Selecting informative patients for phase 2 progressive trials in MS: Design considerations for phase 2 clinical trials in progressive MS.

While relapsing-remitting multiple sclerosis (MS) has many therapeutic options, progressive forms of MS remain largely untreatable. Phase 2 clinical trials are our main tool to advance new treatments for progressive MS. Given the complexities of progressive MS, it will likely require many phase 2 trials to improve its treatment. To conduct informative and efficient phase 2 trials, it is important that such trials are designed in a way that they can identify a successful treatment as quickly and with as few participants as possible. In this topical review, we discuss cohort selection, outcome selection, cohort enrichment, and dosing selection as strategies to optimize the efficiency of phase 2 clinical trials in progressive MS.

Assessing diagnosis disclosure and concealment in multiple sclerosis: Development and initial validation of the DISCO-MS survey.

BACKGROUND: Individuals with multiple sclerosis (MS) regularly report making strategic decisions about whether to share their diagnosis or keep it a secret; for many, this represents a key stressor. Surprisingly, the impact of disclosure and concealment are understudied in MS and a formal measurement instrument is lacking. We developed the Diagnosis Disclosure and Concealment in MS (DISCO-MS) survey, a self-assessment tool evaluating (1) frequency of concealment behaviors and (2) expected consequences of diagnosis disclosure in persons with MS. METHODS: A systematic mixed-methods process was used for the design and initial validation of the DISCO-MS. Associations of DISCO-MS responses to demographics, clinical variables, and mood were examined in 204 participants with MS. RESULTS: The 39-item DISCO-MS shows good psychometric characteristics. Approximately 25% of respondents conceal their diagnosis, particularly in professional settings. Higher concealment behaviors were associated with younger age, shorter disease duration, and lower physical disability. Nearly 50% of respondents believed that talking openly about their diagnosis might have undesirable professional and interpersonal consequences. Younger age, higher depression, and higher anxiety were associated with greater expectations of negative consequences. CONCLUSION: Development and validation of the DISCO-MS presents the first step toward systematic study of the impact of DISCO on people with MS.

Diagnosis concealment is associated with psychosocial outcomes in persons with multiple sclerosis.

Persons with multiple sclerosis (pwMS) frequently conceal their diagnosis, fearing professional and personal repercussions of disclosing. Associations of concealment behavior and expected consequences of disclosure with psychosocial outcomes were examined in 90 pwMS who completed validated self-report measures of diagnosis concealment, loneliness, social support, and self-efficacy. More frequent concealment was related to worse loneliness (rp = 0.213, p = 0.045) and lower social support (rp = -0.211, p = 0.047), controlling for depression. Higher anticipated negative consequences of disclosure were associated with worse loneliness (rp = 0.263, p = 0.013), lower social support (rp = -0.338, p < 0.001), and lower self-efficacy (rp = -0.350, p < 0.001). Findings hold implications for the development of psychological support strategies addressing concealment/disclosure issues and their psychosocial consequences.

Summary metrics of memory subnetwork functional connectivity alterations in multiple sclerosis.

BACKGROUND: Memory dysfunction is common in multiple sclerosis (MS); mechanistic understanding of its causes is lacking. Large-scale network resting-state functional connectivity (RSFC) is sensitive to memory dysfunction. OBJECTIVE: We derived and tested summary metrics of memory network RSFC. METHODS: Cognitive data and 3T magnetic resonance imaging (MRI) scans were collected from 235 MS patients and 35 healthy controls (HCs). Index scores were calculated as RSFC within (anteriority index, AntI) and between (integration index, IntI) dorsomedial anterior temporal and medial temporal memory subnetworks. Group differences in index expression were evaluated. Associations between index scores and memory/non-memory cognition were evaluated; relationships between T2 lesion volume (T2LV) and index scores were assessed. RESULTS: Index scores were related to memory and T2LV in MS patients, who showed marginally elevated AntI relative to HC (p = 0.06); no group differences were found for IntI. Better memory was associated with higher AntI (ß = 0.15, p = 0.018) and IntI (ß = 0.16, p = 0.014). No associations were found for non-memory cognition. Higher T2LV was associated with higher AntI and IntI; exploratory mediation analysis revealed significant inconsistent mediation, that is, higher index scores partially suppressed the negative association between T2LV and memory. CONCLUSION: Summary, within-subject metrics permit replication and circumvent challenges of traditional (incommensurate) RSFC variables to advance development of mechanistic models of memory dysfunction in MS.

Associations of social network structure with cognition and amygdala volume in multiple sclerosis: An exploratory investigation.

BACKGROUND: Humans are inherently social, biologically programmed to connect with others. Social connections are known to impact mental and physical health. OBJECTIVE: The aim of this study was to test whether social network structure is linked to cognition, mood, fatigue, and regional brain volumes in persons with multiple sclerosis (MS). METHODS: A questionnaire quantifying individual-level social network structure (size, density, effective size, and constraint), a comprehensive battery of neuropsychological tests, and magnetic resonance imaging (MRI) was administered to 51 persons with relapsing-remitting MS. Linear regressions assessed associations of network variables to cognition, depression, fatigue, and structural brain volumes. RESULTS: Higher network density and constraint, indicating stronger connections among network members, were associated with worse language functions. Conversely, larger network effective size, a measure of non-redundant network members, was associated with better language functions. No relationships of network structure to depression or fatigue were found. Larger network size was related to larger amygdala volume. CONCLUSION: Findings suggest that social network structure is linked to language function and amygdala volume in persons with MS. Patients with close-knit networks showed worse language function than those with open networks. Longitudinal studies with larger samples are warranted to evaluate potential causal links between social network structure and MS-related cognitive impairment.

Feasibility trial of a telehealth support group intervention to reduce anxiety in multiple sclerosis.

OBJECTIVE: Anxiety is common among persons with MS (PwMS), but widely accepted treatments are lacking. Group-based interventions delivered via telehealth are an accessible treatment option requiring clinical trial evidence to support feasibility and initial efficacy. We conducted a pilot feasibility trial of an online support group intervention to reduce anxiety in PwMS. METHODS: A non-randomized, parallel arm clinical trial was conducted. A total of 31 PwMS were enrolled: 20 completed a 12-week telehealth-delivered support group intervention and 11 were assigned to a survey-only control group. Primary feasibility outcomes were adherence and completion rates. Primary efficacy outcome was anxiety, secondary outcomes were depression, loneliness, distress, self-efficacy, stress, and quality of life. RESULTS: Twenty-six participants completed the study. Intervention group adherence (75%) and completion (85%) rates were acceptable. Results indicated a medium size between-group effect, suggesting a greater reduction in anxiety in the intervention group compared to the control group [U = 39.50, p = 0.045, r = 0.39]. No group differences in other outcomes were observed. CONCLUSION: A telehealth-delivered support group intervention appears feasible for further study and shows initial efficacy for the reduction of anxiety in PwMS.

Hippocampal volume is more related to patient-reported memory than objective memory performance in early multiple sclerosis.

BACKGROUND: When persons with multiple sclerosis (MS) report memory decline but objective memory performance is normal, there is a bias toward believing objective test results. OBJECTIVE: Investigate whether subjective memory decline or objective memory performance is more related to hippocampal and hippocampal subfield volumes in early MS. METHODS: Persons with early MS (n = 185; ⩽5.0 years diagnosed) completed a subjective memory questionnaire; an objective memory composite was derived from four memory tests. Total hippocampal and subfield volumes were derived from high-resolution 3.0 T magnetic resonance images (MRIs). Partial correlations assessed links between hippocampal volumes and both subjective and objective memory, controlling for age, sex, mood, and pre-morbid intelligence quotient (IQ). RESULTS: Lower total hippocampal and CA1 volumes were related to worse subjective memory but not objective memory (controlling for multiple comparisons). Correlations between subjective memory and both CA1 and subiculum were significantly stronger than were correlations between objective memory and these subfields. Patients in the worst tertile of subjective memory complaints (but not objective memory) had lower hippocampal volumes than 35 demographically similar healthy controls. CONCLUSION: Patient-report is inherently a longitudinal assessment of within-person memory change in everyday life, which may be more sensitive to subtle disease-related changes than cross-sectional objective tests. Findings align with the aging literature.

Depression and cognitive function in early multiple sclerosis: Multitasking is more sensitive than traditional assessments.

BACKGROUND: Persons with multiple sclerosis (MS) and depression symptoms report real-world cognitive difficulties that may be missed by laboratory cognitive tests. OBJECTIVE: To examine the relationship of depressive symptoms to cognitive monotasking versus multitasking in early MS. METHOD: Persons with early MS (n = 185; ⩽5 years diagnosed) reported mood, completed monotasking and multitasking cognitive tests, and received high-resolution 3.0 T magnetic resonance imaging (MRI). Partial correlations analyzed associations between mood and cognition, controlling for age, sex, estimated premorbid IQ, T2 lesion volume, and normalized gray matter volume. RESULTS: Depression symptoms were more related to worse cognitive multitasking (-0.353, p < 0.001) than monotasking (r = -0.189, p = 0.011). There was a significant albeit weaker link to cognitive efficiency composite score (r = -0.281, p < 0.001), but not composite memory (r = -0.036, p > 0.50). Findings were replicated with a second depression measure. Multitasking was worse in patients with at least mild depression than both patients with no/minimal depression and healthy controls. Multitasking was not related to mood in healthy controls. CONCLUSIONS: Depression symptoms are linked to cognitive multitasking in early MS; standard monotasking cognitive assessments appear less sensitive to depression-related cognition. Further investigation should determine directionality and mechanisms of this relationship, with the goal of enhancing treatment for cognitive dysfunction and depression in MS.

Classifying multiple sclerosis patients on the basis of SDMT performance using machine learning.

OBJECTIVE: To build a model to predict cognitive status reflecting structural, functional, and white matter integrity changes in early multiple sclerosis (MS). METHODS: Based on Symbol Digit Modalities Test (SDMT) performance, 183 early MS patients were assigned "lower" or "higher" performance groups. Three-dimensional (3D)-T2, T1, diffusion weighted, and resting-state magnetic resonance imaging (MRI) data were acquired in 3T. Using Random Forest, five models were trained to classify patients into two groups based on 1-demographic/clinical, 2-lesion volume/location, 3-local/global tissue volume, 4-local/global diffusion tensor imaging, and 5-whole-brain resting-state-functional-connectivity measures. In a final model, all important features from previous models were concatenated. Area under the receiver operating characteristic curve (AUC) values were calculated to evaluate classifier performance. RESULTS: The highest AUC value (0.90) was achieved by concatenating all important features from neuroimaging models. The top 10 contributing variables included volumes of bilateral nucleus accumbens and right thalamus, mean diffusivity of left cingulum-angular bundle, and functional connectivity among hubs of seven large-scale networks. CONCLUSION: These results provide an indication of a non-random brain pattern mostly compromising areas involved in attentional processes specific to patients who perform worse in SDMT. High accuracy of the final model supports this pattern as a potential neuroimaging biomarker of subtle cognitive changes in early MS.

eSupport: Feasibility trial of telehealth support group participation to reduce loneliness in multiple sclerosis.

BACKGROUND: Loneliness is a risk factor for increased morbidity and mortality. Persons with multiple sclerosis (pwMS) are at increased risk for loneliness. Support groups facilitate meaningful social connections. OBJECTIVE: To conduct a feasibility trial of eSupport: online support groups. METHODS: Participants engaged in 1 hour/week eSupport or eJournal (active control). Primary outcome was feasibility (completion and adherence). We evaluated loneliness and depressive symptoms for preliminary efficacy. RESULTS: Feasibility outcomes were met: completion rate was 96.4%; 88.9% were adherent. Loneliness and depression showed trend-level decreases in both conditions. CONCLUSION: Feasibility of telehealth support group participation for pwMS was supported. eSupport is accessible, affordable, acceptable, and scalable. Results warrant a randomized controlled trial to support efficacy.

Psychological resilience is linked to motor strength and gait endurance in early multiple sclerosis.

BACKGROUND: Psychologically resilient persons persist despite obstacles and bounce back after adversity, leading to better outcomes in non-neurologic populations. It is unknown whether psychological resilience relates to objective functional outcomes in multiple sclerosis (MS). OBJECTIVE: To determine whether psychological resilience explains differential objective cognitive and motor functioning in persons with early MS. METHODS: Psychological resilience was assessed in 185 patients with early MS and 50 matched healthy controls with the Connors-Davidson Resilience Scale (CDRS-10). Subjects completed the MS Functional Composite (MSFC) and a comprehensive neurobehavioral evaluation. Correlations assessed links between CDRS-10 and MSFC, motor indices (Total, Fine Motor, Gross Motor), and cognitive indices (Total, Cognitive Efficiency, Memory). RESULTS: Higher CDRS-10 among patients was linked to better MSFC and motor outcomes (but not cognition), with the most robust relationships for gross motor function (grip strength, gait endurance). Findings were independent of mood and fatigue. CDRS-10 was unrelated to MS disease burden. CDRS-10 was also specifically linked to motor outcomes in healthy controls. CONCLUSION: Functional outcomes vary across persons with MS, even when disease burden and neurologic disability are low. These findings identify high psychological resilience as a non-disease-specific contributor to motor strength and endurance, which may explain differential outcomes across patients.

Word-finding difficulty is a prevalent disease-related deficit in early multiple sclerosis.

BACKGROUND: Persons with multiple sclerosis (MS) commonly report word-finding difficulty clinically, yet this language deficit remains underexplored. OBJECTIVE: To investigate the prevalence and nature of word-finding difficulty in persons with early MS on three levels: patient report, cognitive substrates, and neuroimaging. METHODS: Two samples of early MS patients (n = 185 and n = 55; ⩽5 years diagnosed) and healthy controls (n = 50) reported frequency/severity of cognitive deficits and underwent objective assessment with tasks of rapid automatized naming (RAN), measuring lexical access speed, memory, word generation, and cognitive efficiency. High-resolution brain magnetic resonance imaging (MRI) derived measurements of regional cortical thickness, global and deep gray matter volume, and T2 lesion volume. Relationships among patient-reported word-finding difficulty, cognitive performance, and neural correlates were examined. RESULTS: Word-finding difficulty was the most common cognitive complaint of MS patients and the only complaint reported more by patients than healthy controls. Only RAN performance discriminated MS patients with subjective word-finding deficits from those without subjective complaints and from healthy controls. Thinner left parietal cortical gray matter independently predicted impaired RAN performance, driven primarily by the left precuneus. CONCLUSION: Three levels of evidence (patient-report, objective behavior, regional gray matter) support word-finding difficulty as a prevalent, measurable, disease-related deficit in early MS linked to left parietal cortical thinning.

Dissociable cognitive patterns related to depression and anxiety in multiple sclerosis.

BACKGROUND: Individuals with multiple sclerosis (MS) frequently present with depression and anxiety, as well as cognitive impairment, challenging clinicians to disentangle interrelationships among these symptoms. OBJECTIVE: To identify cognitive functions associated with anxiety and depression in MS. METHODS: Mood and cognition were measured in 185 recently diagnosed patients (Reserve Against Disability in Early Multiple Sclerosis (RADIEMS) cohort), and an independent validation sample (MEM CONNECT cohort, n = 70). Partial correlations evaluated relationships of cognition to anxiety and depression controlling for age, sex, education, and premorbid verbal intelligence. RESULTS: In RADIEMS cohort, lower anxiety was associated with better nonverbal memory (rp = -0.220, p = 0.003) and lower depression to better attention/processing speed (rp = -0.241, p = 0.001). Consistently, in MEM CONNECT cohort, lower anxiety was associated with better nonverbal memory (rp = -0.271, p = 0.028) and lower depression to better attention/processing speed (rp = -0.367, p = 0.002). Relationships were unchanged after controlling for T2 lesion volume and fatigue. CONCLUSION: Consistent mood-cognition relationships were identified in two independent cohorts of MS patients, suggesting that cognitive correlates of anxiety and depression are separable. This dissociation may support more precise models to inform treatment development. Treatment of mood symptoms may mitigate effects on cognition and/or treatment of cognition may mitigate effects on mood.

Mesial temporal lobe and subcortical grey matter volumes differentially predict memory across stages of multiple sclerosis.

BACKGROUND/OBJECTIVE: Memory deficits due to multiple sclerosis (MS) have been variably linked to lower subcortical grey matter (SCGM) and mesial temporal lobe (MTL) volumes. We investigated which is the better predictor and whether this changes across disease stages. METHODS/RESULTS: Memory was assessed in 315 patients. Magnetic resonance imaging (MRI) measured volumes of total brain, grey matter, white matter, MTL (hippocampus, amygdala) and SCGM (thalamus, caudate). MTL predicted memory in the total sample and in patients with earlier (<10 years) or later (⩾10 years) relapsing disease. SCGM (specifically thalamus) predicted memory in progressive patients. CONCLUSIONS: Neuroanatomical correlates of memory deficits differ across disease stages.

Aspirin is an effective pretreatment for exercise in multiple sclerosis: A double-blind randomized controlled pilot trial.

Exercise benefits multiple sclerosis (MS) patients, but exercise-induced overheating is a deterrent for many. We conducted a double-blind crossover-design placebo-controlled pilot of aspirin to increase time-to-exhaustion (TTE) and reduce exercise-induced body temperature increase. A total of 12 patients participated. At enrollment, 8 of 12 reported heat sensitivity during exercise. After 650 mg of aspirin or placebo, participants performed lower body cycle ergometer exercise test. TTE increased after aspirin compared to placebo: t(11) = 2.405, p = 0.035 (Cohen's d = 1.45). Body temperature increase after exercise with acetylsalicylic acid (ASA) was reduced by 56% in heat-sensitive patients, although limited power precluded statistical significance. Aspirin may represent an effective pretreatment for exercise in MS.

Functional network connectivity abnormalities in multiple sclerosis: Correlations with disability and cognitive impairment.

OBJECTIVE: To investigate resting state (RS) functional connectivity (FC) abnormalities within the principal brain networks in a large cohort of multiple sclerosis (MS) patients, to define the trajectory of FC changes over disease stages and their relation with clinical and structural magnetic resonance imaging (MRI) measures. METHODS: RS functional magnetic resonance imaging (fMRI), clinical, and neuropsychological evaluation were obtained from 215 MS patients and 98 healthy controls. Connectivity abnormalities and correlations with clinical/neuropsychological/imaging measures were evaluated. We analyzed seed-voxel FC with seven major hubs, producing one visual/sensory, one motor, two cognitive, one cerebellar, and two subcortical networks. RESULTS: MS patients showed reduced network average RS FC versus controls in the default-mode network. At regional level, a complex pattern of decreased and increased RS FC was found. Reduced RS FC mainly involved sensorimotor, cognitive, thalamic, and cerebellar networks, whereas increased RS FC involved visual/sensory and subcortical networks. Reduced RS FC correlated with T2 lesions. Reduced thalamic RS FC correlated with better neuropsychological performance, whereas for all remaining networks reduced FC correlated with more severe clinical/cognitive impairment. CONCLUSION: Increased and decreased RS FC occurs in MS and contributes to a wide spectrum of clinical manifestations. RS FC reduction is related to T2 lesions. Such a paradigm is inverted for the thalamic network.

Protective personality traits: High openness and low neuroticism linked to better memory in multiple sclerosis.

BACKGROUND: Memory impairment in multiple sclerosis (MS) is common, although few risk/protective factors are known. OBJECTIVE: To examine relationships of personality to memory/non-memory cognition in MS. METHOD: 80 patients completed a cognitive battery and a personality scale measuring the "Big 5" traits: openness, neuroticism, agreeableness, extraversion, and conscientiousness. RESULTS: Memory was most related to openness, with higher openness linked to better memory and lower risk for memory impairment, controlling for age, atrophy, education, and intelligence quotient (IQ). Lower neuroticism was also related to better memory, and lower conscientiousness to memory impairment. Non-memory cognition was unrelated to personality. CONCLUSION: Personality may inform predictive models of memory impairment in MS.