A more unstable resting-state functional network in cognitively declining multiple sclerosis

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

Serum glial fibrillary acidic protein in natalizumab-treated relapsing-remitting multiple sclerosis: An alternative to neurofilament light

BACKGROUND: There is a need in Relapsing-Remitting Multiple Sclerosis (RRMS) treatment for biomarkers that monitor neuroinflammation, neurodegeneration, treatment response, and disease progression despite treatment. OBJECTIVE: To assess the value of serum glial fibrillary acidic protein (sGFAP) as a biomarker for clinical disease progression and brain volume measurements in natalizumab-treated RRMS patients. METHODS: sGFAP and neurofilament light (sNfL) were measured in an observational cohort of natalizumab-treated RRMS patients at baseline, +3, +12, and +24 months and at the last sample follow-up (median 5.17 years). sGFAP was compared between significant clinical progressors and non-progressors and related to magnetic resonance imaging (MRI)-derived volumes of the whole brain, ventricle, thalamus, and lesion. The relationship between sGFAP and sNfL was assessed. RESULTS: sGFAP and neurofilament light (sNfL) were measured in an observational cohort of natalizumab-treated RRMS patients at baseline, +3, +12, and +24 months and at the last sample follow-up (median 5.17 years). sGFAP was compared between significant clinical progressors and non-progressors and related to magnetic resonance imaging (MRI)-derived volumes of the whole brain, ventricle, thalamus, and lesion. The relationship between sGFAP and sNfL was assessed. DISCUSSION: sGFAP levels related to MRI markers of neuroinflammation and neurodegeneration

Evolution from a first clinical demyelinating event to multiple sclerosis in the REFLEX trial: Regional susceptibility in the conversion to multiple sclerosis at disease onset and its amenability to subcutaneous interferon beta-1a

BACKGROUND AND PURPOSE: In the REFLEX trial (ClinicalTrials.gov identifier: NCT00404352), patients with a first clinical demyelinating event (FCDE) displayed significantly delayed onset of multiple sclerosis (MS; McDonald criteria) when treated with subcutaneous interferon β-1a (scIFNβ-1a) versus placebo. This post hoc analysis evaluated the effect of scIFNβ-1a on spatio-temporal evolution of disease activity, assessed by changes in T2 lesion distribution, in specific brain regions of such patients and its relationship with conversion to MS. METHODS: Post hoc analysis of baseline and 24-month MRI data from FCDE patients who received scIFNβ-1a 44 μg once or three times weekly, or placebo in the REFLEX trial. Patients were grouped according to McDonald MS status (converter/non-converter) or treatment (scIFNβ-1a/placebo). For each patient group, a baseline lesion probability map (LPM) and longitudinal new/enlarging and shrinking/disappearing LPMs were created. Lesion location/frequency of lesion occurrence were assessed in the white matter (WM). RESULTS: At Month 24, lesion frequency was significantly higher in the anterior thalamic radiation (ATR) and corticospinal tract (CST) of converters versus non-converters (p<0.05). Additionally, the overall distribution of new/enlarging lesions across the brain at Month 24 was similar in placebo- and scIFNβ-1a-treated patients (ratio: 0.95). Patients treated with scIFNβ-1a versus placebo showed significantly lower new lesion frequency in specific brain regions (cluster corrected): ATR (p=0.025), superior longitudinal fasciculus (p=0.042), CST (p=0.048), and inferior longitudinal fasciculus (p=0.048). CONCLUSIONS: T2 lesion distribution in specific brain locations predict conversion to McDonald MS and show significantly reduced new lesion occurrence after treatment with scIFNβ-1a in an FCDE population

MRI characteristics are predictive for CDMS in monofocal, but not in multifocal patients with a clinically isolated syndrome

BACKGROUND: To diagnose multiple sclerosis (MS), evidence for dissemination in space and time is required. There is no clear definition on how symptoms and signs of a patient indicate clinical dissemination in space. To provide a uniform approach on this subject, a clinical classification system was described recently differentiating patients with mono- and multifocal clinical presentation. Here we assess the predictive value of clinically defined dissemination in space at first presentation for time to clinically definite MS (CDMS). METHODS: Four hundred and sixty-eight patients with a first episode suggestive of MS were classified as clinically mono- or multifocal by two neurologists blinded to magnetic resonance imaging (MRI) results. These patients were part of the BENEFIT study in which 292 patients were randomized to interferon beta-1b (IFNB-1b) and 176 to placebo. By using Kaplan-Meier statistics the risk for CDMS was studied in mono- and multifocal patients of the placebo group, both with and without taking into account MRI measures of potential prognostic relevance. RESULTS: Time to CDMS was similar in monofocal and multifocal patients. In monofocal patients, the risk for CDMS over 2 years was significantly higher when <or= 9 T2 lesions or at least one Gd-enhancing lesion were present at the first event or 3 or 6 months after the first event. In patients with multifocal presentation, these MRI measures had no significant added value in predicting time to CDMS. CONCLUSION: These data indicate that a carefully performed neurological assessment of symptoms and signs, combined with lesions on MRI, is important for defining the risk of conversion to CDMS. TRIAL REGISTRATION: The Benefit trial has been registered under NCT00185211 http://www.clinicaltrials.gov

Mapping the risk of infections in patients with multiple sclerosis: A multi-database study in the United Kingdom Clinical Practice Research Datalink GOLD and Aurum

BACKGROUND: People with multiple sclerosis (pwMS) have an increased risk of infections; risk factors include underlying disease, physical impairment and use of some disease-modifying treatments. OBJECTIVE: To quantify changes in population-level infection rates among pwMS and compare these to the general population and people with rheumatoid arthritis (pwRA), and identify patient characteristics predictive of infections after MS diagnosis. METHODS: We conducted a multi-database study using data on 23,226 people with MS diagnosis from the UK Clinical Practice Research Datalink Aurum and GOLD (January 2000-December 2020). PwMS were matched to MS-free controls and pwRA. We calculated infection rates, and estimated incidence rate ratios (IRR) and 95% confidence intervals (CI) of predictors for infections ⩽ 5 years after MS diagnosis using Poisson regression. RESULTS: Among pwMS, overall infection rates remained stable - 1.51-fold (1.49-1.52) that in MS-free controls and 0.87-fold (0.86-0.88) that in pwRA - although urinary tract infection rate per 1000 person-years increased from 98.7 (96.1-101) (2000-2010) to 136 (134-138) (2011-2020). Recent infection before MS diagnosis was most predictive of infections (1 infection: IRR 1.92 (1.86-1.97); ⩾2 infections: IRR 3.00 (2.89-3.10)). CONCLUSION: The population-level elevated risk of infection among pwMS has remained stable despite the introduction of disease-modifying treatments

The size of the treatment effect: do patients and proxies agree?

Background: This study examined whether MS patients and proxy respondents agreed on change in disease impact, which was induced by treatment. This may be of interest in situations when patients suffer from limitations that interfere with reliable self-assessment, such as cognitive impairment.Methods: MS patients and proxies completed the Multiple Sclerosis Impact Scale (MSIS-29) before and after intravenous steroid treatment. Analyses focused on patient-proxy agreement between MSIS-29 change scores. Transition ratings were used to measure the patient's judgement of change and whether this change was reflected in the MSIS-29 change of patients and proxies. Receiver operating characteristic (ROC) analyses were also performed to examine the diagnostic properties of the MSIS-29 when completed by patients and proxies.Results: 42 patients and proxy respondents completed the MSIS-29 at baseline and follow-up. Patient-proxy differences between change scores on the physical and psychological MSIS-29 subscale were quite small, although large variability was found. The direction of mean change was in concordance with the transition ratings of the patients. Results of the ROC analyses of the MSIS-29 were similar when completed by patients (physical scale: AUC = 0.79, 95% CI: 0.65 - 0.93 and 0.66, 95% CI: 0.48 - 0.84 for the psychological scale) and proxies (physical scale: 0.80, 95% CI: 0.72 - 0.96 and 0.71, 95% CI: 0.56 - 0.87 for the psychological scale)Conclusion: Although the results need to be further explored in larger samples, these results do point towards possible use of proxy respondents to assess patient perceived treatment change at the group level

Longitudinal proxy measurements in multiple sclerosis: patient-proxy agreement on the impact of MS on daily life over a period of two years

Background: The use of self- report measurements in clinical settings is increasing. However, in patients with limitations that interfere with reliable self- assessment such as cognitive impairment or mood disturbances, as may be the case in multiple sclerosis ( MS), data collection might be problematic. In these situations, information obtained from proxy respondents ( e. g. partners) may replace self- ratings. The aim of this study was to examine the value of proxy ratings at separate points in time and to assess patient- proxy agreement on possible changes in disease impact of MS. Methods: Fifty- six MS patients and their partners completed the Multiple Sclerosis Impact Scale ( MSIS- 29) at baseline and follow- up, two years later. Patient- proxy agreement was assessed at both time points by calculating intraclass correlation coefficients ( ICCs), exact and global agreement and the mean directional differences between groups. Agreement of change over time was assessed by calculating ICCs between change scores. In parallel, global ratings of both patients and proxy respondents of the extent to which the patient had improved or deteriorated over the past two years were collected to validate possible changes on the MSIS- 29. Results: At both time points, agreement on the physical scale was higher than agreement on the psychological scale ( ICCs at baseline were 0.81 for the physical scale and 0.72 for the psychological scale; at follow- up, the ICC values were 0.86 and 0.65 respectively). At follow- up, statistically significant mean differences between patients and proxies were noted for the physical scale (- 4.8 +/- 12.7, p = 0.006) and the psychological scale (- 8.9 +/- 18.8, p = 0.001). Agreement between change scores on the MSIS- 29 was fair ( ICC < 0.60). Our analyses suggest that the validity of measuring changes over time might be better for proxy respondents compared to patients. Conclusion: Proxy respondents could act as a reliable source of information in cross- sectional studies. Moreover, results suggested that agreement on change over time might be better for proxy respondents compared to patients. Although this remarkable finding should be interpreted cautiously because of several limitations of the study, it does plead for further investigation of this important topic

Internet-based self-help treatment for depression in multiple sclerosis: study protocol of a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Depression in MS patients is frequent but often not treated adequately. An important underlying factor may be physical limitations that preclude face-to-face contact. Internet-based treatment showed to be effective for depressive symptoms in general and could thus be a promising tool for treatment in MS.</p> <p>Methods/design</p> <p>Here, we present a study protocol to investigate the effectiveness of a 5 week Internet-based self-help problem solving treatment (PST) for depressive symptoms in MS patients in a randomized controlled trial. We aim to include 166 MS patients with moderate to severe depressive symptoms who will be randomly assigned to an Internet-based intervention (with or without supportive text-messages) or waiting list control group. The primary outcome is the change in depressive symptoms defined by a change in the sum score on the Beck Depression Inventory (BDI-II). Secondary outcomes will include measures of anxiety, fatigue, cognitive functioning, physical and psychological impact of MS, quality of life, problem solving skills, social support, mastery, satisfaction and compliance rate. Assessments will take place at baseline (T0), within a week after the intervention (T1), at four months (T2) and at ten months follow-up (T3: only the intervention group). The control group will be measured at the same moments in time. Analysis will be based on the intention-to-treat principle.</p> <p>Discussion</p> <p>If shown to be effective, Internet-based PST will offer new possibilities to reach and treat MS patients with depressive symptoms and to improve the quality of care.</p> <p>Trial Registration</p> <p>The Dutch Cochrane Center, NTR2772</p