Cognitive evolution in people with multiple sclerosis (pwMS) may follow different trajectories. This study investigated long-term cognitive evolution in pwMS while controlling for methodological factors and psychological variables, to refine neuropsychological monitoring. A cohort of pwMS (n = 148) underwent neuropsychological evaluations at three time points: baseline (BL), re-baseline (RBL; 1 year later), and long-term follow-up (LTFU; 6 years after BL). Annualized cognitive change scores were analyzed to compare changes during BL-RBL interval with those in RB-LTFU. Participants were classified over time as cognitively preserved (CP) or cognitively impaired (CI) and McNemar’s test evaluated classification changes. Sensitivity analysis was conducted in a subgroup of recently diagnosed pwMS (n = 91). Reliable Change Indices (RCI) at the 95

Evidence directly comparing ocrelizumab (OCR) and ofatumumab (OFA) after sphingosine-1-phosphate receptor modulators (S1PRMs) withdrawal is limited, even though this transition period carries an increased risk of disease reactivation and the two anti-CD20 agents differ in molecular properties that may influence post-S1PRM outcomes. We compared effectiveness, safety, and tolerability of OFA versus OCR in relapsing–remitting multiple sclerosis (RRMS) after S1PRM therapy. We retrospectively analyzed adult (> 18 years) patients with RRMS from 23 Italian centers who switched from S1PRMs to OCR or OFA (October 2016 to July 2024). Clinical outcomes included annualized relapse rate (ARR), cumulative relapse incidence, confirmed disability progression (CDP), progression independent of relapse activity (PIRA), confirmed disability improvement (CDI), and variation in the expanded disability status scale score (ΔEDSS) from baseline to last follow-up. Magnetic resonance imaging (MRI) outcomes included time to overall MRI activity, new/enlarging T2 lesions, and new T1 Gd-enhancing lesions. Persistence on anti-CD20 and safety were also assessed. We applied inverse probability of treatment weighting (IPTW) to balance baseline covariates, and used Cox, Andersen–Gill, and regression models, further adjusted for variables with residual imbalance, to compare outcomes. We included 225 subjects (mean age 43.3 ± 10.6 years; OCR = 131, OFA = 94), with a median follow-up of 33 months. After IPTW, groups were well balanced. Compared with OCR, OFA was associated with lower ARR (adjusted relative risk [aRR] 0.22, 95

BACKGROUND:The effect of cognitive reserve (CR) on cognition in people with relapsing-remitting multiple sclerosis (pwRRMS) has been partially investigated. OBJECTIVES:We aimed to explore the long-term cognitive trajectories of pwRRMS based on their CR, measured using the Vocabulary Knowledge Test (VOC). METHODS:78 pwRRMS underwent a neuropsychological evaluation at baseline and after a mean follow-up of 6.5 years. We carried out several mixed-design ANCOVA to test the effect of CR on longitudinal cognitive trajectories, controlling for the effects of disability and depression. Regression analyses were performed to assess the clinical predictors of longitudinal cognitive variation. RESULTS:At follow-up, we observed improvements in cognitive scores within pwRRMS with high CR and a decline within pwRRMS with low CR. VOC scores increased at follow-up evaluation in the whole sample, and this change was associated with the female sex. VOC emerged as the only predictor of cognitive changes over time. CONCLUSIONS:CR, estimated by VOC, can increase over time by engaging in intellectually enriching activities, and may predict long-term cognitive outcomes in pwRRMS. The identification of pwRRMS with low CR, and therefore, most at risk of future cognitive decline, should prompt the implementation of CR enhancement interventions to delay the onset of cognitive impairment.

The calcium-dependent enzyme Transglutaminase 2 (TG2) (E.C. 2.3.2.13), which can promote post-translational modifications of proteins, is involved in several physiological processes, including development, neuronal cell death, and differentiation, as well as synaptic plasticity and transmission in the central nervous system (CNS). Several studies highlight the potential role of the TG2/NF-κB activation pathway in neurodegenerative diseases, including Multiple Sclerosis (MS), and the neuroinflammation that is associated with these conditions. The cross-linking activity of TG2, facilitating the formation of isopeptide bonds between glutamine and lysine residues, appears to be involved in forming protein aggregate deposits in these pathological conditions. Specifically, in the chronic neuroinflammation of MS, TG2 seems to play a central role in the fibrotic process of the lesion. Several potential biomarkers have been investigated for the prognosis and monitoring of MS, but no researchers have explored the presence of potential inflammatory signals in peripheral blood mononuclear cells (PBMCs) during the presymptomatic stage of MS, known as Radiologically Isolated Syndrome (RIS), on account of the lack of information regarding its pathological aspects. Since researchers have demonstrated a correlation between TG2 mRNA levels in PBMCs and the clinical and radiological progression of MS, we aimed to evaluate the expression levels of TG2 in RIS patients, comparing them with those in relapsing-remitting MS (RRMS) patients and healthy controls (HCs) using real-time PCR analysis. Preliminary data showed that RIS patients exhibit lower TG2 mRNA expression levels compared to RRMS patients, while no difference in TG2 mRNA expression being observed between RIS patients and HCs. This suggests that RIS patients exhibit a lower neuroinflammation grade than RRMS patients and that TG2 may represent a potential biochemical marker for assessing neuroinflammation associated with this disease. Future investigations may include longitudinal assessments of the potential role of TG2 mRNA blood levels in predicting or monitoring the progression from RIS to MS.

OBJECTIVE:Cognitive impairment is a common feature of multiple sclerosis (MS), and its severity may be influenced by several factors, such as biological sex and levels of cognitive reserve (CR). The relationship between sex, CR, and cognition has not yet been fully investigated. Therefore, the present study aimed to explore sex differences in CR building and the effect of sex and CR on cognitive performance in MS. METHOD:233 participants underwent the Brief Repeatable Battery of Neuropsychological Tests (BRB-N), the Stroop test, and the Cognitive Reserve Scale. The t-test was performed to compare sociodemographic variables, Italian adaptation of the Cognitive Reserve Scale, and cognitive test scores between sexes. To evaluate the effect of CR and sex and their interaction on cognitive performance several models of multivariate analyses of covariance were performed (dependent variables: all subtests of Brief Repeatable Battery of Neuropsychological Tests and Stroop scores; independent variables: sex and CR). Covariates included age, Expanded Disability Status Scale, and BDI-II scores. RESULTS:Women showed higher levels of CR, particularly in daily activities (t = -5.848, p<.001), hobbies (t = -2.591, p = .010), and social life (t = -2.362, p = .011). Sex differences were noted in verbal memory and fluency (with women outperforming men) and processing speed (with men performing better than women). Multivariate analyses revealed a nonsignificant interaction between CR and sex on cognition (Λ=.950, F(10,260)=.813, p = .617, ηp2 = .050). CONCLUSIONS:CR and sex seemed to affect cognitive performance independently in pwMS. This highlights the importance of considering both factors in cognitive assessment, and that both sexes may benefit from specific psychoeducational training aimed at increasing CR levels.

Background Non-relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (nr-MOGAD) is an inflammatory demyelinating disorder of the central nervous system that frequently affects younger populations. The longitudinal impact of nr-MOGAD on cognitive function remains poorly characterized. Objectives To investigate cognitive profiles and longitudinal cognitive changes in patients with nr-MOGAD compared to individuals with Relapsing-Remitting Multiple Sclerosis (pwRRMS) and healthy controls (HCs). Methods A cohort of 8 nr-MOGAD patients, 32 pwRRMS patients, and 22 HCs underwent a baseline and a 12-month follow-up assessment with the Brief Repeatable Battery of Neuropsychological Tests (BRBN) and Stroop test. Results At baseline, nr-MOGAD patients exhibited moderate cognitive deficits, particularly in verbal memory and processing speed domains, with scores intermediate between pwRRMS and HCs. At follow-up, nr-MOGAD patients, especially those with pediatric-onset, showed significant cognitive recovery, contrasting with the stable impairments observed in pwRRMS. Conclusions Cognitive impairment patterns in nr-MOGAD are distinct from those observed in pwRRMS and, particularly in younger patients, show a frequent reversal unlike pwRRMS, in which persistently impaired cognitive performances are much more common.

BACKGROUND AND OBJECTIVES:Autoantibodies against contactin-associated protein-like 2 (CASPR2-IgG) and leucine-rich glioma inactivated 1 protein (LGI1-IgG) identify a subgroup of autoimmune encephalitis (AE). Up to 65% of patients with LGI1/CASPR2 AE show cognitive sequelae that are unpredictable at onset. We aimed to assess the clinical relevance of serum autoantibody titers and neurofilament light chain (NfL) levels as biomarkers in CASPR2/LGI1 AE. METHODS:We selected consecutive CASPR2/LGI1-IgG-positive patients with at least 2 longitudinal serum samples obtained more than 60 days apart. Samples were defined as acute (first diagnostic evaluation after onset or relapse and before immunotherapy) and remission (>2 months from attack). CASPR2/LGI1-IgG was titered with a live cell-based assay. Functional outcome was measured using modified Rankin Scale and Clinical Assessment Scale in AE and cognitive impairment using Montreal Cognitive Assessment (MoCA). RESULTS:We included 23 patients (LGI1 = 15, CASPR2 = 7, CASPR2/LGI1 = 1) with 130 serum samples (acute = 32; remission = 98). Serum titers in the acute phase were higher than in remission and decreased over time and after immunosuppressive treatment. In 9 of 10 patients, relapses occurred with seropositive samples, and in 4 of 5 patients, these occurred with increased titers. Onset titers did not correlate with functional/cognitive outcome at follow-up.Serum NfL median levels in both patients with LGI1 AE (35.3 pg/mL, range: 5.4-164) and CASPR2 AE (31.4 pg/mL, range: 9.11-120) were higher than in age/sex-matched controls (14.55, range: 5.4-56.8, p = 0.004 and p < 0.001, respectively). Acute-phase samples had higher NfL median levels (47.2, range: 9.11-120) compared with remission (31.2 pg/mL; range, 5.4-114, p = 0.02). NfL levels at onset predicted lower MoCA scores at follow-up in univariate linear regression analysis (B = -3.881, p = 0.0256). NfL levels decreased over time, but at the last follow-up remained higher than those in controls (p = 0.02). DISCUSSION:Measuring LGI1 and CASPR2-IgG titers in AE could help to confirm the disease stage and define relapses but has no prognostic implications. Serum NfL at onset could be used to identify patients at higher risk of cognitive sequelae that might deserve tailored management.

BACKGROUND AND OBJECTIVES:Antibodies to proteolipid protein-1 (PLP1-IgG), a major central myelin protein also expressed in the peripheral nervous system (PNS) as the isoform DM20, have been previously identified mostly in patients with multiple sclerosis (MS), with unclear clinical implications. However, most studies relied on nonconformational immunoassays and included few patients with non-MS CNS autoimmune demyelinating disorders (ADDs). We aimed to investigate conformational PLP1-IgG in the whole ADD spectrum. METHODS:We devised a new live cell-based assay (CBA) for PLP1-IgG and used it to test 2 cohorts (retrospective exploratory, n = 284; prospective validation, n = 824) of patients with ADDs and controls (n = 177). Patients were classified as MS, neuromyelitis optica spectrum disorders (NMOSDs), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and other ADDs. PLP1-IgG-positive samples were tested for IgG subclasses, DM20-IgG, and on rat brain tissue-based assay (TBA). Complement-dependent cytotoxicity (CDC) was assessed on a live CBA and antigen specificity and conformational binding through immunoadsorption/colocalization/fixation experiments. RESULTS:PLP1-IgG were found in 0 of 177 controls and 42 of 1104 patients with ADDs mainly diagnosed as other ADDs (19/42) with frequent myelitis/encephalomyelitis (14/19) and coexisting PNS involvement (13/19). Four of 19 patients with other ADDs fulfilled the seronegative NMOSD criteria. PLP1-IgG were also found in patients with MOGAD (11/42), more frequently with PNS involvement (p = 0.01), and in patients with MS (12/42), more frequently with atypical features (p < 0.001). PLP1-IgG-positive MOGAD had higher EDSS scores (p < 0.001) and PLP1-IgG-positive MS had higher severity scores (MSSS, p < 0.001) compared with those PLP1-IgG-negative. Overall, PLP1-IgG were found in 24.1% of patients with CNS+PNS-ADD, 21.2% with atypical MS, 8.3% with MOGAD, 12.0% with seronegative NMOSD, and 1.4% with typical MS. Their frequency within each diagnostic subgroup was consistent between the exploratory and validation cohorts. PLP1-IgG a) colocalized with their target on CBA-TBA, where their binding was abolished after immunoadsorption and fixation-induced conformational epitope alteration; b) mostly pertained to the IgG1/IgG3 subclass (68.3%) and were able to induce CDC; and c) coreacted with DM20 in all 12 patients with PNS involvement tested. DISCUSSION:Conformational PLP1-IgG predominantly identify patients with non-MS ADDs. They should be tested mainly in those with CNS + PNS ADD, coherently with DM20-IgG coreactivity. PLP1-IgG could also be investigated as disease modifiers and prognostic markers in MS and MOGAD. Preliminary evidence supports their pathogenic potential.

BACKGROUND AND OBJECTIVES:Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) international panel criteria have been recently proposed to guide MOGAD diagnosis. The aim of this study was to evaluate the criteria performance and assess the discrepancies in their application in the clinical practice in an Italian multicenter cohort and to discuss some challenging aspects. METHODS:We applied the 2023 MOGAD criteria to patients who tested MOG-Abs positive on cell-based assays and were retrospectively recruited from 29 centers. Detailed clinical and paraclinical data were collected. Patients were classified as true positive/negative (TP/TN) in case of concordance between MOGAD criteria application and enrolling center final diagnosis, as false positive (FP) when MOGAD criteria were fulfilled but final diagnosis was different from MOGAD, and as false negative (FN) when MOGAD criteria were not fulfilled and final diagnosis of MOGAD was confirmed. Central revision of FN and FP cases was performed. RESULTS:We included 214 patients (median age at onset 38.2 years [interquartile range 25.2-50.7], 60.3% female, 23 pediatric patients). Of these, 168 (78.5%) were classified as TP, 9 (4.2%) as FP, 23 (10.7%) as FN, and 14 (6.5%) as TN. The sensitivity of MOGAD criteria was 87.96% (CI 82.5%-92.2%), specificity 60.9% (CI 38.5%-80.3%), positive predictive value 94.9% (CI 91.8%-96.9%), negative predictive value 37.8% (CI 26.7%-50.2%), and accuracy 85.1% (CI 79.6%-89.5%). In 11 of 32 revised cases, available information did not allow a proper diagnosis. Independent revision changed the diagnosis in 17 of 21 remaining cases, increasing the performance of the MOGAD criteria. Of note, in 3 cases, diagnostic criteria were satisfied only at follow-up. The sensitivity and specificity after independent revision were 98.9% (CI 96%-99.9%) and 91.7% (CI 73%-98.9%), respectively. Moreover, 29 of 214 patients (13.6%) had 1 or more asymptomatic radiologic supportive features, and in 50% (3/6) of FP cases, independent revision did not confirm the presence of supportive features. Patients with clear positive serum titer or CSF-only MOG-Abs were those who received more commonly a MOGAD diagnosis. DISCUSSION:MOGAD criteria demonstrate a good performance across different centers; however, controversial cases might benefit from collegial discussion and reassessment of MOGAD criteria during the follow-up. Main challenges include availability of proper radiologic data and interpretation of radiologic supportive features.

Background Live cell-based assay (LCBA) is the gold standard for MOG-IgG detection, and fixed CBA (FCBA) is a widely used commercial alternative. Recent criteria attributed a diagnostic value to MOG-IgG titration with both LCBA and FCBA, with low-titre samples requiring additional supporting features for MOGAD diagnosis. However, FCBA titration is not validated. We aimed to assess the impact of the criteria-based MOG-IgG testing in MOGAD diagnosis. Methods Thirty-eight serum samples of LCBA MOG-IgG1-positive MOGAD patients were titred on MOG-IgG LCBA and FCBA, and the presence of supporting features for MOGAD assessed. MOGAD criteria were evaluated in four testing scenarios: (a) FCBA without titration; (b) FCBA with titration; c) LCBA without titration; (d) LCBA with titration. Results FCBA without titration failed to reach MOGAD diagnosis in 11/38 patients (28.9%, negative results in 5, lack of supporting features in 6). Patients with unconfirmed diagnosis had optic neuritis (ON, n = 8), or transverse myelitis (TM, n = 3). FCBA with titration allowed MOGAD diagnosis in 4 additional patients. Correlation between LCBA and FCBA titres was moderate (Spearman’s rho 0.6, p < 0.001). Conclusions FCBA yields high rate of misdiagnosis mainly due a lower analytical sensitivity. FCBA titration provides a moderate diagnostic advantage in FCBA positive patients.

BackgroundCerebrospinal fluid myelin oligodendrocyte glycoprotein IgG (CSF MOG-IgG) are found in a proportion of patients with MOG antibody-associated disorder (MOGAD) and have been associated with severe disease presentations. However, most studies did not systematically investigate the role of MOG-IgG intrathecal synthesis (ITS).MethodsWe retrospectively studied 960 consecutive patients with paired serum and CSF samples screened for MOG-IgG using a live cell-based assays. MOG-IgG-specific antibody index (AIMOG) was systematically calculated using serum and CSF titres to assess MOG-IgG ITS, and clinical features were compared between MOG-IgG CSF+/CSF− and ITS+/ITS− patients.ResultsMOG-IgG were found in 55/960 patients (5.7%; serum+/CSF−: 58.2%, serum+/CSF+: 34.5%; serum−/CSF+: 7.3%). Serum/CSF MOG-IgG titres showed a moderate correlation in patients without ITS (ρ=0.47 (CI 0.18 to 0.68), p<0.001), but not in those with ITS (ρ=0.14 (CI −0.46 to –0.65), p=0.65). There were no clinical–paraclinical differences between MOG-IgG CSF+ vs CSF− patients. Conversely, patients with MOG-IgG ITS showed pyramidal symptoms (73% vs 32%, p=0.03), spinal cord involvement (82% vs 39%, p=0.02) and severe outcome at follow-up (36% vs 5%, p=0.02) more frequently than those without MOG-IgG ITS. A multivariate logistic regression model indicated that MOG-IgG ITS was an independent predictor of a poor outcome (OR: 14.93 (CI 1.40 to 19.1); p=0.03). AIMOGcorrelated with Expanded Disability Status Scale (EDSS) scores at disease nadir and at last follow-up (p=0.02 and p=0.01).ConclusionsConsistently with physiopathology, MOG-IgG ITS is a promising prognostic factor in MOGAD, and its calculation could enhance the clinical relevance of CSF MOG-IgG testing, making a case for its introduction in clinical practice.