Reliability, construct and concurrent validity of a smartphone-based cognition test in multiple sclerosis.

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 ps < 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.

Performance validity in outpatients with multiple sclerosis and cognitive complaints.

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.

Neuroprotective effects of exercise in people with progressive multiple sclerosis (Exercise PRO-MS): study protocol of a phase II trial.

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 (number NL8265, date 06-01-2020).

rTMS affects working memory performance, brain activation and functional connectivity in patients with multiple sclerosis.

OBJECTIVE: To investigate the effects of high-frequency repetitive transcranial magnetic stimulation (rTMS) of the right dorsolateral prefrontal cortex (DLPFC) on working memory performance, while measuring task-related brain activation and task-related brain connectivity in patients with multiple sclerosis (MS). METHODS: 17 patients with MS and 11 healthy controls (HCs) underwent 3 experimental sessions (baseline, real-rTMS, sham-rTMS), all including an N-back task (3 task loads: N1, N2, N3; control condition: N0) inside the MR scanner. Prior to imaging, real-rTMS (10 Hz) was applied to the right DLPFC. The stimulation site was defined based on individually assessed N-back task activation at baseline and located using neuronavigation. Changes in whole brain functional activation and functional connectivity with the right DLPFC were calculated. RESULTS: N-back task accuracy (N2 and N3) improved after real-rTMS (and not after sham-rTMS) compared with baseline (p=0.029 and p=0.015, respectively), only in patients. At baseline, patients with MS, compared with HCs, showed higher task-related frontal activation (left DLPFC, N2>N0), which disappeared after real-rTMS. Task-related (N1>N0) functional connectivity between the right DLPFC and the right caudate nucleus and bilateral (para)cingulate gyrus increased in patients after real-rTMS when compared with sham stimulation. CONCLUSIONS: In patients with MS, N-back accuracy improved while frontal hyperactivation (seen at baseline relative to HCs) disappeared after real-rTMS. Together with the changes in functional connectivity after real-rTMS in patients, these findings may represent an rTMS-induced change in network efficiency in patients with MS, shifting patients' brain function towards the healthy situation. This implicates a potentially relevant role for rTMS in cognitive rehabilitation in MS.

Regional cortical thinning in multiple sclerosis and its relation with cognitive impairment: A multicenter study.

OBJECTIVES: The objectives of this paper are to compare in a multicenter setting patterns of regional cortical thickness in patients with relapsing-remitting multiple sclerosis (RRMS) and cognitive impairment (CI) and those cognitively preserved (CP), and explore the relationship between cortical thinning and cognitive performance. METHODS: T1-weighted isotropic brain scans were collected at 3T from seven European centers in 60 RRMS patients and 65 healthy controls (HCs). Patients underwent clinical and neuropsychological examinations. Cortical thickness (CTh) measures were calculated using FreeSurfer (failing in four) and both lobar and vertex-based general linear model (GLM) analyses were compared between study groups. RESULTS: Twenty (36%) MS patients were classified as CI. Mean global CTh was smaller in RRMS patients compared to HCs (left 2.43 vs. 2.53 mm, right 2.44 vs. 2.54 mm, p < 0.001). Multivariate GLM regional analysis showed significantly more temporal thinning in CI compared to CP patients. Verbal memory scores correlated to regional cortical thinning in the insula whereas visual memory scores correlated to parietal thinning. CONCLUSIONS: This multicenter study showed mild global cortical thinning in RRMS. The extent of thinning is less pronounced than previously reported. Only subtle regional differences between CI and CP patients were observed, some of which related to specific cognitive domains.

Multimodal MRI study on the relation between WM integrity and connected GM atrophy and its effect on disability in early multiple sclerosis.

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.

Assessment of data consistency through cascades of independently recurrent inference machines for fast and robust accelerated MRI reconstruction.

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 T1-weighted and FLAIR contrast brain data, and T2-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.

Subjective cognitive impairment is related to work status in people with multiple sclerosis.

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.

Introducing Multiple Screener: An unsupervised digital screening tool for cognitive deficits in MS.

BACKGROUND: Cognitive deficits affect up to 70% of all patients with Multiple Sclerosis (MS) and have a significant impact on quality of life. Cognitive assessments need to be performed by a neuropsychologist and are often time-consuming, hampering timely identification and adequate monitoring of cognitive decline in MS. OBJECTIVE: To develop a time-efficient, unsupervised, digital tool to screen for cognitive deficits in MS. METHODS: A digital (adjusted) version of the Brief International Cognitive Assessment for MS, including the Symbol Digit Modalities Test (SDMT, information processing speed), the California Verbal Learning Test (CVLT-II, verbal memory) and the Spatial Recall Test (SPART, visuospatial memory) was developed: Multiple Screener (intellectual property of Sanofi Genzyme). Firstly, the clarity and feasibility of the tool was confirmed by 16 patients with MS (mean age 50.9 years (SD 9.4, range 37-68). Next, in 60 healthy controls (HCs, mean age 44.5 years (SD 14.0, range 18-67), intraclass correlation coefficients (ICC) were calculated to describe how strongly the digital version resembled the paper and pencil-based assessment. Finally, 236 HCs (mean age 42.8 years (SD 12.8, range 18-69) were included to obtain norm scores for each test. RESULTS: ICCs between digital and paper and pencil-based assessment were excellent to good (SDMT (ICC 0.79, confidence interval (CI) 0.67-0.87); CVLT-II (ICC 0.77, CI 0.64-0.85); SPART (ICC 0.61, CI 0.42-0.75)). For each test, a regression-based correction for the effect of age was applied on the raw scores before converting them to norm Z-scores. Additionally, the SDMT scores needed correction for education and the CVLT-II for education and sex (subgroups were created). CONCLUSIONS: Performance on an adjusted, digital version of the BICAMS correlates highly with the standard paper-and-pencil based test scores in HCs. Multiple Screener is an unsupervised, digital tool, with available norm scores, ultimately allowing for easy monitoring of cognitive decline in patients with MS.

Regional DTI differences in multiple sclerosis patients.

Diffusion tensor imaging (DTI) measures have shown to be sensitive to white matter (WM) damage in multiple sclerosis (MS), not only inside focal lesions but also in user-defined regions in the so-called normal-appearing white matter (NAWM). New analysis techniques for DTI measures are now available that allow for hypothesis-free localization of damage. We performed DTI measurements of 30 MS patients selected for low focal lesion loads, and of 31 age-matched healthy controls and analyzed these using tract-based spatial statistics (TBSS). Patients were found to have a lower fractional anisotropy (FA) compared to controls in a number of brain regions, including the fornices, the left corona radiata, the inferior longitudinal fasciculus in both hemispheres, both optic radiations, and parts of the corpus callosum. In the regions of reduced FA, an increase in radial diffusivity and a less pronounced increase of axial diffusivity were found. Neurocognitive assessment showed that patients had normal visuospatial memory performance, just-normal attention, and impaired processing speed; the latter was associated with abnormal FA in the corpus callosum, an area which was relatively devoid of lesions visible on proton density-weighted images in our patients. TBSS can be useful in future studies with other MS patient samples to provide an unbiased localization of damage and generate location-specific hypotheses.

Is impaired information processing speed a matter of structural or functional damage in MS?

OBJECTIVE: Cognitive deficits, especially those of information processing speed (IPS), are common in multiple sclerosis (MS), however, the underlying neurobiological mechanisms remain poorly understood. In this study, we examined structural and functional brain changes separately, but also in an integrative manner, in relation to IPS performance. METHODS: IPS was measured using the symbol digit modalities test (SDMT) in 330 MS patients and 96 controls. Patients with IPS impairment (IPS-I, z-score < -1.5) were compared to patients with preserved IPS performance (IPS-P) on volumetric measures, white matter integrity loss (using diffusion tensor imaging) and the severity of functional connectivity changes (using resting-state fMRI). Significant predictors of IPS performance were used to create groups of mild or severe structural and/or functional damage to determine the relative effect of structural and/or functional changes on IPS. RESULTS: IPS-I patients, compared to IPS-P patients, showed lower deep gray matter volume and less WM integrity, but stronger increases in functional connectivity. Patients with predominantly structural damage had worse IPS (z-score = -1.49) than patients with predominantly functional changes (z-score = -0.84), although both structural and functional measures remained significant in a regression model. Patients with severe structural and functional changes had worst IPS (z-score = -1.95). CONCLUSION: The level of structural damage explains IPS performance better than functional changes. After integrating functional and structural changes, however, we were able to detect more subtle and stepwise decline in IPS. In subgroups with a similar degree of structural damage, more severe functional changes resulted in worse IPS scores than those with only mild functional changes.

Information processing speed in multiple sclerosis: Relevance of default mode network dynamics.

Objective: To explore the added value of dynamic functional connectivity (dFC) of the default mode network (DMN) during resting-state (RS), during an information processing speed (IPS) task, and the within-subject difference between these conditions, on top of conventional brain measures in explaining IPS in people with multiple sclerosis (pwMS). Methods: In 29 pwMS and 18 healthy controls, IPS was assessed with the Letter Digit Substitution Test and Stroop Card I and combined into an IPS-composite score. White matter (WM), grey matter (GM) and lesion volume were measured using 3 T MRI. WM integrity was assessed with diffusion tensor imaging. During RS and task-state fMRI (i.e. symbol digit modalities task, IPS), stationary functional connectivity (sFC; average connectivity over the entire time series) and dFC (variation in connectivity using a sliding window approach) of the DMN was calculated, as well as the difference between both conditions (i.e. task-state minus RS; ΔsFC-DMN and ΔdFC-DMN). Regression analysis was performed to determine the most important predictors for IPS. Results: Compared to controls, pwMS performed worse on IPS-composite (p = 0.022), had lower GM volume (p < 0.05) and WM integrity (p < 0.001), but no alterations in sFC and dFC at the group level. In pwMS, 52% of variance in IPS-composite could be predicted by cortical volume (ß = 0.49, p = 0.01) and ΔdFC-DMN (ß = 0.52, p < 0.01). After adding dFC of the DMN to the model, the explained variance in IPS increased with 26% (p < 0.01). Conclusion: On top of conventional brain measures, dFC from RS to task-state explains additional variance in IPS. This highlights the potential importance of the DMN to adapt upon cognitive demands to maintain intact IPS in pwMS.

The role of sleep on cognition and functional connectivity in patients with multiple sclerosis.

Sleep disturbances are common in multiple sclerosis (MS), but its impact on cognition and functional connectivity (FC) of the hippocampus and thalamus is unknown. Therefore, we investigated the relationship between sleep disturbances, cognitive functioning and resting-state (RS) FC of the hippocampus and thalamus in MS. 71 MS patients and 40 healthy controls underwent neuropsychological testing and filled out self-report questionnaires (anxiety, depression, fatigue, and subjective cognitive problems). Sleep disturbances were assed with the five-item version of the Athens Insomnia Scale. Hippocampal and thalamic volume and RS FC of these regions were determined. Twenty-three patients were categorized as sleep disturbed and 48 as normal sleeping. No differences were found between disturbed and normal sleeping patients concerning cognition and structural MRI. Sleep disturbed patients reported more subjective cognitive problems, and displayed decreased FC between the thalamus and middle and superior frontal gyrus, inferior frontal operculum, anterior cingulate cortex, inferior parietal gyrus, precuneus, and angular gyrus compared to normal sleeping patients. We conclude that sleep disturbances in MS are not (directly) related to objective cognitive functioning, but rather to subjective cognitive problems. In addition, sleep disturbances in MS seem to coincide with a specific pattern of decreased thalamic FC.

Hippocampal and Deep Gray Matter Nuclei Atrophy Is Relevant for Explaining Cognitive Impairment in MS: A Multicenter Study.

BACKGROUND AND PURPOSE: The structural MR imaging correlates of cognitive impairment in multiple sclerosis are still debated. This study assessed lesional and atrophy measures of white matter and gray matter involvement in patients with MS acquired in 7 European sites to identify the MR imaging variables most closely associated with cognitive dysfunction. MATERIALS AND METHODS: Brain dual-echo, 3D T1-weighted, and double inversion recovery scans were acquired at 3T from 62 patients with relapsing-remitting MS and 65 controls. Patients with at least 2 neuropsychological tests with abnormal findings were considered cognitively impaired. Focal WM and cortical lesions were identified, and volumetric measures from WM, cortical GM, the hippocampus, and deep GM nuclei were obtained. Age- and site-adjusted models were used to compare lesion and volumetric MR imaging variables between patients with MS who were cognitively impaired and cognitively preserved. A multivariate analysis identified MR imaging variables associated with cognitive scores and disability. RESULTS: Twenty-three patients (38%) were cognitively impaired. Compared with those with who were cognitively preserved, patients with MS with cognitive impairment had higher T2 and T1 lesion volumes and a trend toward a higher number of cortical lesions. Significant brain, cortical GM, hippocampal, deep GM nuclei, and WM atrophy was found in patients with MS with cognitive impairment versus those who were cognitively preserved. Hippocampal and deep GM nuclei atrophy were the best predictors of cognitive impairment, while WM atrophy was the best predictor of disability. CONCLUSIONS: Hippocampal and deep GM nuclei atrophy are key factors associated with cognitive impairment in MS. These MR imaging measures could be applied in a multicenter context, with cognition as clinical outcome.

White Matter Diffusion Changes during the First Year of Natalizumab Treatment in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND AND PURPOSE: Natalizumab treatment strongly affects relapsing-remitting multiple sclerosis, possibly by restraining white matter damage. This study investigated changes in white matter diffusivity in patients with relapsing-remitting multiple sclerosis during their first year of natalizumab treatment by using diffusion tensor imaging. MATERIALS AND METHODS: The study included patients with relapsing-remitting multiple sclerosis initiating natalizumab at baseline (n = 22), patients with relapsing-remitting multiple sclerosis continuing interferon-ß or glatiramer acetate (n = 17), and healthy controls (n = 12). Diffusion tensor imaging parameters were analyzed at baseline and month 12. We measured the extent and severity of white matter damage with diffusion tensor imaging parameters such as fractional anisotropy, comparing the patient groups with healthy controls at both time points. RESULTS: The extent and severity of white matter damage were reduced significantly in the natalizumab group with time (fractional anisotropy-based extent, 56.8% to 47.2%; severity, z = -0.67 to -0.59; P = .02); this reduction was not observed in the interferon-ß/glatiramer acetate group (extent, 41.4% to 39.1%, and severity, z = -0.64 to -0.67; P = .94). Cognitive performance did not change with time in the patient groups but did correlate with the severity of damage (r = 0.53, P = < .001). CONCLUSIONS: In patients with relapsing-remitting multiple sclerosis starting natalizumab treatment, the extent and severity of white matter damage were reduced significantly in the first year of treatment. These findings may aid in explaining the large observed clinical effect of natalizumab in relapsing-remitting multiple sclerosis.

Ibudilast in relapsing-remitting multiple sclerosis: a neuroprotectant?

BACKGROUND: Ibudilast is a phosphodiesterase inhibitor influencing inflammation and neurodegeneration in multiple sclerosis (MS). This study evaluated the safety, tolerability, and effects on MRI parameters of 2 different doses of ibudilast in relapsing forms of MS. METHODS: In this multicenter, double-blind, phase 2 trial, patients with relapsing MS and gadolinium-enhancing lesions were randomly assigned 1:1:1 to receive 30 or 60 mg ibudilast or placebo every day for 12 months. The primary endpoint was the cumulative number of newly active lesions on bimonthly brain MRI over 12 months. Secondary endpoints included relapse rate, change in Expanded Disability Status Scale (EDSS) score, T2-hyperintense and T1-hypointense lesion volumes, and percent brain volume change (PBVC). RESULTS: A total of 297 patients were randomized in 19 centers. During the first 12 months, the mean number of active lesions and relapse rate did not differ between treatment arms. A reduction in PBVC (p = 0.04) was found in the 60-mg group (0.8%) compared with placebo (1.2%). Post hoc analysis showed a reduction in the proportion active lesions that evolved into persistent black holes for the 60-mg (0.14; p = 0.004) and 30-mg (0.17; p = 0.036) groups compared with the placebo group (0.24). Over 2 years, there were fewer patients (p = 0.026) with confirmed progression on the EDSS. Treatment with ibudilast was generally safe and well tolerated. CONCLUSION: Ibudilast showed no beneficial effect on the rate of newly active lesions and relapses. However, preliminary evidence suggests that ibudilast seems to act in a neuroprotective fashion as measured by 2 independent MRI outcomes, with a possible beneficial clinical effect on disability progression. CLASSIFICATION OF EVIDENCE: This interventional study provides Class III evidence on the effect of ibudilast on disease activity.