Mediterranean diet is linked to less objective disability in multiple sclerosis.

BACKGROUND: The multiple sclerosis (MS) community is highly interested in diet as a potential protective factor against disability, but empirical evidence remains limited. OBJECTIVE: Evaluate associations between patient-reported Mediterranean diet alignment and objective disability in a real-world MS cohort. METHODS: Data were analyzed from persons with MS, aged 18-65, who completed the Mediterranean Diet Adherence Screener (MEDAS), MS Functional Composite (MSFC; primary disability metric), and patient-reported outcomes (PROs; disability, gait disturbance, fatigue, anxiety, and depression) as part of our Comprehensive Annual Assessment Program. Multiple regression predicted MSFC (and PROs) with MEDAS after adjusting for demographic (age, sex, race, ethnicity, and socioeconomic status) and health-related (body mass index (BMI), exercise, sleep disturbance, hypertension, diabetes, hyperlipidemia, and smoking) covariates. RESULTS: Higher MEDAS independently predicted better outcomes across MSFC (z-score, B = 0.10 (95% confidence interval (CI): 0.06, 0.13), ß = 0.18, p < 0.001), MSFC components, and PROs in 563 consecutive patients. Each MEDAS point was associated with 15.0% lower risk for MSFC impairment (⩽ 5th percentile on ⩾ 2 tasks; odds ratio (OR) = 0.850; 95% CI: 0.779, 0.928). Higher MEDAS attenuated effects of progressive disease and longer disease duration on disability. CONCLUSION: With robust control for potential confounds, higher Mediterranean diet alignment predicted lower objective and patient-reported disability. Findings lay the necessary groundwork for longitudinal and interventional studies to guide clinical recommendations in MS.

Depression symptoms and cognition in multiple sclerosis: Longitudinal evidence of a specific link to executive control.

BACKGROUND: Depression symptoms are prevalent in multiple sclerosis (MS) and associated with poorer cognition in cross-sectional studies; it is unknown whether changes in depression symptoms track with cognitive changes longitudinally. OBJECTIVE: Investigate whether changes in depression symptoms correspond with cognitive changes over time in MS, and identify specific cognitive functions related to depression symptoms. METHOD: Persons with early relapse-onset MS (n = 165) completed a depression questionnaire (Beck Depression Inventory FastScreen) and tests of cognitive speed, executive control, and memory at baseline and 3-year follow-up. One-way ANOVAs assessed differences in cognitive change across participants with worsened, stable, or improved depression symptoms from baseline to year 3. RESULTS: Change in depression symptoms was related to change in executive control (p = 0.001, ηp2 = 0.08; worsened mood with worsened executive control; improved mood with improved executive control), even when adjusting for cognitive speed (p = 0.002, ηp2 = 0.08). There were no links to cognitive speed (p = 0.826) or memory (p = 0.243). Regarding individual depression symptoms, executive control was related to loss of pleasure and suicidal thoughts. CONCLUSIONS: Executive control tracks with depression symptoms, raising hope that management of mood may improve executive control. The specific link between executive control and anhedonia implicates dysfunctional reward processing as a key component of MS depression.

EDSS 0 is not normal: Multiple sclerosis disease burden below the clinical threshold.

Little to no above-threshold deficits may be evident in early multiple sclerosis (MS). The Expanded Disability Status Scale (EDSS) is a standard measure of neurologic function, with an EDSS score of 0 defined as "neurologically normal." The topographical model of MS proposes that sub-threshold disease is compensated for by functional reserve. In this short report, we found that physically high-challenge measures of balance and upper extremity coordination reveal sub-threshold deficits in patients with EDSS score of 0 compared with healthy controls. Challenge task performance was correlated with imaging markers of both lesional burden of disease and a volumetric measure of brain reserve.

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.

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.

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.

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.

Beyond rehabilitation: A prevention model of reserve and brain maintenance in multiple sclerosis.

Persons with multiple sclerosis (MS) experience cognitive and physical decline despite more effective disease-modifying therapies (DMTs), and symptomatic treatments currently have limited efficacy. The best treatment of MS disability may, therefore, be prevention of decline. Here, we present a working model of reserve and brain maintenance, with a focus on modifiable risk and protective factors. At disease onset, patients have varying degrees of reserve, broadly conceptualized as the dynamic availability of cerebral resources to support functional capacity. A clinical focus on prevention aims to minimize factors that deplete reserve (e.g. disease burden, comorbidities) and maximize factors that preserve reserve (e.g. DMTs, cardiovascular health). We review evidence for cardiovascular health, diet, and sleep as three potentially important modifiable factors that may modulate cerebral reserve generally, but also in disease-specific ways. We frame the brain as a limited capacity system in which inefficient usage of available cerebral capacity (reserve) leads to or exacerbates functional deficits, and we provide examples of factors that may lead to such inefficiency (e.g. poor mood, obesity, cognitive-motor dual-tasking). Finally, we discuss the challenges and responsibilities of MS neurologists and patients in pursuing comprehensive brain maintenance as a preventive approach.

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.

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.

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.

Effect of Retrieval Practice on Short-Term and Long-Term Retention in HIV+ Individuals.

OBJECTIVES: Episodic memory deficits are both common and impactful among persons infected with HIV; however, we know little about how to improve such deficits in the laboratory or in real life. Retrieval practice, by which retrieval of newly learned material improves subsequent recall more than simple restudy, is a robust memory boosting strategy that is effective in both healthy and clinical populations. In this study, we investigated the benefits of retrieval practice in 52 people living with HIV and 21 seronegatives. METHODS: In a within-subjects design, all participants studied 48 verbal paired associates in 3 learning conditions: Massed-Restudy, Spaced-Restudy, and Spaced-Testing. Retention of verbal paired associates was assessed after short- (30 min) and long- (30 days) delay intervals. RESULTS: After a short delay, both HIV+ persons and seronegatives benefited from retrieval practice more so than massed and spaced restudy. The same pattern of results was observed specifically for HIV+ persons with clinical levels of memory impairment. The long-term retention interval data evidenced a floor effect that precluded further analysis. CONCLUSIONS: This study provides evidence that retrieval practice improves verbal episodic memory more than some other mnemonic strategies among HIV+ persons. (JINS, 2017, 23, 214-222).

Reading, writing, and reserve: Literacy activities are linked to hippocampal volume and memory in multiple sclerosis.

BACKGROUND: Engagement in cognitive leisure activities during early adulthood has been linked to preserved memory and larger hippocampal volume in persons with multiple sclerosis (MS). OBJECTIVE: To investigate which specific types of cognitive leisure activities contribute to hippocampal volume and memory. METHODS: We investigated links between three types of cognitive activities (Reading-Writing, Art-Music, Games-Hobbies) and (a) hippocampal volume within independent samples of Italian (n=187) and American (n=55) MS patients and (b) memory in subsamples of Italian (n=97) and American (n=53) patients. RESULTS: Reading-Writing was the only predictor of hippocampal volume (rp=.204, p=.002), and the best predictor of memory (rp=.288, p=.001). CONCLUSIONS: Findings inform the development of targeted evidence-based enrichment programs aiming to bolster reserve against memory decline.

General Mathematical Ability Predicts PASAT Performance in MS Patients: Implications for Clinical Interpretation and Cognitive Reserve.

OBJECTIVES: The Paced Auditory Serial Addition Test (PASAT) is used to assess cognitive status in multiple sclerosis (MS). Although the mathematical demands of the PASAT seem minor (single-digit arithmetic), cognitive psychology research links greater mathematical ability (e.g., algebra, calculus) to more rapid retrieval of single-digit math facts (e.g., 5+6=11). The present study evaluated the hypotheses that (a) mathematical ability is related to PASAT performance and (b) both the relationship between intelligence and PASAT performance as well as the relationship between education and PASAT performance are both mediated by mathematical ability. METHODS: Forty-five MS patients were assessed using the Wechsler Test of Adult Reading, PASAT and Calculation Subtest of the Woodcock-Johnson-III. Regression based path analysis and bootstrapping were used to compute 95% confidence intervals and test for mediation. RESULTS: Mathematical ability (a) was related to PASAT (ß=.61; p<.001) and (b) fully mediated the relationship between Intelligence and PASAT (ß=.76; 95% confidence interval (CI95)=.28, 1.45; direct effect of Intelligence, ß=.42; CI95=-.39, 1.23) as well as the relationship between Education and PASAT (ß=2.43, CI95=.81, 5.16, direct effect of Education, ß=.83, CI95=-1.95, 3.61). DISCUSSION: Mathematical ability represents a source of error in the clinical interpretation of cognitive decline using the PASAT. Domain-specific cognitive reserve is discussed.

Retrieval practice as an effective memory strategy in children and adolescents with traumatic brain injury.

OBJECTIVE: To investigate whether retrieval practice (RP) is a more effective memory strategy than restudy in children and adolescents with traumatic brain injury (TBI). DESIGN: Three × two within-subjects experiment: 3 (learning condition: massed restudy [MR], spaced restudy [SR], retrieval practice [RP]) × 2 (stimulus type: verbal paired associates [VPAs] and face-name pairs [FNPs]). The dependent measure was delayed recall of VPAs and FNPs. SETTING: Subacute pediatric neurorehabilitation center. PARTICIPANTS: Pediatric survivors of TBI (N=15) aged 8 to 16 years with below-average memory. INTERVENTION: During RP, participants were quizzed on to-be-learned information (VPAs and FNPs) shortly after it was presented, such that they practiced retrieval during the learning phase. MR consisted of repeated restudy (tantamount to cramming). SR consisted of restudy trials separated in time (ie, distributed learning). MAIN OUTCOME MEASURES: Delayed recall of 24 VPAs and 24 FNPs after a 25-minute delay. VPAs and FNPs were equally divided across 3 learning conditions (16 per condition). RESULTS: There was a large main effect of learning condition on delayed recall (P<.001; ηp(2)=.84), with better mean recall of VPAs and FNPs studied through RP (6.23±1.39) relative to MR (3.60±1.53; P<.001) and SR (4.77±1.39; P<.001). Moreover, RP was the single best learning strategy for every participant. CONCLUSIONS: Memory problems and related academic learning difficulties are common after pediatric TBI. Herein, we identify RP as a promising and simple strategy to support learning and improve memory in children and adolescents with TBI. Our experimental findings were quite robust and set the stage for subsequent randomized controlled trials of RP in pediatric TBI.