Prospective trial of natalizumab personalised extended interval dosing by therapeutic drug monitoring in relapsing-remitting multiple sclerosis (NEXT-MS).

BACKGROUND: Extended interval dosing (EID) of natalizumab is a promising strategy to optimise treatment in multiple sclerosis (MS). Personalised EID by therapeutic drug monitoring can enable further extension of treatment intervals. METHODS: The NEXT-MS trial is an investigator-initiated prospective phase IV non-randomised study. Adults with a diagnosis of relapsing-remitting MS who received ≥6 natalizumab infusions were included in three groups: personalised EID with a target drug trough concentration of 10 µg/mL (EID10), an exploratory group of personalised EID with a target of 5 µg/mL (EID5) and standard interval dosing (SID) of 4 weeks. The primary outcome is radiological disease activity (new/newly enlarged T2 lesions) comparing the EID10 group to a historical cohort of SID (HSID). RESULTS: Results of the first phase of the NEXT-MS trial are reported here (n=376) as the study will continue with an amended protocol. In the EID10 group (n=251), incidence rate of radiological activity was 10.0 per 1000 person-years, which was non-inferior to the HSID cohort (24.7 per 1000 person-years (n=87), incidence rate difference 14.7, 90% CI -4.5 to 34.0). Incidence rate of radiological activity was 10.0 per 1000 person-years in the EID5 group (n=65), and 47.0 per 1000 person-years in the SID group (n=60). Serum neurofilament light levels did not increase over time within the EID groups. There were no cases of progressive multifocal leukoencephalopathy. CONCLUSIONS: MS disease activity is adequately controlled with personalised natalizumab EID. Interval extension to a drug trough concentration of 5 µg/mL is likely a safe target to extend natalizumab treatment intervals >6 weeks. TRIAL REGISTRATION NUMBER: NCT04225312.

Don't be late! Postponing cognitive decline and preventing early unemployment in people with multiple sclerosis: a study protocol.

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.

Don't be late! Timely identification of cognitive impairment in people with multiple sclerosis: a study protocol.

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.

The association between weight during early life and multiple sclerosis onset in a nationwide Dutch birth year cohort.

BACKGROUND: The relationship between being overweight during early life and disease course in multiple sclerosis (MS) is unresolved. We investigated the association between being overweight or obese during early life (childhood and adolescence) and MS case status, age of first symptom onset and onset type in people with MS (pwMS) of the same birth year. METHODS: We enrolled 363 PwMS and 125 healthy controls (HC) from Project Y, a Dutch population-based cross-sectional cohort study including all PwMS born in 1966 and age and sex-matched HC. The associations between weight during childhood and adolescence (non-overweight vs. overweight or obese) and MS, age at symptom onset and onset type (relapsing vs. progressive) were assessed using logistic and linear regressions. In addition, sex-separated associations were explored. RESULTS: Being overweight or obese during childhood (OR = 2.82, 95% CI 1.17-6.80) and adolescence (OR = 2.45, 95% CI 1.13-5.34) was associated with developing MS. Furthermore, being overweight or obese during adolescence was associated with a younger age of onset (ß = -0.11, p = 0.041). Of all 47 patients with a primary progressive (PP) onset type, only one patient (2.1%) was overweight or obese during childhood, whereas 45 patients with a relapsing remitting (RR) onset (14.3%) were overweight or obese during childhood (PP vs. RR p = 0.017; PP vs. HC p = 0.676; RR vs. HC, p = 0.015). However, using logistic regression analysis we did not find evidence of a significant association. CONCLUSION: In a nationwide population-based birth year cohort, being overweight or obese during childhood or adolescence is associated with MS prevalence and an earlier age of onset, but does not seem to associate with the type of onset.

Decrease of natalizumab drug levels after switching from intravenous to subcutaneous administration in patients with multiple sclerosis.

BACKGROUND: Natalizumab is effective in the treatment of multiple sclerosis (MS). In 2021, the European Medicines Agency approved the subcutaneous (SC) variant of natalizumab which can be used instead of intravenous administration. However, the course of drug levels varies between administration routes, and the Food and Drug Administration rejected the request for approval of natalizumab SC for reasons that were not disclosed. Our objective was to evaluate the course of natalizumab trough drug levels in patients who switched from natalizumab intravenous to SC on various treatment intervals. METHODS: The NEXT-MS trial (N=382) investigates personalised treatment of natalizumab, in which infusion intervals are prolonged based on individual natalizumab trough drug levels. In 2021, an amendment was approved allowing participants to switch from intravenous to SC administration with frequent measurements of natalizumab drug levels and antidrug antibodies (ADAs). Results were compared with linear mixed model analyses. RESULTS: Until December 2022, 15 participants switched to SC natalizumab. Natalizumab drug levels with SC administration were on average 55% lower compared with intravenous administration (Exp (estimate) 0.45, 95% CI 0.39 to 0.53, p<0.001), leading to very low trough drug levels in three patients on extended treatment intervals. No natalizumab ADAs were detected during intravenous or SC treatment. None of the participants on natalizumab SC showed evidence of MS disease activity. CONCLUSIONS: Natalizumab trough drug levels can decrease after switching from natalizumab intravenous to SC administration. We advise to monitor trough drug levels in patients with low natalizumab drug levels during intravenous treatment, patients with higher body mass index or patients on extended treatment intervals who switch to SC administration of natalizumab.

Neurophysiological MEG markers of cognitive impairment and performance validity in multiple sclerosis.

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.

A randomized trial predicting response to cognitive rehabilitation in multiple sclerosis: Is there a window of opportunity?

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 R2 = 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.

Natalizumab concentrations during pregnancy in three patients with multiple sclerosis.

In women with very active multiple sclerosis (MS), natalizumab can be continued during pregnancy to prevent rebound disease activity. Our aim was to evaluate changes in serum natalizumab trough concentrations during pregnancy. Blood samples of 3 patients were collected before, during, and after pregnancy. Natalizumab trough concentrations gradually decreased during pregnancy. The patient with the lowest trough concentrations during the third trimester was treated with extended interval dosing (EID). After delivery, natalizumab concentrations increased to similar levels as before pregnancy. All patients remained clinically and radiologically stable. MS neurologists should be aware of decreasing natalizumab concentrations during pregnancy, especially in patients with low initial trough concentrations and patients with EID.

Personalized B-cell tailored dosing of ocrelizumab in patients with multiple sclerosis during the COVID-19 pandemic.

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

Whole Exome Sequencing in Multi-Incident Families Identifies Novel Candidate Genes for Multiple Sclerosis.

Multiple sclerosis (MS) is a degenerative disease of the central nervous system in which auto-immunity-induced demyelination occurs. MS is thought to be caused by a complex interplay of environmental and genetic risk factors. While most genetic studies have focused on identifying common genetic variants for MS through genome-wide association studies, the objective of the present study was to identify rare genetic variants contributing to MS susceptibility. We used whole exome sequencing (WES) followed by co-segregation analyses in nine multi-incident families with two to four affected individuals. WES was performed in 31 family members with and without MS. After applying a suite of selection criteria, co-segregation analyses for a number of rare variants selected from the WES results were performed, adding 24 family members. This approach resulted in 12 exonic rare variants that showed acceptable co-segregation with MS within the nine families, implicating the genes MBP, PLK1, MECP2, MTMR7, TOX3, CPT1A, SORCS1, TRIM66, ITPR3, TTC28, CACNA1F, and PRAM1. Of these, three genes (MBP, MECP2, and CPT1A) have been previously reported as carrying MS-related rare variants. Six additional genes (MTMR7, TOX3, SORCS1, ITPR3, TTC28, and PRAM1) have also been implicated in MS through common genetic variants. The proteins encoded by all twelve genes containing rare variants interact in a molecular framework that points to biological processes involved in (de-/re-)myelination and auto-immunity. Our approach provides clues to possible molecular mechanisms underlying MS that should be studied further in cellular and/or animal models.

Functional brain network organization measured with magnetoencephalography predicts cognitive decline in multiple sclerosis.

BACKGROUND: Cognitive decline remains difficult to predict as structural brain damage cannot fully explain the extensive heterogeneity found between MS patients. OBJECTIVE: To investigate whether functional brain network organization measured with magnetoencephalography (MEG) predicts cognitive decline in MS patients after 5 years and to explore its value beyond structural pathology. METHODS: Resting-state MEG recordings, structural MRI, and neuropsychological assessments were analyzed of 146 MS patients, and 100 patients had a 5-year follow-up neuropsychological assessment. Network properties of the minimum spanning tree (i.e. backbone of the functional brain network) indicating network integration and overload were related to baseline and longitudinal cognition, correcting for structural damage. RESULTS: A more integrated beta band network (i.e. smaller diameter) and a less integrated delta band network (i.e. lower leaf fraction) predicted cognitive decline after 5 years (Radj2=15%), independent of structural damage. Cross-sectional analyses showed that a less integrated network (e.g. lower tree hierarchy) related to worse cognition, independent of frequency band. CONCLUSIONS: The level of functional brain network integration was an independent predictive marker of cognitive decline, in addition to the severity of structural damage. This work thereby indicates the promise of MEG-derived network measures in predicting disease progression in MS.

CSF levels of glutamine synthetase and GFAP to explore astrocytic damage in seronegative NMOSD.

OBJECTIVE: To explore levels of astrocytopathy in neuromyelitis optica spectrum disorder (NMOSD) by measuring levels of the astrocytic enzyme glutamine synthetase (GS) and glial fibrillary acidic protein (GFAP), an established astrocytic biomarker known to be associated with disease activity in multiple sclerosis. METHODS: Cerebrospinal fluid concentrations of GS and GFAP were measured by ELISA in patients with NMOSD (n=39, 28 aquaporin-4 (AQP4)-Ab-seropositive, 3 double-Ab-seronegative, 4 myelin oligodendrocyte glycoprotein (MOG)-Ab-seropositive and 4 AQP4-Ab-seronegative with unknown MOG-Ab-serostatus), multiple sclerosis (MS) (n=69), optic neuritis (n=5) and non-neurological controls (n=37). RESULTS: GFAP and GS concentrations differed significantly across groups (both p<0.001), showing a similar pattern of elevation in patients with AQP4-Ab-seropositive NMOSD. GS and GFAP were significantly correlated, particularly in patients with AQP4-Ab-seropositive NMOSD (rs=0.70, p<0.001). Interestingly, GFAP levels in some patients with double-Ab-seronegative NMOSD were markedly increased. CONCLUSIONS: Our data indicate astrocytic injury occurs in some patients with double-Ab-seronegative NMOSD, which hints at the possible existence of yet undiscovered astrocytic autoimmune targets. We hypothesise that elevated GS and GFAP levels could identify those double-Ab-seronegative patients suitable to undergo in-depth autoimmune screening for astrocytic antibodies.

The clinical value of the patient-reported multiple sclerosis neuropsychological screening questionnaire.

BACKGROUND: Cognitive problems are difficult to identify in patients with multiple sclerosis (MS). OBJECTIVE: To investigate the clinical applicability of the patient-reported MS Neuropsychological Screening Questionnaire (MSNQ-P). METHODS: Cut-off scores were determined to differentiate between cognitively impaired (n = 90), mildly cognitively impaired (n = 115), and cognitively preserved (n = 147) MS patients using receiver operating characteristic analyses. RESULTS: We could not define specific and sensitive cut-off scores. Higher scores (≥27) did indicate cognitive impairment. Among patients with a higher education, lower scores (<12) indicated intact cognition. CONCLUSION: Certain scores can indicate intact or impaired cognitive function. Still, MSNQ-P scores should be interpreted with caution.

Regulator of oligodendrocyte maturation, miR-219, a potential biomarker for MS.

BACKGROUND: Multiple sclerosis (MS) is a demyelinating and degenerative disease of the central nervous system. Normally, demyelination is followed by remyelination, which requires repopulation of a demyelinated area by oligodendrocyte precursor cells. Although large numbers of precursor cells are present in MS lesions, remyelination often fails, in part by the inability of precursor cells to differentiate into mature myelin-forming cells. In mouse and rat, miR-219 is required for this differentiation. Previously, we identified decreased miR-219 expression in tissue of MS patients compared to controls. Cell-free miRNAs have been detected in many different body fluids including cerebrospinal fluid (CSF) and may reflect disease processes going on in the central nervous system. This prompted us to investigate the biomarker performance of CSF miR-219 for MS diagnosis. METHODS: Quantitative PCR was performed measuring miR-219 levels in CSF of MS patients and controls in three independent cohorts. RESULTS: All three cohorts of MS patients and controls revealed that absence of miR-219 detection in CSF is consistently associated with MS. CONCLUSIONS: We have been able to identify and validate absence of miR-219 detection in CSF of MS patients compared to controls, suggesting that it may emerge as a candidate biomarker for MS diagnosis.

Cognitive rehabilitation and mindfulness in multiple sclerosis (REMIND-MS): a study protocol for a randomised controlled trial.

BACKGROUND: Cognitive problems frequently occur in patients with multiple sclerosis (MS) and profoundly affect their quality of life. So far, the best cognitive treatment options for MS patients are a matter of debate. Therefore, this study aims to investigate the effectiveness of two promising non-pharmacological treatments: cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT). Furthermore, this study aims to gain additional knowledge about the aetiology of cognitive problems among MS patients, since this may help to develop and guide effective cognitive treatments. METHODS/DESIGN: In a dual-centre, single-blind randomised controlled trial (RCT), 120 MS patients will be randomised into one of three parallel groups: CRT, MBCT or enhanced treatment as usual (ETAU). Both CRT and MBCT consist of a structured 9-week program. ETAU consists of one appointment with an MS specialist nurse. Measurements will be performed at baseline, post-intervention and 6 months after the interventions. The primary outcome measure is the level of subjective cognitive complaints. Secondary outcome measures are objective cognitive function, functional brain network measures (using magnetoencephalography), psychological symptoms, well-being, quality of life and daily life functioning. DISCUSSION: To our knowledge, this will be the first RCT that investigates the effect of MBCT on cognitive function among MS patients. In addition, studying the effect of CRT on cognitive function may provide direction to the contradictory evidence that is currently available. This study will also provide information on changes in functional brain networks in relation to cognitive function. To conclude, this study may help to understand and treat cognitive problems among MS patients. TRIAL REGISTRATION: This trial was prospectively registered at the Dutch Trial Registration (number NTR6459 , registered on 31 May 2017).

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation: clinical and genetic characterization and target for therapy.

Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is a disorder caused by recessive mutations in the gene DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. Recent observations indicate that the phenotypic range of the disease is much wider than initially thought. Currently, no treatment is available. The aims of our study were (i) to explore a possible genotype-phenotype correlation; and (ii) to identify potential therapeutic agents that modulate the splice site mutations in intron 2 of DARS2, present in almost all patients. A cross-sectional observational study was performed in 78 patients with two DARS2 mutations in the Amsterdam and Helsinki databases up to December 2012. Clinical information was collected via questionnaires. An inventory was made of the DARS2 mutations in these patients and those previously published. An assay was developed to assess mitochondrial aspartyl-tRNA synthetase enzyme activity in cells. Using a fluorescence reporter system we screened for drugs that modulate DARS2 splicing. Clinical information of 66 patients was obtained. The clinical severity varied from infantile onset, rapidly fatal disease to adult onset, slow and mild disease. The most common phenotype was characterized by childhood onset and slow neurological deterioration. Full wheelchair dependency was rare and usually began in adulthood. In total, 60 different DARS2 mutations were identified, 13 of which have not been reported before. Except for 4 of 42 cases published by others, all patients were compound heterozygous. Ninety-four per cent of the patients had a splice site mutation in intron 2. The groups of patients sharing the same two mutations were too small for formal assessment of genotype-phenotype correlation. However, some combinations of mutations were consistently associated with a mild phenotype. The mitochondrial aspartyl-tRNA synthetase activity was strongly reduced in patient cells. Among the compounds screened, cantharidin was identified as the most potent modulator of DARS2 splicing. In conclusion, the phenotypic spectrum of leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation is wide, but most often the disease has a relatively slow and mild course. The available evidence suggests that the genotype influences the phenotype, but because of the high number of private mutations, larger numbers of patients are necessary to confirm this. The activity of mitochondrial aspartyl-tRNA synthetase is significantly reduced in patient cells. A compound screen established a 'proof of principle' that the splice site mutation can be influenced. This finding is promising for future therapeutic strategies.

[Treatment of multiple sclerosis]. / Behandelmogelijkheden bij multiple sclerose.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, caused by an autoimmune reaction. Treatment options have largely increased over the years. In this article, we present two clinical cases. Patient A has a classic relapsing remitting course of multiple sclerosis with satisfactory effect on second line therapy. Patient B had a stable disease course until a new relapse occurred after the initiation of TNF-alpha blocking therapy because of Crohn's disease. The co-occurrence of multiple auto-immune diseases creates challenges, but also opportunities in choosing the right treatment strategy.

Relative aerobic load of walking in people with multiple sclerosis.

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.

Neurophysiological brain function predicts response to cognitive rehabilitation and mindfulness in multiple sclerosis: a randomized trial.

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 ).

Improved quality of life and psychological symptoms following mindfulness and cognitive rehabilitation in multiple sclerosis and their mediating role for cognition: a randomized controlled trial.

BACKGROUND: Multiple sclerosis (MS) frequently gives rise to depressive and anxiety symptoms, but these are often undertreated. This study investigated the effect of mindfulness-based cognitive therapy (MBCT) and cognitive rehabilitation therapy (CRT) on psychological outcomes and quality of life (QoL), and whether they mediate treatment effects on MS-related cognitive problems. METHODS: This randomized controlled trial included MS patients with cognitive complaints (n = 99) and compared MBCT (n = 32) and CRT (n = 32) to enhanced treatment as usual (n = 35). Baseline, post-treatment and 6-months follow-up assessments included patient-reported outcome measures (PROMS) and cognitive outcomes (self-reported and neuropsychological assessment). PROMS concerned psychological symptoms, well-being, QoL, and daily life function. Linear mixed models indicated intervention effects on PROMS and mediation effects of PROMS on cognitive outcomes. RESULTS: MBCT positively affected depressive symptoms (Cohen's d (d) = -0.46), fatigue (d = -0.39), brooding (d = -0.34), mindfulness skills (d = 0.49), and mental QoL (d = -0.73) at post-treatment. Effects on mindfulness skills remained significant 6 months later (d = 0.42). CRT positively affected depressive symptoms (d = -0.46), mindfulness skills (d = 0.37), and mental QoL (d = -0.45) at post-treatment, but not at 6-month follow-up. No effects on anxiety, well-being, self-compassion, physical QoL, and daily life function were found. Treatment effects on self-reported, but not objective, cognition were mediated by psychological symptoms and mindfulness skills. CONCLUSIONS: MBCT and CRT reduced a wide array of psychological symptoms and improved mental QoL. These improvements seemed to impact self-reported cognitive problems after both treatments, whereas objective cognitive improvements after MBCT seemed independent of improvement in psychological symptoms. Future studies should investigate long-term sustainability of these beneficial effects. TRIAL REGISTRATION: The trial was prospectively registered in the Dutch Trial registry on 31 May 2017 (NL6285; https://trialsearch.who.int/Trial2.aspx?TrialID=NTR6459 ).