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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), β = 0.18, p 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.

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.

BACKGROUND AND PURPOSE This study aims todetermine the sensitivity of superficial white matter (SWM) integrity as a metric to distinguish early multiple sclerosis (MS) patients from healthy controls (HC). METHODS Fractional anisotropy and mean diffusivity (MD) values from SWM bundles across the cortex and major deep white matter (DWM) tracts were extracted from 29 early MS patients and 31 age- and sex-matched HC. Thickness of 68 cortical regions and resting-state functional-connectivity (RSFC) among them were calculated. The distribution of structural and functional metrics between groups were compared using Wilcoxon rank-sum test. Utilizing a machine learning method (adaptive boosting), 6 models were built based on: 1-SWM, 2-DWM, 3-SWM and DWM, 4-cortical thickness, or 5-RSFC measures. In model 6, all features from previous models were incorporated. The models were trained with nested 5-folds cross-validation. Area under the receiver operating characteristic curve (AUCroc ) values were calculated to evaluate classification performance of each model. Permutation tests were used to compare the AUCroc values. RESULTS Patients had higher MD in SWM bundles including insula, inferior frontal, orbitofrontal, superior and medial temporal, and pre- and post-central cortices (p < .05). No group differences were found for any other MRI metric. The model incorporating SWM and DWM features provided the best classification (AUCroc = 0.75). The SWM model provided higher AUCroc (0.74), compared to DWM (0.63), cortical thickness (0.67), RSFC (0.63), and all-features (0.68) models (p < .001 for all). CONCLUSION Our results reveal a non-random pattern of SWM abnormalities at early stages of MS even before pronounced structural and functional alterations emerge.

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 0.50). 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.

ObjectiveTo test the hypothesis that higher-challenge gait and balance tasks are more sensitive than traditional metrics to subtle patient-reported gait dysfunction and future fall risk in early multiple sclerosis (MS).MethodsPersons with early MS (n = 185; ≤5 years diagnosed) reported gait function (MS Walking Scale) and underwent traditional disability metrics (Expanded Disability Status Scale [EDSS], Timed 25 Foot Walk). Patients and healthy controls (n = 50) completed clinically feasible challenge tasks of gait endurance (2-Minute Walk Test), standing balance (NIH Toolbox), and dynamic balance (balance boards; tandem walk on 2 ten-foot boards of different widths, 4.5 and 1.5 in). MRI assessed global and regional brain volumes, total T2 lesion volume (T2LV), infratentorial T2LVs and counts, and cervical cord lesion counts. Falls, near falls, and fall-related injuries were assessed after 1 year. We examined links between all tasks and patient-reported gait, MRI markers, and fall data.ResultsPatients performed worse on higher challenge balance, but not gait, tasks compared with healthy controls. Worse patient-reported gait disturbance was associated with worse performance on all tasks, but only dynamic balance was sensitive to mild patient-reported gait difficulty. Balance tasks were more correlated with MRI metrics than were walking tasks or EDSS score. Thirty percent of patients reported either a fall or near fall after 1 year, with poor dynamic balance as the only task independently predicting falls.ConclusionsBalance plays a leading role in gait dysfunction early in MS. Clinically feasible higher-challenge balance tasks were most sensitive to patient-reported gait, MRI disease markers, and risk of future falls, highlighting potential to advance functional outcomes in clinical practice and trials.

Thalamic atrophy is prominent in multiple sclerosis; however, it is unclear which thalamic nuclei are most vulnerable, especially early in disease.To investigate which thalamic nuclei differ between patients in early stages of relapsing-remitting multiple sclerosis (RRMS) versus healthy controls and examine the relationship between thalamic nuclei volume and T2 lesion volume.We derived 15 thalamic subfields from high-resolution 3T magnetic resonance images in 182 patients with early RRMS (diagnosed ≤5.0 years, median 2.0 years). Independent t-tests assessed differences between patients and 35 controls across thalamic subfield volumes. Pearson correlations assessed the relationships between thalamic volumes and T2 lesion volumes.Patients had lower anterior and posterior nuclei volume than controls, whereas medial and ventral nuclei volumes were preserved. Higher T2 lesion volumes were disproportionately related to lower posterior subfield volumes.We found specific thalamic subfields were more vulnerable to early disease-related changes. We discuss potential mechanisms of differential thalamic subfield atrophy in early MS, including cortical demyelination, CSF toxicity, leptomeningeal inflammation, and iron deposition.

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.

Background and ObjectivesTo evaluate the impact of fatigue after autoimmune encephalitis, determine associations with patients' characteristics, and identify factors that contribute to its development.MethodsIn a first cohort recruited via several encephalitis support organizations, self-reported questionnaires were used to evaluate fatigue, depression, and sleep quality in adults after autoimmune encephalitis. In a second cohort where more in-depth clinical characterization could be performed, adults with encephalitis from 2 tertiary hospitals were evaluated using the same questionnaires. Patients' characteristics were retrospectively captured.ResultsIn the first cohort (mean [SD] age; 43 [16] years, 220 [65%] female), 220 of 338 participants (65%) reported fatigue, 175 of 307 (57%) depression, and 211 of 285 (74%) poor sleep quality. In the second cohort (48 [19] years; 43 [50%] women), 42 of 69 participants (61%) reported fatigue, whereas 23 of 68 (34%) reported depression and 44 of 66 (67%) poor sleep quality, despite more than 80% having “good” modified Rankin scale (mRS) scores (0–2). Individuals with anti-NMDA receptor encephalitis reported lower fatigue scores than those with other autoimmune encephalitis types. In a multivariate analysis examining factors at discharge that might predict fatigue scores, only anti-NMDA receptor encephalitis was a (negative) predictor of fatigue and remained so when potential confounders were included.DiscussionThe impact of fatigue after autoimmune encephalitis is prominent and not fully accounted for by depression or sleep quality, nor adequately captured by mRS scores for disability. Fatigue is pervasive across autoimmune encephalitis, although lower scores are reported in anti-NMDA receptor encephalitis. Fatigue should be screened routinely, considered as an outcome measure in clinical trials, and further studied from a mechanistic standpoint.

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.

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.

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.

BACKGROUND: Despite significant interest in diet by the MS community, research on this topic is limited; there are no published studies evaluating associations between diet and neuroimaging in MS. METHODS: We utilized baseline data from the RADIEMS cohort of early MS (diagnosed

Background The Symbol Digit Modalities Test (SDMT) is the most sensitive metric of neurocognitive function in multiple sclerosis (MS), and is consistently interpreted as a measure of information processing speed (IPS). Objective To evaluate the cognitive psychometric profile captured by the SDMT to identify whether different cognitive processes independently underlie performance. Methods Three samples of MS patients (total n=661; 185 research patients at MS center; 370 clinical patients at MS center; 106 persons with MS from the community) completed objective assessments of neuropsychological function across cognitive domains. Exploratory factor analysis (EFA) was used to derive latent cognitive factor scores, and operationalize cognitive domain composite scores, to understand the unique, shared and redundant contribution of different cognitive domains to SDMT performance using hierarchical multiple regression and commonality analysis. Results Across three independent samples we provide converging strong evidence that the cognitive domains of Memory, IPS and Rapid Automatized Naming (lexical access speed) jointly and uniquely contribute to SDMT performance. Conclusion The SDMT measures multiple cognitive processes, which likely explains the high degree of sensitivity to cognitive change in MS. Researchers and clinicians should interpret the SDMT as a multifarious measure of general cognition rather than a specific test of IPS.

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.

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.

There is a sizeable literature describing the behavioral sequelae of multiple sclerosis (MS). This has traditionally been divided into 2 broad categories, namely, disorders of cognition and emotion. Few studies have explored the relationship between them and those that have were focused predominantly on depression rather than anxiety. In general, the results show that deficits in processing speed, working memory, and executive function can arise as a consequence of depression, albeit at the more severe end of the depressive spectrum. Given that cognitive dysfunction is a common and currently intractable symptom of MS, affecting up to 70% of people and impeding employment, relationships, and leisure pursuits,1 any condition that adds to this burden must be cause for concern.

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.

Objective: The brain reserve hypothesis links larger maximal lifetime brain growth (MLBG, estimated with intracranial volume [ICV]) with lower risk for cognitive decline/dementia. We examined whether larger MLBG is also linked to less physical disability progression over 5 years in a prospective sample of treatment-naive patients with multiple sclerosis (MS). Methods: Physical disability was measured with the Expanded Disability Status Scale (EDSS) at baseline and 5-year follow-up in 52 treatment-naive Serbian patients with MS. MRI measured disease burden (cerebral atrophy, T2 lesion volume) and MLBG: a genetically determined, premorbid (established during adolescence, stable thereafter) patient characteristic estimated with ICV (adjusted for sex). Logistic regression tested whether MLBG (smaller vs larger) predicts disability progression (stable vs worsened) independently of disease burden. Results: Disability progression was observed in 29 (55.8%) patients. Larger MLBG predicted lower risk for progression (odds ratio 0.13, 95% confidence interval 0.02–0.78), independently of disease burden. We also calculated absolute change in EDSS scores, and observed that patients with smaller MLBG showed worse EDSS change (0.91 ± 0.71) than patients with larger MLBG (0.42 ± 0.87). Conclusions: Larger MLBG was linked to lower risk for disability progression in patients with MS over 5 years, which is the first extension of the brain reserve hypothesis to physical disability. MLBG (ICV) represents a clinically available metric that may help gauge risk for future disability in patients with MS, which may advance the science and practice of early intervention. Potential avenues for future research are discussed.

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 (β=.61; p<.001) and (b) fully mediated the relationship between Intelligence and PASAT (β=.76; 95% confidence interval (CI95)=.28, 1.45; direct effect of Intelligence, β=.42; CI95=−.39, 1.23) as well as the relationship between Education and PASAT (β=2.43, CI95=.81, 5.16, direct effect of Education, β=.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. (JINS, 2016, 22, 375–378)

Cognitive decline is recognized as a prevalent and debilitating symptom of multiple sclerosis (MS), especially deficits in episodic memory and processing speed. The field aims to (1) incorporate cognitive assessment into standard clinical care and clinical trials, (2) utilize state-of-the-art neuroimaging to more thoroughly understand neural bases of cognitive deficits, and (3) develop effective, evidence-based, clinically feasible interventions to prevent or treat cognitive dysfunction, which are lacking. There are obstacles to these goals. Our group of MS researchers and clinicians with varied expertise took stock of the current state of the field, and we identify several important practical and theoretical challenges, including key knowledge gaps and methodologic limitations related to (1) understanding and measurement of cognitive deficits, (2) neuroimaging of neural bases and correlates of deficits, and (3) development of effective treatments. This is not a comprehensive review of the extensive literature, but instead a statement of guidelines and priorities for the field. For instance, we provide recommendations for improving the scientific basis and methodologic rigor for cognitive rehabilitation research. Toward this end, we call for multidisciplinary collaborations toward development of biologically based theoretical models of cognition capable of empirical validation and evidence-based refinement, providing the scientific context for effective treatment discovery.

Background and purpose Cognitive impairment in primary-progressive multiple sclerosis (PP-MS) is correlated with global brain atrophy. Unfortunately, brain volume computation requires processing resources that are not widely available in clinical practice. Therefore, we decided to test the predictive role of retinal atrophy metrics on cognitive decline, applying them as a proxy of gray matter atrophy in PP-MS. Methods Twenty-five patients with PP-MS completed the Brief International Cognitive Assessment for Multiple Sclerosis and underwent spectral-domain optical coherence tomography (OCT) and 3.0-T magnetic resonance imaging. We tested, through a stepwise logistic regression, whether OCT metrics [retinal nerve fiber layer, ganglion cell + inner plexiform layer (GCIPL) and total macular volume] predicted cognitive impairment and explored the role of gray matter atrophy in mediating these correlations. Results Among OCT metrics, only GCIPL was associated with cognitive impairment (rp = 0.448, P = 0.036) and predictive of objective cognitive impairment (Wald [1] = 4.40, P = 0.036). Controlling for demographics, normalized brain volume and thalamic volume were correlated with GCIPL (rp = 0.427, P = 0.047 and rp = 0.674, P = 0.001, respectively) and cognitive scores (rp = 0.593, P = 0.004 and rp = 0.501, P = 0.017, respectively), with thalamic volume nearly mediating the association between GCIPL and cognition (Sobel z = 1.86, P = 0.063). Conclusions The GCIPL thickness is a suitable measure of neurodegeneration. In comparison with brain atrophy, GCIPL offers higher histopathological specificity, being a pure correlate of neuronal loss, and may be a non-invasive, easy-to-perform way to quantitatively evaluate and monitor neuronal loss related to cognitive impairment in PP-MS.

Cognitive decline is recognized as a prevalent and debilitating symptom of multiple sclerosis (MS),1 with cognitive changes often occurring early in the disease course.2 Even relatively subtle cognitive decline can have substantial real-life consequences, including negative effects on employment3 and quality of life, both for people with MS and their caregivers.4 Heightened awareness of disease-related cognitive decline has motivated cognitive screenings as a key component of comprehensive care at clinical MS centers; however, increased awareness and clinical attention has also highlighted the lack of effective symptomatic treatments for cognitive deficits.5,6 Obstacles encumbering validation of effective treatments have been discussed,1 including a lack of methodologic rigor in clinical trials aiming to improve cognition.5,6

In patients with multiple sclerosis (MS), grey matter damage is widespread and might underlie many of the clinical symptoms, especially cognitive impairment. This relation between grey matter damage and cognitive impairment has been lent support by findings from clinical and MRI studies. However, many aspects of cognitive impairment in patients with MS still need to be characterised. Standardised neuropsychological tests that are easy to administer and sensitive to disease-related abnormalities are needed to gain a better understanding of the factors affecting cognitive performance in patients with MS than exists at present. Imaging measures of the grey matter are necessary, but not sufficient to fully characterise cognitive decline in MS. Imaging measures of both lesioned and normal-appearing white matter lend support to the hypothesis of the existence of an underlying disconnection syndrome that causes clinical symptoms to trigger. Findings on cortical reorganisation support the contribution of brain plasticity and cognitive reserve in limiting cognitive deficits. The development of clinical and imaging biomarkers that can monitor disease development and treatment response is crucial to allow early identification of patients with MS who are at risk of cognitive impairment.

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.

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 (Conclusions: Neuroanatomical correlates of memory deficits differ across disease stages.

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)

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.

Memory impairment affects 50% of multiple sclerosis (MS) patients. Altered resting-state functional connectivity (FC) has been observed in the default network (DN) of MS patients. No study to date has examined the association of DN FC to its behavioral concomitant, memory. The approach of the present study represents a methodological shift allowing straightforward interpretation of FC alterations in MS, as it presupposes specificity of a network to its paired cognitive function. We examined FC from fMRI collected during rest in the DN of 43 MS patients with and without memory-impairment. Memory-intact patients showed increased DN FC relative to memory-impaired patients. There were no regions of higher FC in memory-impaired patients. DN FC was positively correlated with memory function, such that higher FC was associated with better memory performance. Results were unchanged after controlling for cognitive efficiency, supporting specificity of the DN to memory and not cognitive status more generally. These findings support DN FC as a marker of memory function in MS patients that can be targeted by future treatment interventions. Pairing a functional network with its behavioral concomitant represents a straightforward method for interpreting FC alterations in patients with MS. (JINS, 2014, 20, 1–8)

Some individuals with multiple sclerosis (MS) show decrements in long-term memory (LTM) while other individuals do not. The theory of cognitive reserve suggests that individuals with greater pre-morbid intellectual enrichment are protected from disease-related cognitive decline. How intellectual enrichment affords this benefit remains poorly understood. The present study tested an exploratory meditational hypothesis whereby working memory (WM) capacity may mediate the relationship between intellectual enrichment and verbal LTM decline in MS. Intellectual enrichment, verbal LTM, and WM capacity were estimated with the Wechsler Test of Adult Reading and Peabody Picture Vocabulary Test, delayed recall of the Hopkins Verbal Learning Test-Revised and Logical Memory of the Wechsler Memory Scale, and Digit Span Total, respectively. Intellectual enrichment predicted LTM (B=.54;p=.003) and predicted WM capacity (B=.91;pB=.44;pB=.24;p=.27) and LTM (B=.33,p=.03), Sobel test,Z=3.31,pJINS, 2014,20, 1–5)

Objectives To investigate whether (1) resting body temperature is elevated in patients with relapsing-remitting multiple sclerosis (RRMS) relative to healthy individuals and patients with secondary progressive multiple sclerosis (SPMS), and (2) warmer body temperature is linked to worse fatigue in patients with RRMS. Design Cross-sectional study. Setting Climate-controlled laboratory (∼22°C) within a nonprofit medical rehabilitation research center. Participants Patients with RRMS (n=50), matched healthy controls (n=40), and patients with SPMS (n=22). Intervention Not applicable. Main Outcome Measures Body temperature was measured with an aural infrared thermometer (normative body temperature for this thermometer, 36.75°C), and differences were compared across patients with RRMS and SPMS and healthy persons. Patients with RRMS completed measures of general fatigue (Fatigue Severity Scale [FSS]), as well as physical and cognitive fatigue (Modified Fatigue Impact Scale [MFIS]). Results There was a large effect of group ( P p 2 =.132) whereby body temperature was higher in patients with RRMS (37.04°±.27°C) relative to healthy controls (36.83°±.33°C; P =.009) and patients with SPMS (36.75°±.39°C; P =.001). Warmer body temperature in patients with RRMS was associated with worse general fatigue (FSS; r p =.315, P =.028) and physical fatigue (physical fatigue subscale of the MFIS; r p =.318, P =.026), but not cognitive fatigue (cognitive fatigue subscale of the MIFS; r p =–.017, P =.909). Conclusions These are the first-ever demonstrations that body temperature is elevated endogenously in patients with RRMS and linked to worse fatigue. We discuss these findings in the context of failed treatments for fatigue in RRMS, including several failed randomized controlled trials (RCTs) of stimulants (modafinil). In contrast, our findings may help explain how RCTs of cooling garments and antipyretics (aspirin) have effectively reduced MS fatigue, and encourage further research on cooling/antipyretic treatments of fatigue in RRMS.

Objective: Based on the theories of brain reserve and cognitive reserve, we investigated whether larger maximal lifetime brain growth (MLBG) and/or greater lifetime intellectual enrichment protect against cognitive decline over time. Methods: Forty patients with multiple sclerosis (MS) underwent baseline and 4.5-year follow-up evaluations of cognitive efficiency (Symbol Digit Modalities Test, Paced Auditory Serial Addition Task) and memory (Selective Reminding Test, Spatial Recall Test). Baseline and follow-up MRIs quantified disease progression: percentage brain volume change (cerebral atrophy), percentage change in T2 lesion volume. MLBG (brain reserve) was estimated with intracranial volume; intellectual enrichment (cognitive reserve) was estimated with vocabulary. We performed repeated-measures analyses of covariance to investigate whether larger MLBG and/or greater intellectual enrichment moderate/attenuate cognitive decline over time, controlling for disease progression. Results: Patients with MS declined in cognitive efficiency and memory ( p p = 0.031, η p 2 = 0.122), with larger MLBG protecting against decline. MLBG did not moderate memory decline ( p = 0.234, η p 2 = 0.039). Intellectual enrichment moderated decline in cognitive efficiency ( p = 0.031, η p 2 = 0.126) and memory ( p = 0.037, η p 2 = 0.115), with greater intellectual enrichment protecting against decline. MS disease progression was more negatively associated with change in cognitive efficiency and memory among patients with lower vs higher MLBG and intellectual enrichment. Conclusion: We provide longitudinal support for theories of brain reserve and cognitive reserve in MS. Larger MLBG protects against decline in cognitive efficiency, and greater intellectual enrichment protects against decline in cognitive efficiency and memory. Consideration of these protective factors should improve prediction of future cognitive decline in patients with MS.

Elevated body temperature was recently reported for the first time in patients with relapsing-remitting multiple sclerosis (RRMS) relative to healthy controls. In addition, warmer body temperature was associated with worse fatigue. These findings are highly novel, may indicate a novel pathophysiology for MS fatigue, and therefore warrant replication in a geographically separate sample. Here, we investigated body temperature and its association to fatigue in an Italian sample of 44 RRMS patients and 44 age- and sex-matched healthy controls. Consistent with our original report, we found elevated body temperature in the RRMS sample compared to healthy controls. Warmer body temperature was associated with worse fatigue, thereby supporting the notion of endogenous temperature elevations in patients with RRMS as a novel pathophysiological factor underlying fatigue. Our findings highlight a paradigm shift in our understanding of the effect of heat in RRMS, from exogenous (i.e., Uhthoff's phenomenon) to endogenous. Although randomized controlled trials of cooling treatments (i.e., aspirin, cooling garments) to reduce fatigue in RRMS have been successful, consideration of endogenously elevated body temperature as the underlying target will enhance our development of novel treatments.

Cognitive impairment is common among persons with multiple sclerosis (MS), but some patients are able to withstand considerable disease burden (e.g. white matter lesions, cerebral atrophy) without cognitive impairment (cognitive inefficiency, memory decline). What protects these patients from cognitive impairment? We review the literature on cognitive reserve in MS, which shows that heritable (larger maximal lifetime brain growth) and environmental (greater intellectual enrichment) factors attenuate the negative effect of disease burden on cognitive status. That is, persons with larger maximal lifetime brain growth, greater vocabulary knowledge, and/or greater early life participation in cognitive leisure activities (e.g. reading, hobbies) are better able to cope with MS disease without cognitive impairment. We review evidence that benefits of intellectual enrichment on cognitive status may stem from more efficient patterns of brain function. We discuss clinical implications and highlight important unanswered questions for future research on reserve against cognitive impairment in MS.

Memory impairment is prevalent in multiple sclerosis (MS). Retrieval practice is a powerful memory technique whereby retrieving information (quizzing oneself) leads to better memory than restudying. In a within-subjects experiment, 12 memory-impaired MS patients encoded verbal paired associates (VPAs) through massed restudy (MR), spaced restudy (SR), or retrieval practice (RP). Half of VPAs were tested after short delay (30 minutes) and half after long delay (one week). RP robustly improved memory more than restudy. Short delay: MR=15.6%, SR=27.1%, RP=72.9%. Long delay: MR=1.0%, SR=4.2%, RP=24.0%. RP was the best memory technique for nearly all patients after both short and long delays.

Summary: A previous investigation of the cognitive processes underlying note-taking found that handwriting speed was the only significant predictor of notes, and notes were the only significant predictor of test performance. This investigation sought to extend these results by evaluating the effects of handwriting speed, language comprehension, two measures of working memory (complex span and executive attention) and an outline on note-taking and test performance (written summary). Participants were randomly assigned to an outline or not no-outline group (Group) to determine the effect of an outline on handwriting speed. Results from a path analysis indicated that handwriting speed, language comprehension and Group were significantly related to notes. The relationship between the independent variables and the written summary was not completely mediated by notes as in the previous investigation. Notes, Group and language comprehension were related to the written summary. The implications of the findings are discussed. Copyright © 2012 John Wiley & Sons, Ltd. After approximately three decades of research (Berninger & Richards, 2012), there seems to be a consensus about the cognitive processes related to writing essays. Theory and research suggests that writers must be fluent in (i) generating

Head movement during functional magnetic resonance imaging (fMRI) degrades data qual- ity. The effects of small movements can be ameliorated during data postprocessing, but data associ- ated with severe movement is frequently discarded. In discarding these data, it is often assumed that head-movement is a source of random error, and that data can be discarded from subjects with severe movement without biasing the sample. We tested this assumption by examining whether head movement was related to task difficulty and cognitive status among persons with multiple scle- rosis (MS). Thirty-four persons with MS were scanned while performing a working memory task with three levels of difficulty (the N-back task). Maximum movement (angle, shift) was estimated for each difficulty level. Cognitive status was assessed by combining performance on a working memory and processing speed task. An interaction was found between task difficulty and cognitive status (high vs. low cognitive ability): there was a linear increase in movement as task difficulty increased that was larger among subjects with lower cognitive ability. Analyses of the signal-to-noise ratio (SNR) confirmed that increases in movement degraded data quality. Similar, though far smaller, effects were found in a cohort of healthy control (HC) subjects. Therefore, discarding data with severe movement artifact may bias MS samples such that only those with less-severe cognitive impairment are included in the analyses. However, even if such data are not discarded outright, sub- jects who move more (MS and HC) will contribute less to the group-level results because of

Patients with multiple sclerosis (MS) suffer memory impairment but the link between MS-related neuroanatomical changes (brain atrophy) and memory is relatively weak.The purpose of this study was to use functional magnetic resonance imaging (fMRI) to investigate task-induced default network (DN) deactivation as a neurophysiologic biomarker of memory functioning in MS.Twenty-eight MS patients underwent high-resolution MRIs to measure brain atrophy (third ventricle width, cerebral gray matter, cerebral white matter, parenchymal fraction, and thalamic, caudate, hippocampal, and amygdala volumes), and fMRI blood oxygen level dependent (BOLD) signal to measure DN deactivation during sustained attention relative to rest. Neuropsychological assessment of episodic memory was performed on a separate day. We used hierarchical regression to predict memory, with age, education, and depression in step one, brain atrophy within step two, DN activity within step three, and the interaction between brain atrophy and DN activity in step four.Brain atrophy predicted worse memory but DN activity independently predicted memory over-and-above measurements of brain atrophy (R (2)=0.108), with greater DN activity (lesser deactivation) linked to better memory. A significant brain atrophy by DN activity interaction indicated a stronger relationship between memory and DN activity among patients with more advanced disease, at which point higher DN activity protects patients from disease/atrophy-related memory impairment. To establish specificity, we showed no relationship between DN activity and non-memory cognition, and no relationship between non-DN brain activity and memory.Maintenance of DN activity during sustained attention was supported as a sensitive and specific neurophysiologic biomarker of episodic memory functioning in MS, even when controlling for neuroanatomical changes (brain atrophy).

Generally, so-called control processes are thought to be necessary when we must perform one out of several competing actions. Some examples include performance of a less well-practiced action instead of a well-practiced one (prepotency); learning a new action (novelty); and rapidly switching from one action to another (task-switching). While it certainly is difficult to perform the desired action in these circumstances, it is less clear that a separate set of processes (e.g., control processes) are necessary to explain the observed behavior. Another way to approach the study of control processes is to investigate physiological dependent measures (e.g., electrophysiological or neuroimaging measures). Although these offer another avenue of inquiry into control processes, they have yet to furnish unambiguous evidence that control processes exist. While this might suggest that there are no control processes, it is also possible that our methods are insufficiently sensitive to measure control processes. We have investigated this latter possibility using tasks that are neuroanatomically distinct, though within the same modality (vision). This approach did not yield evidence for a separable set of control processes. However, recent works using a task-switching paradigm in which subjects switch between a visual and an auditory task suggest that switching both task and modality may be importantly different than switching task within a given modality. This may represent a way forward in the study of control processes.

Summary Despite the importance of notes to test performance, very little is known about the cognitive variables related to notetaking, especially text notes. The primary purpose of this study was to evaluate the contributions of transcription fluency, reading comprehension, verbal working memory, executive attention, and background knowledge to the quality of text notes. A secondary purpose was to evaluate the relationship of all of the other aforementioned variables to three test types to determine if notes are more important to some test types than others: a free recall essay and two types of multiple choice items: memory items and inference items. Results indicated that transcription fluency was the best predictor of notes (reading comprehension was also significant predictor), which extends previous findings on the importance of transcription fluency to lecture notes. Notes' were the best predictor of the essay and the memory multiple choice items but not the inference items. Copyright © 2011 John Wiley & Sons, Ltd.

Background: Memory impairment is prevalent in multiple sclerosis (MS), but no drugs are approved to treat these memory problems. Objective: The objective of the study was to examine the effect of l-amphetamine versus placebo on auditory/verbal memory and visual/spatial memory in MS patients with and without baseline memory impairment. Methods: We conducted a re-analysis of a previously published clinical trial in which MS patients were randomly assigned to treatment (30 mg l-amphetamine, N = 99) or placebo ( N = 37) in a four-week, double-blind, parallel-group, dose titration trial. Auditory/verbal memory (CVLT-II: Long Delay Free Recall) and visual/spatial memory (BVMT-R: Delayed Recall) were assessed at baseline and follow-up across subgroups of patients with intact baseline memory (mean = 50th percentile) or impaired baseline memory (mean = 2nd percentile). Primary analyses: 2 ( l-amphetamine, placebo) × 2 (baseline, follow-up), × 2 (baseline memory intact, baseline memory impaired) ANOVAs performed separately for auditory/verbal and visual/spatial memory. Results: For both auditory/verbal and visual/spatial memory, we observed significant 2 × 2 × 2 interactions whereby l-amphetamine improved memory more than placebo, and this effect was specific to patients with baseline memory impairment. Conclusions: Among memory-impaired patients, memory improved about 48.5% for those on l-amphetamine, but only 1.0% on placebo. Treatment with l-amphetamine produced large memory gains among memory-impaired MS patients.

Consistent with the cognitive reserve hypothesis, higher education and vocabulary help persons with Alzheimer disease (AD) and multiple sclerosis (MS) better withstand neuropathology before developing cognitive impairment. Also, premorbid cognitive leisure (e.g., reading, hobbies) is an independent source of cognitive reserve for elders with AD, but there is no research on the contribution of leisure activity to cognition in MS. We investigated whether premorbid cognitive leisure protects patients with MS from cognitive impairment.Premorbid cognitive leisure was surveyed in 36 patients with MS. Neurologic disease severity was estimated with brain atrophy, measured as third ventricle width on high-resolution MRI. Cognitive status was measured with a composite score of processing speed and memory.Controlling for brain atrophy, premorbid cognitive leisure was positively associated with current cognitive status (r(p) = 0.49, p0.01), even when controlling for vocabulary (r(p) = 0.39, p0.05) and education (r(p) = 0.47, p0.01). Also, premorbid cognitive leisure was unrelated to brain atrophy (r = 0.03, p0.5), but a positive partial correlation between leisure and atrophy emerged when controlling for cognitive status (r(p) = 0.37, p0.05), which remained when also controlling for vocabulary (r(p) = 0.34, p0.05) and education (r(p) = 0.35, p0.05).Premorbid cognitive leisure contributes to cognitive status in patients with MS independently of vocabulary and education. Also, patients with MS who engaged in more cognitive leisure were able to withstand more severe brain atrophy at a given cognitive status. Premorbid cognitive leisure is supported as an independent source of cognitive reserve in patients with MS.

Memory impairment is common following traumatic brain injury (TBI), but interventions to improve memory in persons with TBI have been ineffective. Retrieval practice is a robust memory strategy among healthy undergraduates, whereby practice retrieving information shortly after it is presented leads to better delayed recall than simple restudy. In a verbal paired associate paradigm, we investigated the effect of retrieval practice relative to massed and spaced restudy on delayed recall in 14 persons with chronic memory impairment following a TBI and 14 age-matched healthy controls. A significant learning condition (massed restudy, spaced restudy, retrieval practice) by group (TBI, healthy) interaction emerged, whereby only healthy controls benefited from spaced restudy (i.e., distributed learning) over massed restudy, but both groups greatly benefited from retrieval practice over massed and spaced restudy. That is, retrieval practice greatly improves memory in persons with TBI, even when other mnemonic strategies (e.g., distributed learning) are less effective. (JINS, 2010, 16, 1147–1150.)