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Background: Suboptimal performance during neuropsychological assessment renders cognitive test results invalid. However, suboptimal performance has rarely been investigated in multiple sclerosis (MS). Objectives: To investigate potential underlying mechanisms of suboptimal performance in MS. Methods: Performance validity testing, neuropsychological assessments, neuroimaging, and questionnaires were analyzed in 99 MS outpatients with cognitive complaints. Based on performance validity testing patients were classified as valid or invalid performers, and based on neuropsychological test results as cognitively impaired or preserved. Group comparisons and correlational analyses were performed on demographics, patient-reported, and disease-related outcomes. Results: Twenty percent displayed invalid performance. Invalid and valid performers did not differ regarding demographic, patient-reported, and disease-related outcomes. Disease severity of invalid and valid performers with cognitive impairment was comparable, but worse than cognitively preserved valid performers. Lower performance validity scores related to lower cognitive functioning, lower education, being male, and higher disability levels (p < 0.05). Conclusion: Suboptimal performance frequently occurs in patients with MS and cognitive complaints. In both clinical practice and in cognitive research, suboptimal performance should be considered in the interpretation of cognitive outcomes. Identification of factors that differentiate between suboptimal and optimal performers with cognitive impairment needs further exploration. [ABSTRACT FROM AUTHOR]

Background: Early detection and monitoring of cognitive dysfunction in multiple sclerosis (MS) may be enabled with smartphone-adapted tests that allow frequent measurements in the everyday environment. Objectives: The aim of this study was to determine the reliability, construct and concurrent validity of a smartphone-adapted Symbol Digit Modalities Test (sSDMT). Methods: During a 28-day follow-up, 102 patients with MS and 24 healthy controls (HC) used the MS sherpa® app to perform the sSDMT every 3 days on their own smartphone. Patients performed the Brief International Cognitive Assessment for MS at baseline. Test–retest reliability (intraclass correlation coefficients, ICC), construct validity (group analyses between cognitively impaired (CI), cognitively preserved (CP) and HC for differences) and concurrent validity (correlation coefficients) were assessed. Results: Patients with MS and HC completed an average of 23.2 (SD = 10.0) and 18.3 (SD = 10.2) sSDMT, respectively. sSDMT demonstrated high test–retest reliability (ICCs > 0.8) with a smallest detectable change of 7 points. sSDMT scores were different between CI patients, CP patients and HC (all p s < 0.05). sSDMT correlated modestly with the clinical SDMT (highest r = 0.690), verbal (highest r = 0.516) and visuospatial memory (highest r = 0.599). Conclusion: Self-administered smartphone-adapted SDMT scores were reliable and different between patients who were CI, CP and HC and demonstrated concurrent validity in assessing information processing speed. [ABSTRACT FROM AUTHOR]

Background: Literature on the intricate relationship between self-reported and objectively assessed cognitive functioning suggests a discrepancy between self-reported cognitive complaints (SCC) and actual test performance., Objectives: To investigate the interplay between patient-reported outcome measures (PROMs) and objective cognitive functioning using network analysis in people with multiple sclerosis (PwMS)., Methods: We collected PROMs on anxiety, depression, fatigue and SCC, and cognitive functioning across six domains ( n = 703 PwMS; 71% female, mean age = 46.3 ± 11.2 years). We constructed cognitive symptom networks using Gaussian Graphical Models, in which the aforementioned variables were presented as nodes linked by regularized partial correlations. We compared global network strength between relevant subgroups., Results: The networks primarily showed clustering of PROMs and cognitive domains into two separate modules, with weaker links connecting both modules. Global network strength was lower for PwMS with impaired information processing speed (IPS; indicating lower symptom interrelatedness) compared to those with preserved IPS (3.57 versus 4.51, p = 0.001), but not when comparing SCC subgroups ( p = 0.140)., Conclusions: Cognitive symptom networks deepen our understanding of the discrepancy between self-reported and objectively assessed cognitive functioning. Lower symptom interrelatedness in PwMS with impaired IPS might suggest a nonlinear relation between PROMs and cognitive domains, which depends on the cognitive status., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: M.v.D. is supported by a research grant from BMS. I.M.N. is supported by the Dutch MS Research Foundation, grant no. 15-911, and the National MS Foundation. B.A.d.J. reported receiving grants from Dutch MS Research Foundation (project number 15–911) and National MS Foundation. B.A.d.J. is a member of the medical advisory board of the Dutch MS Society, chair of the committee for the revision of the guideline on disease-modifying therapy and MS for the Netherlands Society of Neurology, and chair of the committee of the Dutch National MS registration of the Netherlands Society of Neurology. M.M.S. serves on the editorial board of Neurology and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW (Vidi grant, project number 09150172010056) and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck. B.M.J.U. reported research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva, and Immunic Therapeutics. H.E.H. serves on the editorial board of Multiple Sclerosis Journal, receives research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay, and Merck BV. L.D. serves as an associate editor for Human Brain Mapping and is on the editorial board of the Journal of Neuro-Oncology. J.G.R. and M.K. report no conflict of interest.

Background: Multiple sclerosis (MS) is characterized by extensive tissue damage leading to a range of complex symptoms, including physical disability and cognitive dysfunction. Recent work has indicated the clinical relevance of bioactive lipid mediators (LMs), which are known to orchestrate inflammation and its resolution and are deregulated in MS. However, it is unknown whether LM profiles relate to white matter (WM) damage., Objectives: To investigate the potential association between plasma-derived LMs and MRI-quantified WM damage using fractional anisotropy (FA) and grey matter (GM) atrophy in dimethyl fumarate-treated relapsing remitting MS (RRMS) patients., Methods: Severity of FA-based WM damage and GM atrophy was determined in RRMS patients (n = 28) compared to age- and sex-matched controls (n = 31) at treatment initiation (baseline) and after 6 months. Plasma LMs were assessed using HPLC-MS/MS and baseline LMs were correlated to changes in FA and brain volumes., Results: We observed significant WM damage in RRMS patients (mean age 41.4 [SD 9.1]) at baseline and follow-up (z-score=-0.33 and 0.31, respectively) compared to controls (mean age 41.9 [SD 9.5]; p < 0.001 for both comparisons). Patients with severe WM damage showed a decline of thalamic volume (p = 0.02), and this decline correlated (r = 0.51, p < 0.001) with lower baseline levels of 9-HODE. This LM also predicted FA worsening (beta = 0.14, p < 0.001) over time at 6 months., Conclusion: Despite the relatively small sample size, lower baseline levels of the LM 9-HODE correlated with more thalamic atrophy and predicted subsequent worsening of WM damage in RRMS patients., Competing Interests: Declaration of competing interest W.H. Fung: nothing to disclose; M.R. van Lingen was supported during this study by a research grant of Biogen and currently by MEGIN; J.Y. Broos: nothing to disclose; K.H. Lam: nothing to disclose; M. van Dam is supported by a research grant from BMS; W.K. Fung: nothing to disclose; S. Notenboom: nothing to disclose; I. Koubiyr: nothing to disclose; H.E. de Vries: nothing to disclose; B. Jasperse: nothing to disclose; C.E. Teunissen reports funding from National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR (Horizon 2020, grant no 831,434). CET has a research contract with Celgene. She serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology & Neuroinflammation, and is editor of a Neuromethods book Springer; M. Giera: nothing to disclose; J. Killestein received research grants for multicentre investigator initiated trials DOT-MS trial, ClinicalTrials. gov Identifier: NCT04260711 (ZonMW) and BLOOMS trial (ZonMW and Treatmeds), ClinicalTrials. gov Identifier: NCT05296161); received consulting fees for F. Hoffmann-La Roche, Biogen, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); reports speaker relationships with F. Hoffmann-La Roche, Biogen, Immunic, Teva, Merck, Novartis and Sanofi/Genzyme (all payments to institution); adjudication committee of MS clinical trial of Immunic (payments to institution only); H.E. Hulst is an editor of the Multiple Sclerosis Journal controversies sections, receives research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay and Merck BV; E.M.M. Strijbis serves on the editorial board of Frontiers in Neurology and receives research support from Stichting MS Research and ZonMW. She has received speaker fees from Merck and Novartis. M.M. Schoonheim serves on the editorial board of Neurology, Multiple Sclerosis Journal and Frontiers in Neurology, receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, EIP, Sanofi, MedDay and Merck; Gijs Kooij received research support from Biogen, Novartis and Merck., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: It is unclear how self-reported severe fatigue and difficulty concentrating after SARS-CoV-2 infection relate to objective neuropsychological functioning. The study aimed to compare neuropsychological functioning between individuals with and without these persistent subjective complaints. Method : Individuals with and without persistent severe fatigue (Checklist Individual Strength (CIS) fatigue ≥ 35) and difficulty concentrating (CIS concentration ≥ 18) at least 3 months after SARS-CoV-2 infection were included. Neuropsychological assessment was performed on overall cognitive functioning, attention, processing speed, executive functioning, memory, visuo-construction, and language (18 tests). T-scores -1.5 SD below population normative data ( T  ≤ 35) were classified as "impaired". Results: 230 participants were included in the study, of whom 22 were excluded from the analysis due to invalid performance. Of the participants included in the analysis, 111 reported persistent complaints of severe fatigue and difficulty concentrating and 97 did not. Median age was 54 years, 59% ( n  = 126) were female, and participants were assessed a median of 23 months after first infection (IQR: 16-28). With bivariate logistic regression, individuals with persistent complaints had an increased likelihood of slower information processing speed performance on the Stroop word reading (OR = 2.45, 95%CI = 1.02-5.84) compared to those without persistent complaints. Demographic or clinical covariates (e.g. hospitalization) did not influence this association. With linear regression techniques, persistent complaints were associated with lower t-scores on the D2 CP, TMT B, and TMT B|A. There were no differences in performance on the other neuropsychological tests. Conclusions: Individuals with subjective severe fatigue and difficulty concentrating after COVID-19 do not typically demonstrate cognitive impairment on extensive neuropsychological testing.

Background: The heterogeneous nature of cognitive impairment in people with multiple sclerosis (PwMS) hampers understanding of the underlying mechanisms and developing patient-tailored interventions. We aim to identify and classify cognitive profiles in PwMS, comparing these to cognitive status (preserved versus impaired)., Methods: We included 1213 PwMS (72% female, age 45.4 ± 10.7 years, 83% relapsing-remitting MS). Cognitive test scores were converted to Z-scores compared to healthy controls for the functions: attention, inhibition, information processing speed (IPS), verbal fluency and verbal/visuospatial memory. Concerning cognitive status, impaired cognition (CI) was defined as performing at Z ≤ - 1.5 SD on ≥ 2 functions. Cognitive profiles were constructed using latent profile analysis on all cognitive functions. Cognitive profiles or status was classified using gradient boosting decision trees, providing the importance of each feature (demographics, clinical, cognitive and psychological functioning) for the overall classification., Results: Six profiles were identified, showing variations in overall performance and specific deficits (attention, inhibition, IPS, verbal fluency, verbal memory and visuospatial memory). Across the profiles, IPS was the most impaired function (%CI most preserved profile, Profile 1 = 22.4%; %CI most impaired profile, Profile 6 = 76.6%). Cognitive impairment varied from 11.8% in Profile 1 to 95.3% in Profile 6. Of all cognitive functions, visuospatial memory was most important in classifying profiles and IPS the least (area under the curve (AUC) = 0.910). For cognitive status, IPS was the most important classifier (AUC = 0.997)., Conclusions: This study demonstrated that cognitive heterogeneity in MS reflects a continuum of cognitive severity, distinguishable by distinct cognitive profiles, primarily explained by variations in visuospatial memory functioning., (© 2024. The Author(s).)

Objectives: To study the frequency of isolated (i.e., single-domain) cognitive impairments, domain specific MRI correlates, and its longitudinal development in people with multiple sclerosis (PwMS)., Methods: 348 PwMS (mean age 48 ± 11 years, 67% female, 244RR/52SP/38PP) underwent neuropsychological testing (extended BRB-N) at baseline and at five-year follow-up. At baseline, structural MRI was acquired. Isolated cognitive impairment was defined as a Z-score of at least 1.5 SD below normative data in one domain only (processing speed, memory, executive functioning/working memory, and attention). Multi-domain cognitive impairment was defined as being affected in ≥ 2 domains, and cognitively preserved otherwise. For PwMS with isolated cognitive impairment, MRI correlates were explored using linear regression. Development of isolated cognitive impairment over time was evaluated based on reliable change index., Results: At baseline, 108 (31%) PwMS displayed isolated cognitive impairment, 148 (43%) PwMS displayed multi-domain cognitive impairment. Most PwMS with isolated cognitive impairment were impaired on executive functioning/working memory (EF/WM; N = 37), followed by processing speed (IPS; N = 25), memory (N = 23), and attention (N = 23). Isolated IPS impairment was explained by a model of cortical volume and fractional anisotropy (adj. R 2  = 0.539, p < 0.001); memory by a model with cortical volume and hippocampal volume (adj. R 2  = 0.493, p = 0.002); EF/WM and attention were not associated with any MRI measure. At follow-up, cognitive decline was present in 11/16 (69%) of PwMS with isolated IPS impairment at baseline. This percentage varied between 18 and 31% of PwMS with isolated cognitive impairment in domains other than IPS at baseline., Conclusion: Isolated cognitive impairment is frequently present in PwMS and can serve as a proxy for further decline, particularly when it concerns processing speed. Cortical and deep grey matter atrophy seem to play a pivotal role in isolated cognitive impairment. Timely detection and patient-tailored intervention, predominantly for IPS, may help to postpone further cognitive decline., (© 2024. The Author(s).)

Background: Cognitive treatment response varies highly in people with multiple sclerosis (PwMS). Identification of mechanisms is essential for predicting response., Objectives: This study aimed to investigate whether brain network function predicts response to cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT)., Methods: PwMS with cognitive complaints completed CRT, MBCT, or enhanced treatment as usual (ETAU) and performed three measurements (baseline, post-treatment, 6-month follow-up). Baseline magnetoencephalography (MEG) measures were used to predict treatment effects on cognitive complaints, personalized cognitive goals, and information processing speed (IPS) using mixed models (secondary analysis REMIND-MS study)., Results: We included 105 PwMS (96 included in prediction analyses; 32 CRT, 31 MBCT, 33 ETAU), and 56 healthy controls with baseline MEG. MEG did not predict reductions in complaints. Higher connectivity predicted better goal achievement after MBCT (p = 0.010) and CRT (p = 0.018). Lower gamma power (p = 0.006) and higher connectivity (p = 0.020) predicted larger IPS benefits after MBCT. These MEG predictors indicated worse brain function compared to healthy controls (p < 0.05)., Conclusions: Brain network function predicted better cognitive goal achievement after MBCT and CRT, and IPS improvements after MBCT. PwMS with neuronal slowing and hyperconnectivity were most prone to show treatment response, making network function a promising tool for personalized treatment recommendations., Trial Registration: The REMIND-MS study was prospectively registered in the Dutch Trial registry (NL6285; https://trialsearch.who.int/Trial2.aspx?TrialID=NTR6459 )., (© 2024. The Author(s).)

Background: Cognitive phenotyping may be useful for predicting rehabilitation response in multiple sclerosis., Objective: To evaluate the association between cognitive phenotype(s) and response to restorative cognitive rehabilitation (RRCR)., Methods: In a post hoc retrospective analysis of the RRCR study including 51 multiple sclerosis patients, we evaluated both impairment within specific cognitive domains as well as overall global impairment severity to investigate their relationship to improvement following rehabilitation., Results: Greater improvement in executive function was predicted by impairment within this domain as well as by having fewer impaired cognitive domains overall. Similar results were observed for visuospatial memory., Conclusions: Patients most likely to benefit from restorative cognitive rehabilitation may exhibit impairment within the domain of interest yet lower cognitive burden overall., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.Z. and T.F. have nothing to disclose. M.G.D. received grant support from Novartis, Bristol Myers Squibb, Mapi Pharma, Merck Serono, Keystone Heart Ltd., Protembis GmbH, and V-Wave Ltd. and consulting fees from Bristol Myers Squibb, Merck Serono, and Keystone Heart Ltd. R.Z. has received personal compensation from Bristol Myers Squibb, EMD Serono, Sanofi, Janssen, Sanofi, 415 Capital, Filterlex, and Mapi Pharma for speaking and as consultant fees. He received financial support for research activities from Novartis, Bristol Myers Squibb, EMD Serono, Octave, Mapi Pharma, CorEvitas, Protembis, and V-WAVE Medical. H.E.H. is an editor of the Multiple Sclerosis Journal controversies sections and receives research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay, and Merck BV. M.C. received honoraria for research or speaking and funds for travel from Roche, Sanofi Genzyme, Merck Serono, Biogen Idec, Teva, and Novartis Pharma. R.H.B.B. received research support from Biogen, Bristol Meyers Squibb, Novartis, National Institute of Health, and National Multiple Sclerosis Society; consultant fees from Bristol Meyers Squibb, Novartis, Roche, Sanofi; speaking fees from Bristol Meyers Squibb, EMD Serono; and royalties for Psychological Assessment Resources.

Objective: To examine the energy demand of walking relative to aerobic capacity in people with multiple sclerosis., Design: Cross-sectional cohort study., Patients: A total of 45 people with multiple sclerosis (32 females), median disease duration 15 years (interquartile range (IQR) 9; 20), median Expanded Disability Status Scale 4 (min-max range: 2.0; 6.0)., Methods: Aerobic capacity, derived from a cardiopulmonary exercise test and gas exchange measurements, assessed during a 6-min overground walk test at comfortable speed, were analysed. The relative aerobic load of walking was determined as the energy demand of walking relative to oxygen uptake at peak and at the first ventilatory threshold. Healthy reference data were used for clinical inference., Results: People with multiple sclerosis walk at a mean relative aerobic load of 60.0% (standard deviation 12.8%) relative to peak aerobic capacity, and 89.1% (standard deviation 19.9%) relative to the first ventilatory threshold. Fourteen participants walked above the first ventilatory threshold (31%). Peak aerobic capacity was reduced in 45% of participants, and energy demands were increased in 52% of participants., Conclusion: People with multiple sclerosis walk at a relative aerobic load close to their first ventilatory threshold. A high relative aerobic load can guide clinicians to improve aerobic capacity or reduce the energy demands of walking.

Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: P.T.W. has no conflict of interest regarding this publication. M.F.L.R. has no conflict of interest regarding this publication. H.E.H. is an editor of the Multiple Sclerosis Journal controversies sections, who received research support from the Dutch MS Research Foundation and the Dutch Research Council. She has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Novartis, Celgene/Bristol Meyers Squibb, Sanofi Genzyme, MedDay, and Merck BV.

During the course of multiple sclerosis, many patients experience cognitive deficits which are not simply driven by lesion number or location. By considering the full complexity of white matter structure at macro- and microstructural levels, our understanding of cognitive impairment in multiple sclerosis may increase substantially. Accordingly, this study aimed to investigate specific patterns of white matter degeneration, the evolution over time, the manifestation across different stages of the disease and their role in cognitive impairment using a novel fixel-based approach. Neuropsychological test scores and MRI scans including 30-direction diffusion-weighted images were collected from 327 multiple sclerosis patients (mean age = 48.34 years, 221 female) and 95 healthy controls (mean age = 45.70 years, 55 female). Of those, 233 patients and 61 healthy controls had similar follow-up assessments 5 years after. Patients scoring 1.5 or 2 standard deviations below healthy controls on at least two out of seven cognitive domains (from the Brief Repeatable Battery of Neuropsychological Tests, BRB-N) were classified as mildly cognitively impaired or cognitively impaired, respectively, or otherwise cognitively preserved. Fixel-based analysis of diffusion data was used to calculate fibre-specific measures (fibre density, reflecting microstructural diffuse axonal damage; fibre cross-section, reflecting macrostructural tract atrophy) within atlas-based white matter tracts at each visit. At baseline, all fixel-based measures were significantly worse in multiple sclerosis compared with healthy controls ( P < 0.05). For both fibre density and fibre cross-section, a similar pattern was observed, with secondary progressive multiple sclerosis patients having the most severe damage, followed by primary progressive and relapsing-remitting multiple sclerosis. Similarly, damage was least severe in cognitively preserved ( n = 177), more severe in mildly cognitively impaired ( n = 63) and worst in cognitively impaired ( n = 87; P < 0.05). Microstructural damage was most pronounced in the cingulum, while macrostructural alterations were most pronounced in the corticospinal tract, cingulum and superior longitudinal fasciculus. Over time, white matter alterations worsened most severely in progressive multiple sclerosis ( P < 0.05), with white matter atrophy progression mainly seen in the corticospinal tract and microstructural axonal damage worsening in cingulum and superior longitudinal fasciculus. Cognitive decline at follow-up could be predicted by baseline fixel-based measures ( R 2 = 0.45, P < 0.001). Fixel-based approaches are sensitive to white matter degeneration patterns in multiple sclerosis and can have strong predictive value for cognitive impairment. Longitudinal deterioration was most marked in progressive multiple sclerosis, indicating that degeneration in white matter remains important to characterize further in this phenotype., Competing Interests: I.K. received research grants from LabEx TRAIL (Translational Research and Advanced Imaging Laboratory) and ARSEP (Fondation pour l'Aide à la Recherche sur la Sclérose En Plaques). He received speakers’ honoraria from Celgene. E.A.K. report no conflicts of interests. A.J.C.E. reports no conflicts of interests. I.D. has received speaking honoraria from Roche. H.E.H receives research support from the Dutch MS Research Foundation, ZonMW, NWO, ATARA, Biogen, Celgene/BMS, Merck and MedDay; serves as a consultant for Sanofi Genzyme, Merck BV, Biogen Idec, Roche and Novartis; and received honorary from these parties paid to her institution. She is on the editorial board of Multiple Sclerosis Journal. B.M.J.U. reports research support and/or consultancy fees from Biogen Idec, Genzyme, Merck Serono, Novartis, Roche, Teva and Immunic Therapeutics. F.B. is in the steering committee and iDMC member for Biogen, Merck, Roche and EISAI; a consultant for Roche, Biogen, Merck, IXICO, Jansen and Combinostics; has research agreements with Novartis, Merck, Biogen, GE and Roche; and is a co-founder and shareholder of Queen Square Analytics LTD. J.J.G.G. has received research support or compensation for consulting services from the Dutch MS Research Foundation, Ammodo, Eurostars-EUREKA, Biogen, Celgene/BMS, Merck, MedDay, Novartis and Sanofi Genzyme. M.M.S. serves on the editorial board of Neurology and Frontiers in Neurology; receives research support from the Dutch MS Research Foundation, Eurostars-EUREKA, ARSEP, Amsterdam Neuroscience, MAGNIMS and ZonMW; and has served as a consultant for or received research support from Atara Biotherapeutics, Biogen, Celgene/Bristol Meyers Squibb, Genzyme, MedDay and Merck., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Up to 65% of people with multiple sclerosis (PwMS) develop cognitive deficits, which hampers their ability to work, participating in day-to-day life and ultimately reducing quality of life (QoL). Early cognitive symptoms are often less tangible to PwMS and their direct environment and are noticed only when symptoms and work functioning problems become more advanced, i.e., when (brain) damage is already advanced. Treatment of symptoms at a late stage can lead to cognitive impairment and unemployment, highlighting the need for preventative interventions in PwMS., Aims: This study aims to evaluate the (cost-) effectiveness of two innovative preventative interventions, aimed at postponing cognitive decline and work functioning problems, compared to enhanced usual care in improving health-related QoL (HRQoL)., Methods: Randomised controlled trial including 270 PwMS with mild cognitive impairment, who have paid employment ≥ 12 h per week and are able to participate in physical exercise (Expanded Disability Status Scale < 6.0). Participants are randomised across three study arms: 1) 'strengthening the brain' - a lifestyle intervention combining personal fitness, mental coaching, dietary advice, and cognitive training; 2) 'strengthening the mind' - a work-focused intervention combining the capability approach and the participatory approach in one-on-one coaching by trained work coaches who have MS themselves; 3) Control group-receiving general information about cognitive impairment in MS and receiving care as usual. Intervention duration is four months, with short-term and long-term follow-up measurements at 10 and 16 months, respectively. The primary outcome measure of the Don't be late! intervention study will be HRQoL as measured with the 36-item Short Form. Secondary outcomes include cognition, work related outcomes, physical functioning, structural and functional brain changes, psychological functioning, and societal costs. Semi-structured interviews and focus groups with stakeholders will be organised to qualitatively reflect on the process and outcome of the interventions., Discussion: This study seeks to prevent (further) cognitive decline and job loss due to MS by introducing tailor-made interventions at an early stage of cognitive symptoms, thereby maintaining or improving HRQoL. Qualitative analyses will be performed to allow successful implementation into clinical practice., Trial Registration: Retrospectively registered at ClinicalTrials.gov with reference number NCT06068582 on 10 October 2023., (© 2024. The Author(s).)

Background: Cognitive impairment occurs in up to 65% of people with multiple sclerosis (PwMS), negatively affecting daily functioning and health-related quality of life. In general, neuropsychological testing is not part of standard MS-care due to insufficient time and trained personnel. Consequently, a baseline assessment of cognitive functioning is often lacking, hampering early identification of cognitive decline and change within a person over time. To assess cognitive functioning in PwMS in a time-efficient manner, a BICAMS-based self-explanatory digital screening tool called the Multiple Screener © , has recently been developed. The aim of the current study is to validate the Multiple Screener © in a representative sample of PwMS in the Netherlands. Additionally, we aim to investigate how cognitive functioning is related to psychological factors, and both work and societal participation., Methods: In this cross-sectional multicentre study, 750 PwMS (aged 18-67 years) are included. To obtain a representative sample, PwMS are recruited via 12 hospitals across the Netherlands. They undergo assessment with the Minimal Assessment of Cognitive Functioning in MS (MACFIMS; reference-standard) and the Multiple Screener © . Sensitivity, specificity, and predictive values for identifying (mild) cognitive impairment are determined in a subset of 300 participants. In a second step, the identified cut-off values are tested in an independent subset of at least 150 PwMS. Moreover, test-retest reliability for the Multiple Screener © is determined in 30 PwMS. Information on psychological and work-related factors is assessed with questionnaires., Discussion: Validating the Multiple Screener © in PwMS and investigating cognition and its determinants will further facilitate early identification and adequate monitoring of cognitive decline in PwMS., (© 2024. The Author(s).)

Background: Multiple sclerosis (MS) is characterized by pathology in white matter (WM) and atrophy of grey matter (GM), but it remains unclear how these processes are related, or how they influence clinical progression., Objective: To study the spatial and temporal relationship between GM atrophy and damage in connected WM in relapsing-remitting (RR) MS in relation to clinical progression., Methods: Healthy control (HC) and early RRMS subjects visited our center twice with a 1-year interval for MRI and clinical examinations, including the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) scores. RRMS subjects were categorized as MSFC decliners or non-decliners based on ΔMSFC over time. Ten deep (D)GM and 62 cortical (C) GM structures were segmented and probabilistic tractography was performed to identify the connected WM. WM integrity was determined per tract with, amongst others, fractional anisotropy (FA), mean diffusivity (MD), neurite density index (NDI), and myelin water fraction (MWF). Linear mixed models (LMMs) were used to investigate GM and WM differences between HC and RRMS, and between MSFC decliners and non-decliners. LMM was also used to test associations between baseline WM z-scores and changes in connected GM z-scores, and between baseline GM z-scores and changes in connected WM z-scores, in HC/RRMS subjects and in MSFC decliners/non-decliners., Results: We included 13 HCs and 31 RRMS subjects with an average disease duration of 3.5 years and a median EDSS of 3.0. Fifteen RRMS subjects showed declining MSFC scores over time, and they showed higher atrophy rates and greater WM integrity loss compared to non-decliners. Lower baseline WM integrity was associated with increased CGM atrophy over time in RRMS, but not in HC subjects. This effect was only seen in MSFC decliners, especially when an extended WM z-score was used, which included FA, MD, NDI and MWF. Baseline GM measures were not significantly related to WM integrity changes over time in any of the groups., Discussion: Lower baseline WM integrity was related to more cortical atrophy in RRMS subjects that showed clinical progression over a 1-year follow-up, while baseline GM did not affect WM integrity changes over time. WM damage, therefore, seems to drive atrophy more than conversely., (© 2023. The Author(s).)

Background: Cognitive impairment in people with MS (PwMS) has primarily been investigated using conventional imaging markers or fluid biomarkers of neurodegeneration separately. However, the single use of these markers do only partially explain the large heterogeneity found in PwMS., Objective: To investigate the use of multimodal (bio)markers: i.e., serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and conventional imaging markers in predicting cognitive functioning in PwMS., Methods: Eighty-two PwMS (56 females, disease duration = 14 ± 9 years) underwent neuropsychological and neurological examination, structural magnetic resonance imaging, blood sampling and lumbar puncture. PwMS were classified as cognitively impaired (CI) if scoring ≥ 1.5SD below normative scores on ≥ 20% of test scores. Otherwise, PwMS were defined as cognitively preserved (CP). Association between fluid and imaging (bio)markers were investigated, as well as binary logistics regression to predict cognitive status. Finally, a multimodal marker was calculated using statistically important predictors of cognitive status., Results: Only higher NfL levels (in serum and CSF) correlated with worse processing speed (r = - 0.286, p = 0.012 and r = - 0.364, p = 0.007, respectively). sNfL added unique variance in the prediction of cognitive status on top of grey matter volume (NGMV), p = 0.002). A multimodal marker of NGMV and sNfL yielded most promising results in predicting cognitive status (sensitivity = 85%, specificity = 58%)., Conclusion: Fluid and imaging (bio)markers reflect different aspects of neurodegeneration and cannot be used interchangeably as markers for cognitive functioning in PwMS. The use of a multimodal marker, i.e., the combination of grey matter volume and sNfL, seems most promising for detecting cognitive deficits in MS., (© 2023. The Author(s).)

Background: Suboptimal performance during neuropsychological testing frequently occurs in multiple sclerosis (MS), leading to unreliable cognitive outcomes. Neurophysiological alterations correlate with MS-related cognitive impairment, but studies have not yet considered performance validity., Objectives: To investigate neurophysiological markers of cognitive impairment in MS, while explicitly addressing performance validity., Methods: Magnetoencephalography recordings, neuropsychological assessments, and performance validity testing were obtained from 90 MS outpatients with cognitive complaints. Spectral and resting-state functional connectivity (rsFC) properties were compared between cognitively impaired (CI), cognitively preserved (CP), and suboptimally performing (SUB) patients using regression models and permutation testing., Results: CI had higher power in low-frequency bands and lower power in high bands compared to CP, indicating neuronal slowing. CI also showed lower beta power compared to SUB. Overall power spectra visually differed between CI and CP, and SUB showed overlap with both groups. CI had lower rsFC than CP and SUB patients. CP and SUB patients showed no differences., Conclusion: Neuronal slowing and altered rsFC can be considered cognitive markers in MS. Patients who performed suboptimally showed resemblance with patients with and without cognitive impairments, and although their overall neurophysiological profile was more similar to patients without impairments, it suggests heterogeneity regarding their pathophysiology.

Introduction: The risk factors for persistent fatigue and cognitive complaints after infection with SARS-CoV-2 and the underlying pathophysiology are largely unknown. Both clinical factors and cognitive-behavioural factors have been suggested to play a role in the perpetuation of complaints. A neurobiological aetiology, such as neuroinflammation, could be the underlying pathophysiological mechanism for persisting complaints.To unravel factors associated with persisting complaints, VeCosCO will compare individuals with and without persistent fatigue and cognitive complaints >3 months after infection with SARS-CoV-2. The study consists of two work packages. The first work package aims to (1) investigate the relation between persisting complaints and neuropsychological functioning; (2) determine risk factors and at-risk phenotypes for the development of persistent fatigue and cognitive complaints, including the presence of postexertional malaise and (3) describe consequences of persistent complaints on quality of life, healthcare consumption and physical functioning. The second work package aims to (1) determine the presence of neuroinflammation with [ 18 F]DPA-714 whole-body positron emission tomography (PET) scans in patients with persisting complaints and (2) explore the relationship between (neuro)inflammation and brain structure and functioning measured with MRI., Methods and Analysis: This is a prospective case-control study in participants with and without persistent fatigue and cognitive complaints, >3 months after laboratory-confirmed SARS-CoV-2 infection. Participants will be mainly included from existing COVID-19 cohorts in the Netherlands covering the full spectrum of COVID-19 acute disease severity. Primary outcomes are neuropsychological functioning, postexertional malaise, neuroinflammation measured using [ 18 F]DPA-714 PET, and brain functioning and structure using (f)MRI., Ethics and Dissemination: Work package 1 (NL79575.018.21) and 2 (NL77033.029.21) were approved by the medical ethical review board of the Amsterdam University Medical Centers (The Netherlands). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in peer-reviewed journals and shared with the key population., Competing Interests: Competing interests: FB: Steering committee or iDMC member for Biogen, Merck, Roche, EISAI and Prothena. Consultant for Roche, Biogen, Merck, IXICO, Jansen, Combinostics. Research agreements with Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Cognitive impairment occurs in 40-65% of persons with multiple sclerosis and may be related to alterations in glutamatergic and GABAergic neurotransmission. Therefore, the aim of this study was to determine how glutamatergic and GABAergic changes relate to cognitive functioning in multiple sclerosis in vivo . Sixty persons with multiple sclerosis (mean age 45.5 ± 9.6 years, 48 females, 51 relapsing-remitting multiple sclerosis) and 22 age-matched healthy controls (45.6 ± 22.0 years, 17 females) underwent neuropsychological testing and MRI. Persons with multiple sclerosis were classified as cognitively impaired when scoring at least 1.5 standard deviations below normative scores on ≥30% of tests. Glutamate and GABA concentrations were determined in the right hippocampus and bilateral thalamus using magnetic resonance spectroscopy. GABA-receptor density was assessed using quantitative [ 11 C]flumazenil positron emission tomography in a subset of participants. Positron emission tomography outcome measures were the influx rate constant (a measure predominantly reflecting perfusion) and volume of distribution, which is a measure of GABA-receptor density. Twenty persons with multiple sclerosis (33%) fulfilled the criteria for cognitive impairment. No differences were observed in glutamate or GABA concentrations between persons with multiple sclerosis and healthy controls, or between cognitively preserved, impaired and healthy control groups. Twenty-two persons with multiple sclerosis (12 cognitively preserved and 10 impaired) and 10 healthy controls successfully underwent [ 11 C]flumazenil positron emission tomography. Persons with multiple sclerosis showed a lower influx rate constant in the thalamus, indicating lower perfusion. For the volume of distribution, persons with multiple sclerosis showed higher values than controls in deep grey matter, reflecting increased GABA-receptor density. When comparing cognitively impaired and preserved patients to controls, the preserved group showed a significantly higher volume of distribution in cortical and deep grey matter and hippocampus. Positive correlations were observed between both positron emission tomography measures and information processing speed in the multiple sclerosis group only. Whereas concentrations of glutamate and GABA did not differ between multiple sclerosis and control nor between cognitively impaired, preserved and control groups, increased GABA-receptor density was observed in preserved persons with multiple sclerosis that was not seen in cognitively impaired patients. In addition, GABA-receptor density correlated to cognition, in particular with information processing speed. This could indicate that GABA-receptor density is upregulated in the cognitively preserved phase of multiple sclerosis as a means to regulate neurotransmission and potentially preserve cognitive functioning., Competing Interests: M. Huiskamp receives research support from the Dutch MS Research Foundation. Prof. Dr. Killestein reports speaker and consulting fees and grants from Biogen, Celgene, Genzyme, Immunic, Merck, Novartis, Roche, Sanofi and Teva. Prof. Dr. van Berckel has received research support from EU-FP7, CTMM, ZonMw, NWO and Alzheimer Nederland. BvB has performed contract research for Rodin, IONIS, AVID, Eli Lilly, UCB, DIAN-TUI and Janssen. BvB was a speaker at a symposium organized by Springer Healthcare. BvB has a consultancy agreement with IXICO for the reading of PET scans. BvB is a trainer for GE. BvB only receives financial compensation from Amsterdam UMC. Prof. Dr. Geurts has served as a consultant for Merck-Serono, Biogen, Novartis, Genzyme and Teva Pharmaceuticals; he has received research support from the Dutch MS Research Foundation, Ammodo, Eurostars-EUREKA, Biogen, Celgene/BMS, Merck, MedDay and Novartis. Prof. Dr. Hulst receives research support from Dutch MS Research Foundation, ZonMW, NWO, ATARA, Biogen, Celgene/BMS, Merck and Medday, serves as a consultant for Sanofi Genzyme, Merck BV, Biogen Idec, Roche and Novartis and is on the editorial board of Multiple Sclerosis Journal. Other authors report no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Neuroinflammation and neurodegeneration are pathological hallmarks of multiple sclerosis (MS). Brain-derived neurotrophic factor (BDNF), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are blood-based biomarkers for neurogenesis, axonal damage and astrocyte reactivity, respectively. We hypothesize that exercise has a neuroprotective effect on MS reflected by normalization of BDNF, NfL and GFAP levels., Objectives: To investigate the neuroprotective effect of aerobic training (AT) compared to a control intervention on blood-based biomarkers (i.e. BDNF, NfL, GFAP) in people with MS (pwMS)., Methods: In the TREFAMS-AT (Treating Fatigue in Multiple Sclerosis - Aerobic Training) study, 89 pwMS were randomly allocated to either a 16-week AT intervention or a control intervention (3 visits to a MS nurse). In this secondary analysis, blood-based biomarker concentrations were measured in 55 patients using Simoa technology. Changes in pre- and post-intervention concentrations were compared and between-group differences were assessed using analysis of covariance (ANCOVA). Confounding effects of age, sex, MS-related disability assessed using the Expanded Disability Status Scale (EDSS), MS duration, use of disease-modifying medication, and Body Mass Index were considered., Results: Blood samples were available for 30 AT and 25 control group participants (mean age 45.6 years, 71% female, median disease duration 8 years, median EDSS score 2.5). Within-group changes in both study groups were small and non-significant, with the exception of BDNF in the control group (median (interquartile range) -2.1 (-4.7; 0)). No between-group differences were found for any biomarker: BDNF (β = 0.11, 95%CI (-3.78 to 4.00)), NfL (β = -0.04, 95%CI (-0.26 to 0.18)), and GFAP (β = -0.01, 95%CI (-0.16 to 0.15)), adjusted for confounders., Conclusion: Aerobic exercise therapy did not result in statistically significant changes in the tested neuro-specific blood-based biomarkers in people with MS., Trial Registration: this study is registered under number ISRCTN69520623 (https://www.isrctn.com/ISRCTN695206)., Competing Interests: Declaration of Competing Interest HH receives research support from the ZonMW, NWO, ATARA, Biogen, Celgene/BMS, Merck and MedDay and serves as a consultant for Sanofi Genzyme, Merck BV, Biogen Idec, Roche and Novartis, and received honorary from these parties paid to her institution. She serves on the editorial board of Multiple Sclerosis Journal. CT receives research support from the National MS Society (Progressive MS alliance) and Innovative Medicines Initiatives 3TR, has a research contract with Celgene. She serves on editorial boards of Medidact Neurologie/Springer, Neurology: Neuroimmunology & Neuroinflammation. She is editor of a Neuromethods book Springer. VG, HB, AG, EW, BJ declare to have no competing interests., (Copyright © 2022. Published by Elsevier B.V.)

Background: Unemployment is common among people with multiple sclerosis (pwMS) and has been associated with subjective cognitive difficulties, specifically in memory, attention, and executive functioning. However, longitudinal research on subjective cognitive difficulties and employment is scarce., Objective: We investigated whether subjective cognitive impairment (SCI), based on the clinical cut-off score of the MS Neuropsychological Screening Questionnaire (MSNQ), was associated with work status and negative work events (NWE) at baseline and after 2 years. Moreover, we investigated whether four MSNQ subdomains were related to work status and NWE., Methods: 287 participants (77.4% female, median age = 42 years) completed questionnaires on subjective cognitive functioning, depression, anxiety, and fatigue, and completed the Symbol Digit Modalities Test (SDMT). After baseline comparisons, logistic regression analyses were performed, with work status and NWE at baseline, and employment change and NWE change within 2 years after baseline as dependent variables. Independent variables included SCI and the MSNQ domains. Covariates anxiety, depression, fatigue, and SDMT were added., Results: SCI, depression and anxiety were associated with work status ( Nagelkerke R 2 = .286), but only SCI was associated with employment change ( Nagelkerke R 2 = .164). No predictors were associated with NWE at baseline or follow-up. In addition, no MSNQ subdomain was related to work status, employment change or NWE., Conclusion: Unemployed pwMS and pwMS with a deteriorated work status reported more cognitive difficulties after 2 years than employed pwMS or pwMS with a stable work status. In addition, depression, and anxiety were associated with work status., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Background: Cognitive training elicits mild-to-moderate improvements in cognitive functioning in people with multiple sclerosis (PwMS), although response heterogeneity limits overall effectiveness., Objective: To identify patient characteristics associated with response and non-response to cognitive training., Methods: Eighty-two PwMS were randomized into a 7-week attention training ( n  = 58, age = 48.4 ± 10.2 years) or a waiting-list control group ( n  = 24, age = 48.5 ± 9.4 years). Structural and functional magnetic resonance imaging (MRI) was obtained at baseline and post-intervention. Twenty-one healthy controls (HCs, age = 50.27 ± 10.15 years) were included at baseline. Responders were defined with a reliable change index of 1.64 on at least 2/6 cognitive domains. General linear models and logistic regression were applied., Results: Responders ( n  = 36) and non-responders ( n  = 22) did not differ on demographics, clinical variables and baseline cognition and structural MRI. However, non-responders exhibited a higher baseline functional connectivity (FC) between the default-mode network (DMN) and the ventral attention network (VAN), compared with responders ( p  = 0.018) and HCs ( p  = 0.001). Conversely, responders exhibited no significant baseline differences in FC compared with HCs. Response to cognitive training was predicted by lower DMN-VAN FC ( p  = 0.004) and DMN-frontoparietal FC ( p  = 0.029) (Nagelkerke R 2  = 0.25)., Conclusion: An intact pre-intervention FC is associated with cognitive training responsivity in pwMS, suggesting a window of opportunity for successful cognitive interventions.

Background: Synaptic and neuronal loss contribute to network dysfunction and disability in multiple sclerosis (MS). However, it is unknown whether excitatory or inhibitory synapses and neurons are more vulnerable and how their losses impact network functioning., Objective: To quantify excitatory and inhibitory synapses and neurons and to investigate how synaptic loss affects network functioning through computational modeling., Methods: Using immunofluorescent staining and confocal microscopy, densities of glutamatergic and GABAergic synapses and neurons were compared between post-mortem MS and non-neurological control cases. Then, a corticothalamic biophysical model was employed to study how MS-induced excitatory and inhibitory synaptic loss affect network functioning., Results: In layer VI of normal-appearing MS cortex, excitatory and inhibitory synaptic densities were significantly lower than controls (reductions up to 14.9%), but demyelinated cortex showed larger losses of inhibitory synapses (29%). In our computational model, reducing inhibitory synapses impacted the network most, leading to a disinhibitory increase in neuronal activity and connectivity., Conclusion: In MS, excitatory and inhibitory synaptic losses were observed, predominantly for inhibitory synapses in demyelinated cortex. Inhibitory synaptic loss affected network functioning most, leading to increased neuronal activity and connectivity. As network disinhibition relates to cognitive impairment, inhibitory synaptic loss seems particularly relevant in MS.

Objective. Machine Learning methods can learn how to reconstruct magnetic resonance images (MRI) and thereby accelerate acquisition, which is of paramount importance to the clinical workflow. Physics-informed networks incorporate the forward model of accelerated MRI reconstruction in the learning process. With increasing network complexity, robustness is not ensured when reconstructing data unseen during training. We aim to embed data consistency (DC) in deep networks while balancing the degree of network complexity. While doing so, we will assess whether either explicit or implicit enforcement of DC in varying network architectures is preferred to optimize performance. Approach. We propose a scheme called Cascades of Independently Recurrent Inference Machines (CIRIM) to assess DC through unrolled optimization. Herein we assess DC both implicitly by gradient descent and explicitly by a designed term. Extensive comparison of the CIRIM to compressed sensing as well as other Machine Learning methods is performed: the End-to-End Variational Network (E2EVN), CascadeNet, KIKINet, LPDNet, RIM, IRIM, and UNet. Models were trained and evaluated on T 1 -weighted and FLAIR contrast brain data, and T 2 -weighted knee data. Both 1D and 2D undersampling patterns were evaluated. Robustness was tested by reconstructing 7.5× prospectively undersampled 3D FLAIR MRI data of multiple sclerosis (MS) patients with white matter lesions. Main results. The CIRIM performed best when implicitly enforcing DC, while the E2EVN required an explicit DC formulation. Through its cascades, the CIRIM was able to score higher on structural similarity and PSNR compared to other methods, in particular under heterogeneous imaging conditions. In reconstructing MS patient data, prospectively acquired with a sampling pattern unseen during model training, the CIRIM maintained lesion contrast while efficiently denoising the images. Significance. The CIRIM showed highly promising generalization capabilities maintaining a very fair trade-off between reconstructed image quality and fast reconstruction times, which is crucial in the clinical workflow., (Creative Commons Attribution license.)

Cognitive deficits strongly affect the quality of life of patients with multiple sclerosis (MS). However, no cognitive MS biomarkers are currently available. Extracellular vesicles (EVs) contain markers of parental cells and are able to pass from the brain into blood, representing a source of disease biomarkers. The aim of this study was to investigate whether small non-coding microRNAs (miRNAs) targeting synaptic genes and packaged in plasma EVs may reflect cognitive deficits in MS patients. Total EVs were precipitated by Exoquick from the plasma of twenty-six cognitively preserved (CP) and twenty-three cognitively impaired (CI) MS patients belonging to two independent cohorts. Myeloid EVs were extracted by affinity capture from total EVs using Isolectin B4 (IB4). Fourteen miRNAs targeting synaptic genes were selected and measured by RT-PCR in both total and myeloid EVs. Myeloid EVs from CI patients expressed higher levels of miR-150-5p and lower levels of let-7b-5p compared to CP patients. Stratification for progressive MS (PMS) and relapsing-remitting MS (RRMS) and correlation with clinical parameters suggested that these alterations might be attributable to cognitive deficits rather than disease progression. This study identifies miR-150-5p and let-7b-5p packaged in blood myeloid EVs as possible biomarkers for cognitive deficits in MS.

Background: Conscientiousness is a personality trait that declines in people with multiple sclerosis (PwMS) and its decline predicts worse clinical outcomes. This study aims to investigate the neural underpinnings of lower Conscientiousness in PwMS by examining MRI anomalies in functional network dynamics., Methods: 70 PwMS and 50 healthy controls underwent personality assessment and resting-state MRI. Associations with dynamic functional network properties (i.e., eigenvector centrality) were evaluated, using a dynamic sliding-window approach., Results: In PwMS, lower Conscientiousness was associated with increased variability of centrality in the left insula (t max  = 4.21) and right inferior parietal lobule (t max  = 3.79); a relationship also observed in regressions accounting for handedness, disease duration, disability, and tract disruption in relevant structural networks (ΔR 2  = 0.071, p = 0.003; ΔR 2  = 0.094, p = 0.004). Centrality dynamics of the observed regions were not associated with Neuroticism (R 2  < 0.001, p = 0.956; R 2  < 0.001, p = 0.945). As well, higher Conscientiousness was associated with greater variability in connectivity for the left insula with the default-mode network (F = 3.92, p = 0.023) and limbic network (F = 5.66, p = 0.005)., Conclusion: Lower Conscientiousness in PwMS was associated with increased variability in network centrality, most prominently for the left insula and right inferior parietal cortex. This effect, specific to Conscientiousness and significant after accounting for disability and structural network damage, could indicate that overall stable network centrality is lost in patients with low Conscientiousness, especially for the insula and right parietal cortex. The positive relationship between Conscientiousness and variability of connectivity between left insula and default-mode network potentially affirms that dynamics between the salience and default-mode networks is related to the regulation of behavior., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Cognitive impairment is common in people with multiple sclerosis and strongly affects their daily functioning. Reports have linked disturbed cognitive functioning in multiple sclerosis to changes in the organization of the functional network. In a healthy brain, communication between brain regions and which network a region belongs to is continuously and dynamically adapted to enable adequate cognitive function. However, this dynamic network adaptation has not been investigated in multiple sclerosis, and longitudinal network data remain particularly rare. Therefore, the aim of this study was to longitudinally identify patterns of dynamic network reconfigurations that are related to the worsening of cognitive decline in multiple sclerosis. Resting-state functional MRI and cognitive scores (expanded Brief Repeatable Battery of Neuropsychological tests) were acquired in 230 patients with multiple sclerosis and 59 matched healthy controls, at baseline (mean disease duration: 15 years) and at 5-year follow-up. A sliding-window approach was used for functional MRI analyses, where brain regions were dynamically assigned to one of seven literature-based subnetworks. Dynamic reconfigurations of subnetworks were characterized using measures of promiscuity (number of subnetworks switched to), flexibility (number of switches), cohesion (mutual switches) and disjointedness (independent switches). Cross-sectional differences between cognitive groups and longitudinal changes were assessed, as well as relations with structural damage and performance on specific cognitive domains. At baseline, 23% of patients were cognitively impaired (≥2/7 domains Z  < -2) and 18% were mildly impaired (≥2/7 domains Z  < -1.5). Longitudinally, 28% of patients declined over time (0.25 yearly change on ≥2/7 domains based on reliable change index). Cognitively impaired patients displayed more dynamic network reconfigurations across the whole brain compared with cognitively preserved patients and controls, i.e. showing higher promiscuity ( P  = 0.047), flexibility ( P  = 0.008) and cohesion ( P  = 0.008). Over time, cognitively declining patients showed a further increase in cohesion ( P  = 0.004), which was not seen in stable patients ( P  = 0.544). More cohesion was related to more severe structural damage (average r  = 0.166, P  = 0.015) and worse verbal memory ( r  = -0.156, P  = 0.022), information processing speed ( r  = -0.202, P  = 0.003) and working memory ( r  = -0.163, P  = 0.017). Cognitively impaired multiple sclerosis patients exhibited a more unstable network reconfiguration compared to preserved patients, i.e. brain regions switched between subnetworks more often, which was related to structural damage. This shift to more unstable network reconfigurations was also demonstrated longitudinally in patients that showed cognitive decline only. These results indicate the potential relevance of a progressive destabilization of network topology for understanding cognitive decline in multiple sclerosis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Cortical lesions are highly inconspicuous on magnetic resonance imaging (MRI). Double inversion recovery (DIR) has a higher sensitivity than conventional clinical sequences (i.e. T1, T2, FLAIR) but is difficult to acquire, leading to overseen cortical lesions in clinical care and clinical trials., Objective: To evaluate the usability of artificially generated DIR (aDIR) images for cortical lesion detection compared to conventionally acquired DIR (cDIR)., Methods: The dataset consisted of 3D-T1 and 2D-proton density (PD) T2 images of 73 patients (49RR, 20SP, 4PP) at 1.5 T. Using a 4:1 train:test-ratio, a fully convolutional neural network was trained to predict 3D-aDIR from 3D-T1 and 2D-PD/T2 images. Randomized blind scoring of the test set was used to determine detection reliability, precision and recall., Results: A total of 626 vs 696 cortical lesions were detected on 15 aDIR vs cDIR images (intraclass correlation coefficient (ICC) = 0.92). Compared to cDIR, precision and recall were 0.84 ± 0.06 and 0.76 ± 0.09, respectively. The frontal and temporal lobes showed the largest differences in discernibility., Conclusion: Cortical lesions can be detected with good reliability on artificial DIR. The technique has potential to broaden the availability of DIR in clinical care and provides the opportunity of ex post facto implementation of cortical lesions imaging in existing clinical trial data.

Background: Brain functional connectivity (FC) in multiple sclerosis (MS) is abnormal compared to healthy controls (HCs). More longitudinal studies in MS are needed to evaluate whether FC stability is clinically relevant., Objective: To compare functional magnetic resonance imaging (fMRI)-based FC between MS and HC, and to determine the relationship between longitudinal FC changes and structural brain damage, cognitive performance and physical disability., Methods: T1-weighted MPRAGE and resting-state fMRI (1.5T) were acquired from 70 relapsing-remitting MS patients and 94 matched HC at baseline (mean months since diagnosis 14.0 ± 11) and from 60 MS patients after 5 years. Independent component analysis and network modelling were used to measure longitudinal FC stability and cross-sectional comparisons with HC. Linear mixed models, adjusted for age and sex, were used to calculate correlations., Results: At baseline, patients with MS showed FC abnormalities both within networks and in single connections compared to HC. Longitudinal analyses revealed functional stability and no significant relationships with clinical disability, cognitive performance, lesion or brain volume., Conclusion: FC abnormalities occur already at the first decade of MS, yet we found no relevant clinical correlations for these network deviations. Future large-scale longitudinal fMRI studies across a range of MS subtypes and outcomes are required.

Background: Suboptimal performance during neuropsychological assessment renders cognitive test results invalid. However, suboptimal performance has rarely been investigated in multiple sclerosis (MS)., Objectives: To investigate potential underlying mechanisms of suboptimal performance in MS., Methods: Performance validity testing, neuropsychological assessments, neuroimaging, and questionnaires were analyzed in 99 MS outpatients with cognitive complaints. Based on performance validity testing patients were classified as valid or invalid performers, and based on neuropsychological test results as cognitively impaired or preserved. Group comparisons and correlational analyses were performed on demographics, patient-reported, and disease-related outcomes., Results: Twenty percent displayed invalid performance. Invalid and valid performers did not differ regarding demographic, patient-reported, and disease-related outcomes. Disease severity of invalid and valid performers with cognitive impairment was comparable, but worse than cognitively preserved valid performers. Lower performance validity scores related to lower cognitive functioning, lower education, being male, and higher disability levels ( p  < 0.05)., Conclusion: Suboptimal performance frequently occurs in patients with MS and cognitive complaints. In both clinical practice and in cognitive research, suboptimal performance should be considered in the interpretation of cognitive outcomes. Identification of factors that differentiate between suboptimal and optimal performers with cognitive impairment needs further exploration.

Background: Early detection and monitoring of cognitive dysfunction in multiple sclerosis (MS) may be enabled with smartphone-adapted tests that allow frequent measurements in the everyday environment., Objectives: The aim of this study was to determine the reliability, construct and concurrent validity of a smartphone-adapted Symbol Digit Modalities Test (sSDMT)., Methods: During a 28-day follow-up, 102 patients with MS and 24 healthy controls (HC) used the MS sherpa ® app to perform the sSDMT every 3 days on their own smartphone. Patients performed the Brief International Cognitive Assessment for MS at baseline. Test-retest reliability (intraclass correlation coefficients, ICC), construct validity (group analyses between cognitively impaired (CI), cognitively preserved (CP) and HC for differences) and concurrent validity (correlation coefficients) were assessed., Results: Patients with MS and HC completed an average of 23.2 ( SD = 10.0) and 18.3 ( SD = 10.2) sSDMT, respectively. sSDMT demonstrated high test-retest reliability (ICCs > 0.8) with a smallest detectable change of 7 points. sSDMT scores were different between CI patients, CP patients and HC (all p s < 0.05). sSDMT correlated modestly with the clinical SDMT (highest r = 0.690), verbal (highest r = 0.516) and visuospatial memory (highest r = 0.599)., Conclusion: Self-administered smartphone-adapted SDMT scores were reliable and different between patients who were CI, CP and HC and demonstrated concurrent validity in assessing information processing speed.

Background: The feasibility of cognitive rehabilitation is rarely investigated in patients with advanced multiple sclerosis., Methods: Eighteen patients with advanced multiple sclerosis (median EDSS = 7.5) were randomized into restorative or compensatory cognitive rehabilitation. Feasibility was determined by adherence rate, completion rate, patient satisfaction, self-reported fatigue, training difficulty, and training duration., Results: Adherence rates and completion rates were over 70%, and patients were highly satisfied in both groups. Energy levels decreased minimally during the sessions (pre = 6.9 vs post = 6.4). Training difficulty (4.6) and duration (5.7) were close to ideal (scale 1-10, 5 = ideal)., Conclusions: Cognitive rehabilitation, with minor adjustments, appears feasible in patients with advanced multiple sclerosis., Competing Interests: Declaration of conflicting interests: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S.E. Prouskas has nothing to disclose. N.D. Chiaravalloti has nothing to disclose. N. Kant has nothing to disclose. K.K. Ball holds stock in the Visual Awareness Research Group (formerly Visual Awareness, Inc.), and Posit Science, Inc., the companies that market the Useful Field of View Test and speed of processing training software. V. de Groot has nothing to disclose. B.M.J. Uitdehaag received compensation for consulting from Biogen, Genzyme, Merck Serono, Novartis, Roche, and Teva Pharmaceuticals. J.J.G. Geurts is an editor of MS journal and serves on the editorial boards of Neurology and Frontiers of Neurology and is president of the Netherlands organization for health research and innovation and has served as a consultant for Merck-Serono, Biogen, Novartis, Genzyme and Teva Pharmaceuticals. E.A. Kooij has nothing to disclose. H.E. Hulst serves on the editorial board of MSJ and has received compensation for consulting services or speaker honoraria from Sanofi Genzyme, Merck Serono and Biogen Idec., (© The Author(s), 2021.)

Objective: To characterize functional network changes related to conversion to cognitive impairment in a large sample of patients with multiple sclerosis (MS) over a period of 5 years., Methods: Two hundred twenty-seven patients with MS and 59 healthy controls of the Amsterdam MS cohort underwent neuropsychological testing and resting-state fMRI at 2 time points (time interval 4.9 ± 0.9 years). At both baseline and follow-up, patients were categorized as cognitively preserved (CP; n = 123), mildly impaired (MCI; z < -1.5 on ≥2 cognitive tests, n = 32), or impaired (CI; z < -2 on ≥2 tests, n = 72), and longitudinal conversion between groups was determined. Network function was quantified with eigenvector centrality, a measure of regional network importance, which was computed for individual resting-state networks at both time points., Results: Over time, 18.9% of patients converted to a worse phenotype; 22 of 123 patients who were CP (17.9%) converted from CP to MCI, 10 of 123 from CP to CI (8.1%), and 12 of 32 patients with MCI converted to CI (37.5%). At baseline, default-mode network (DMN) centrality was higher in CI individuals compared to controls ( p = 0.05). Longitudinally, ventral attention network (VAN) importance increased in CP, driven by stable CP and CP-to-MCI converters ( p < 0.05)., Conclusions: Of all patients, 19% worsened in their cognitive status over 5 years. Conversion from intact cognition to impairment is related to an initial disturbed functioning of the VAN, then shifting toward DMN dysfunction in CI. Because the VAN normally relays information to the DMN, these results could indicate that in MS normal processes crucial for maintaining overall network stability are progressively disrupted as patients clinically progress., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Neuropsychological test scores in people with MS (PwMS) do not fully reflect cognitive functioning in daily life. Therefore, we developed a questionnaire based on instrumental activities of daily living (IADL), using the Amsterdam IADL-Q © for Alzheimer's disease as starting point. Forty-eight items were evaluated on relevance and clarity by (inter)national experts (n = 30), PwMS (n = 61) and proxies (n = 30). Consequently, four items were omitted, two items were merged and seven items were added. Fifty items were included in the IADL questionnaire specific to cognitive functioning in MS (the MS-IADL-Q). Future studies are warranted to assess the psychometric properties of the MS-IADL-Q., (© The Author(s) 2021.)

Background: Performing a cognitive task and a motor task simultaneously is an everyday act that can lead to decreased performance on both tasks., Objective: To provide insight into the neural correlates associated with cognitive-motor dual tasking in individuals with a neurologic disorder., Method: We searched the PubMed and Web of Science databases for studies that had been published up to January 16th, 2019. Studies investigating the neural correlates of cognitive-motor dual task performance in individuals with a variety of neurologic disorders were included, independently from whether the study included healthy controls. Clinical and imaging data were abstracted for the comparison between single tasks and a dual task in the individuals with a neurologic disorder and for the comparison between the healthy controls and the individuals with a neurologic disorder., Results: Eighteen studies met the inclusion criteria. Study populations included individuals with Parkinson disease, multiple sclerosis, mild cognitive impairment, Alzheimer disease, traumatic brain injury, and stroke. Neuroimaging types used to study the neural correlates of cognitive-motor dual tasking during upper limb or gait tasks included fMRI, functional near-infrared spectroscopy, EEG, and PET., Conclusion: Despite large heterogeneity in study methodologies, some recurrent patterns were noted. Particularly, in neurologic patients, an already higher brain activation during single tasks was seen compared with healthy controls, perhaps compromising the patients' ability to further adapt brain activation with increasing load during dual tasking and resulting in reduced behavioral dual task performance., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)