS with only little demyelination of the cerebral cortex (non-CL group).A subset of the patients in the CL group (12 patients) showed rims of activated microglia (RAM) at the border of the CLs (RAM-CL group), whereas the other 10 patients in this group did not show microglia activation (non-RAM-CL group). A subsequent comparison between groups showed that patients with MS harboring RAM-CLs were significantly younger at the time of their death (53.5 years) than patients harboring mainly non-RAM-CLs (68.7 years; p0.05) or patients without extensive numbers of CLs (66.9 years; p0.01). In addition, a significantly shorter disease duration was found for the RAM-CL group (mean 20.9 years) than for the non-CL group (mean 34.5 years; p0.05). We also found that the presence of RAM-CLs is associated with a higher number of chronic active white matter (WM) lesions (Spearman ρ = 0.74; p0.0001).RAM-CLs were found in a subset of patients with MS who also have more active WM inflammation and a less favorable disease course.

Background: Several genetic markers have been associated with multiple sclerosis (MS) susceptibility; however, uncovering the genetic aetiology of the complex phenotypic expression of MS has been more difficult so far. The most common approach in imaging genetics is based on mass-univariate linear modelling (MULM), which faces several limitations. Objective: Here we apply a novel multivariate statistical model, sparse reduced-rank regression (sRRR), to identify possible associations of glutamate related single nucleotide polymorphisms (SNPs) and multiple MRI-derived phenotypes in MS. Methods: Seven phenotypes related to brain and lesion volumes for a total number of 326 relapsing–remitting and secondary-progressive MS patients and a total of 3809 glutamate related and control SNPs were analysed with sRRR, which resulted in a ranking of SNPs in decreasing order of importance (‘selection probability’). Lasso regression and MULM were used as comparative statistical techniques to assess consistency of the most important associations over different statistical models. Results: Five SNPs within the NMDA-receptor-2A-subunit (GRIN2A) domain were identified by sRRR in association with normalized brain volume (NBV), normalized grey matter volume and normalized white matter volume (NMWM). The association between GRIN2A and both NBV and NWMV was confirmed in MULM and Lasso analysis. Conclusions: Using a novel, multivariate regression model confirmed by two other statistical approaches we show associations between GRIN2A SNPs and phenotypic variation in NBV and NWMV in this first exploratory study. Replications in independent datasets are now necessary to validate these findings.

Neuroimaging measures hold promise for enhancing the detection of disease-related genetic variants. In this study, we use advanced multivariate regression methods to assess the predictive value of single nucleotide polymorphisms (SNPs) on several brain volumetric- and lesion-related neuroimaging measures in a well-characterized cohort of 326 patients with multiple sclerosis (MS). SNP selection was constrained to key epigenetic regulatory genes to further explore the emerging role of epigenetics in MS. Regression models consistently identified rs2522129, rs2675231, and rs2389963 as having among the highest predictive values for explaining differences related to brain volume measures. These SNPs are all contained in genes from the same superfamily, histone deacetylases, which have biological functions that are relevant to MS, neurodegeneration, and aging. Our preliminary findings generate hypotheses for testing in future independent MS data sets as well as other neurodegenerative conditions.

PURPOSE. With the introduction of spectral domain-optical coherence tomography (SD-OCT), changes in retinal nerve fiber layer (RNFL) thickness and macular volume (MV) can be detected with high precision. The aim of this study was to determine whether there is a physiological quantifiable degree of variation of these structures in humans. METHODS. This study took place during a 10-km charity run at VU University Medical Center Amsterdam. Weight, height, hydration status, RNFL thickness (ring scan, 12° around the optic nerve head), and MV (20° × 20°) were assessed in 69 subjects (44 runners, 25 controls) using SD-OCT with eye-tracking function. The SD-OCT scans were assessed before running (normal status), after running (more dehydrated status), and 1 to 1.5 hours after finishing the run (rehydrated status). Controls were measured at the same time intervals as the runners but did not participate in the running event. Changes over time were assessed by general linear models, correcting for repeated measurements. RESULTS. In runners, a significant increase in both RNFL thickness (94.4 μm [baseline] to 95.2 μm [rehydration], P = 0.04) and MV (288.9 μm [baseline] to 291.0 μm [rehydration], P < 0.001) over time was observed. Controls did not show significant changes over time. Anatomically, the physiological change of RNFL thickness was most marked in the nasal sectors. CONCLUSIONS. This prospective study demonstrated a significant physiological variation of the RNFL thickness and MV at a proportion that, on an individual patient level, may be relevant for longitudinal studies in neurodegenerative diseases. © 2012 The Association for Research in Vision and Ophthalmology, Inc.