Brigit A. de Jong

Background: To reduce patients’ burden of completing lengthy questionnaires, Computerized Adaptive Tests (CATs) of the Patient-Reported Outcomes Measurement Information System (PROMIS®) are being implemented in multiple sclerosis (MS) care. The purpose of this study is to assess the test-retest reliability of seven PROMIS CATs in people with MS which is crucial for interpretation of changes in PROMIS CAT scores. Methods: This observational study was conducted in an academic hospital where the PROMIS CATs Fatigue, Depression, Anxiety, Physical Function, Sleep Disturbance, Ability to Participate in Social Roles and Activities, and Pain Interference, are routinely taken in the MS outpatient clinics. People with MS aged ≥ 18 years, who completed at least one PROMIS CAT were invited for a retest within 28 days. To assess reliability of the PROMIS CATs, Intraclass Correlation Coefficients (ICC), Standard Error of Measurements (SEM) and Smallest Detectable Change (SDC) were calculated. Results: The final study sample consisted of 58 people with MS. Forty-six (78%) participants were younger than 55, and 39 (66%) were female. The ICC (with 95% CI) of the PROMIS CAT item bank T-scores ranged from 0.59 (0.31–0.79) (Pain Interference), 0.75 (0.60–0.85) (Anxiety), 0.78 (0.64–0.86) (Depression), 0.85 (0.75–0.91) (Fatigue), 0.86 (0.75–0.92) (Participation), 0.86 (0.77–0.92) (Sleep Disturbance) to 0.86 (0.75–0.93) (Physical Function). SEM and SDC ranged from 4.1 and 11.6 for Pain Interference to 2.3 and 6.3 for Physical Function. Conclusions: Reliability of the PROMIS CATs was sufficient to good, except for Pain Interference which needs further investigation.

The brain-predicted age difference (brain-PAD) is considered a marker of neurodegeneration in people with multiple sclerosis (pwMS) and is associated with greater disability and cognitive impairment. However, the impact of disease-modifying factors (DMFs) on brain-PAD remains unknown, as does the extent to which their effect on disability and cognition is mediated through brain-PAD. The goal of this study was to investigate this in pwMS using a same-age cohort to eliminate calendar age as a confounding factor. Brain age was determined using brainageR from 3-dimensional T1-weighted MRI scans, and brain-PAD was calculated as the difference between predicted and chronological age. Disability was evaluated with the Expanded Disability Status Scale (EDSS), the 9-hole peg test (9HPT), and timed 25-foot walk test (T25FWT). Cognitive function was assessed using the Minimal Assessment of Cognitive Function in MS battery and converted to Z-scores. DMFs included lifetime smoking, alcohol consumption, physical activity, diet, leisure, and educational level, as well as body mass index (BMI) at 18 years. The effect of DMFs on brain-PAD was examined using linear regression, adjusting for sex. Mediation analyses were performed to investigate to what extent brain-PAD is a mediator of DMF effects on disability and cognition. The study included 117 healthy controls (mean age 52.8 ± 1.1 years, 74.3% female) and 242 pwMS (mean age 52.8 ± 0.9 years, 70.6% female), with a median disease duration of 15.2 years (interquartile range [IQR] 8.2-24.5) and a median EDSS score of 3.5 (IQR 2.5-4.0). Smoking (β = 0.20, p = 0.002), alcohol consumption (β = 0.18, p = 0.007), and BMI at 18 years (β = 0.15, p = 0.021) were associated with a higher brain-PAD, whereas higher physical activity (β = -0.13, p = 0.041) was linked to a lower brain-PAD. Mediation analysis demonstrated an indirect effect of smoking and alcohol on EDSS score (β = 0.039, p = 0.003; β = 0.039, p = 0.009), 9HPT (β = 0.057, p < 0.0001; β = 0.055, p = 0.004), T25FWT score (β = 0.045, p = 0.009; β = 0.044, p = 0.013), and cognitive performance (β = -0.066, p = 0.0004; β = -0.060, p = 0.016). Physical activity demonstrated an indirect effect of better performance on EDSS score (β = -0.027, p = 0.032) and cognitive performance (β = 0.042, p = 0.034). DMFs unrelated to MS, particularly smoking, alcohol use, and BMI at 18 years, accelerate brain aging. Brain-PAD mediates these effects and contributes to worsening disability and cognition, underscoring the potential of lifestyle interventions to mitigate neurodegeneration and preserve function in pwMS.

Objective: To examine the effects of a multi-domain lifestyle intervention that advocated a Mediterranean style diet, and concurrently targeted physical activity, stress and sleep, on multiple sclerosis. Methods: A longitudinal observational study investigating the effect of a multi-domain lifestyle intervention (i.e., diet, exercise, stress, and sleep management) at four timepoints: start run-in, start and stop 3-month intensive interval, and 3-month follow-up. The primary outcome (i.e., impact of multiple sclerosis on daily functioning) and secondary outcomes (i.e., quality of life, general health, multiple sclerosis-specific symptoms, and lifestyle factors) were analyzed using mixed models. Analyses were repeated among subgroups based on program compliance, body mass index, education level, and multiple sclerosis-subtype. Results: Out of 668 participants, 579 were included (age 46.2 ± 10.5 years, 84.5% women, and 71% relapsing–remitting multiple sclerosis). The impact of multiple sclerosis on physical functioning remained stable during the run-in period, but reduced significantly from baseline to both post-intervention (β = −2.50 [−3.40, −1.60]) and to 3-month follow-up (β = −2.00 [−2.93, −1.07]). The impact of multiple sclerosis on mental functioning decreased significantly across all time periods (run-in β = 1.86 [0.78, 2.94], post-intervention β = −3.48 [−4.58, −2.39], and 3-month follow-up β = −2.44 [−3.56, 1.31]). Effect size was greatest among participants with higher compliance, lower education, and obesity. Interpretation: The lifestyle program was associated with reduced impact of multiple sclerosis on daily functioning, multiple sclerosis-related symptoms, mental quality of life, and general health determinants. Future randomized trials are needed to establish causal effects of lifestyle adjustments on multiple sclerosis.

Background and objectives: Serum neurofilament light (sNfL) is a biomarker for neuro-axonal damage in multiple sclerosis (MS). Clinical implementation remains limited. We investigated the impact of implementation on clinical decisions using questionnaires at the MS Center Amsterdam, a tertiary outpatient clinic. Methods: sNfL assessments were added to routine clinical practice (August 2021–December 2022). Before and after the results, clinicians filled in questionnaires on context of testing, clinical decisions, certainty herein, expectation of magnetic resonance imaging (MRI) activity, urgency, and motivation to receive the sNfL result and perceived value of sNfL. Results: sNfL was assessed in 166 cases (age 41 ± 12 years, 68% female, 64% disease-modifying therapy (DMT) use) for the following contexts: “DMT monitoring” (55%), “new symptoms” (18%), “differential diagnosis” (17%), and “DMT baseline” (11%). Clinical decisions changed in 19.3% of cases post-disclosure, particularly in context “new symptoms” (38%) and with higher sNfL levels (β = 0.03, p = 0.04). Certainty increased ( p = 0.004), while expectation of MRI activity decreased with disclosure of low sNfL levels ( p = 0.01). Motivation was highest in context “differential diagnosis” ( p < 0.001); perceived value and urgency were highest in context “new symptoms” ( p = 0.02). Conclusion: In this study, sNfL implementation had considerable impact on clinical decision-making and certainty herein. Standard implementation may complement patient care but warrants caution and more exploration in diverse clinical settings

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.

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.

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.

Objective To determine whether B-cell presence in brainstem and white matter (WM) lesions is associated with poorer pathological and clinical characteristics in advanced MS autopsy cases. Methods Autopsy tissue of 140 MS and 24 control cases and biopsy tissue of 24 patients with MS were examined for CD20⁺ B cells and CD138⁺ plasma cells. The presence of these cells was compared with pathological and clinical characteristics. In corresponding CSF and plasma, immunoglobulin (Ig) G ratio and oligoclonal band (OCB) patterns were determined. In a clinical cohort of 73 patients, the presence of OCBs was determined during follow-up and compared to status at diagnosis. Results In 34% of active and 71% of mixed active/inactive lesions, B cells were absent, which correlated with less pronounced meningeal B-cell infiltration (p < 0.0001). The absence of B cells and plasma cells in brainstem and WM lesions was associated with a longer disease duration (p = 0.001), less frequent secondary progressive MS compared with relapsing and primary progressive MS (p < 0.0001 and p = 0.046, respectively), a lower proportion of mixed active/inactive lesions (p = 0.01), and less often perivascular T-cell clustering (p < 0.0001). Moreover, a lower CSF IgG ratio (p = 0.006) and more frequent absence of OCBs (p < 0.0001) were noted. In a clinical cohort, numbers of patients without OCBs in CSF were increased at follow-up (27.4%). Conclusions The absence of B cells is associated with a favorable clinical and pathological profile. This finding may reflect extremes of a continuum of genetic or environmental constitution, but also a regression of WM humoral immunopathology in the natural course of advanced MS.

Background: Neurodegeneration, rather than inflammation, plays a key role in the progressive phase of multiple sclerosis (MS). Current disease modifying treatment options for people with progressive MS (PMS) do not specifically target neurodegeneration. Preliminary evidence suggests that exercise therapy might have neuroprotective effects. However, neuroprotective effect studies of exercise interventions in PMS are scarce and the possible mode of action underlying neuroprotective effects of exercise are unknown and need to be elucidated. The main aim of this phase II trial is to assess whether progressive resistance training (PRT) and high intensity interval training (HIIT), can slow down neurodegeneration in people with PMS.Methods: In a single-blinded phase II clinical trial with an extended baseline period, 60 people with PMS will be randomly assigned to PRT or HIIT. The participants should have had a relapse onset of MS with confirmed disease progression, however still ambulatory. The duration of the study is 48 weeks, consisting of 16 weeks baseline period (no intervention), 16 weeks intervention and 16 weeks follow-up. Patient-tailored training will be performed 3 times per week for one hour in groups, led by an experienced physiotherapist. The primary outcome measure is neurodegeneration, measured as whole brain atrophy on magnetic resonance imaging (MRI). Secondary outcome parameters will include other biomarkers associated with neurodegeneration (i.e. regional brain atrophy, lesion load, white matter integrity, resting state functional connectivity, blood biomarkers (brain derived neurotrophic factor (BDNF) and serum neurofilament light (sNFL)), patient functioning (physical and cognitive) and cardiovascular risk factors.Discussion: Besides the primary outcome measures, this study will examine a large variety of biomarkers associated with neurodegeneration after an exercise intervention. Combining outcome parameters may help to elucidate the mode of action underlying neuroprotective effects of exercise.Trial registration: This trial is prospectively registered at the Dutch Trial Registry (numberNL8265, date 06-01-2020).