Cognitive Function In Multiple Sclerosis Research Articles

Optimizing Detection and Prediction of Cognitive Function in Multiple Sclerosis With Ambulatory Cognitive Tests: Protocol for the Longitudinal Observational CogDetect-MS Study.

Cognitive dysfunction is a common problem in multiple sclerosis (MS). Progress toward understanding and treating cognitive dysfunction is thwarted by the limitations of traditional cognitive tests, which demonstrate poor sensitivity and ecological validity. Ambulatory methods of assessing cognitive function in the lived environment may improve the detection of subtle changes in cognitive function and the identification of predictors of cognitive changes and downstream effects of cognitive change on other functional domains. This paper describes the study design and protocol for the Optimizing Detection and Prediction of Cognitive Function in Multiple Sclerosis (CogDetect-MS) study, a 2-year longitudinal observational study designed to examine short- and long-term changes in cognition, predictors of cognitive change, and effects of cognitive change on social and physical function in MS. Participants-ambulatory adults with medically documented MS-are assessed over the course of 2 years on an annual basis (3 assessments: T1, T2, and T3). A comprehensive survey battery, in-laboratory cognitive and physical performance tests, and 14 days of ambulatory data collection are completed at each annual assessment. The 14-day ambulatory data collection includes continuous wrist-worn accelerometry (to measure daytime activity and sleep); ecological momentary assessments (real-time self-report) of somatic symptoms, mood, and contextual factors; and 2 brief, validated cognitive tests, administered by smartphone app 4 times per day. Our aim was to recruit 250 participants. To ensure standard test protocol administration, all examiners passed a rigorous examiner certification process. Planned analyses include (1) nonparametric 2-tailed t tests to compare in-person to ambulatory cognitive test scores; (2) mixed effects models to examine cognitive changes over time; (3) mixed effects multilevel models to evaluate whether ambulatory measures of physical activity, sleep, fatigue, pain, mood, and stress predict changes in objective or subjective measures of cognitive functioning; and (4) mixed effects multilevel models to examine whether ambulatory measures of cognitive functioning predict social and physical functioning over short (within-day) and long (over years) time frames. The study was funded in August 2021 and approved by the University of Michigan Medical Institutional Review Board on January 27, 2022. A total of 274 adults with MS (first participant enrolled on May 12, 2022) have been recruited and provided T1 data. Follow-up data collection will continue through March 2026. Results from the CogDetect-MS study will shed new light on the temporal dynamics of cognitive function, somatic and mood symptoms, sleep, physical activity, and physical and social function. These insights have the potential to improve our understanding of changes in cognitive function in MS and enable us to generate new interventions to maintain or improve cognitive function in those with MS. ClinicalTrials.gov NCT05252195; https://clinicaltrials.gov/study/NCT05252195. DERR1-10.2196/59876.

Lowered ratio of corticospinal excitation to inhibition predicts greater disability, poorer motor and cognitive function in multiple sclerosis

ObjectiveInvestigate excitatory-inhibitory (E/I) (im)balance using transcranial magnetic stimulation (TMS) in individuals with Multiple Sclerosis (MS) and determine its validity as a neurophysiological biomarker of disability. MethodsParticipants with MS (n = 83) underwent TMS, cognitive, and motor function assessments. TMS-induced motor evoked potential amplitudes (excitability) and cortical silent periods (inhibition) were assessed bilaterally through recruitment curves. The E/I ratio was calculated as the ratio of excitation to inhibition. ResultsParticipants with greater disability (Expanded Disability Status Scale, EDSS≥3) exhibited lower excitability and increased inhibition compared to those with lower disability (EDSS<3). This resulted in lower E/I ratios in the higher disability group. Individuals with higher disability presented with asymmetrical E/I ratios between brain hemispheres, a pattern not present in the group with lower disability. In regression analyses controlling for demographics, lowered TMS-probed E/I ratio predicted variance in disability (R2 = 0.37, p < 0.001), upper extremity function (R2 = 0.35, p < 0.001), walking speed (R2 = 0.22, p = 0.005), and cognitive performance (R2 = 0.25, p = 0.007). Receiver Operating Characteristic curve analysis confirmed ‘excellent’ discriminative ability of the E/I ratio in distinguishing high and low disability. Finally, excitation superiorly correlated with the E/I ratio than overall inhibition in both hemispheres (p ≤ 0.01). ConclusionThe E/I ratio is a potential neurophysiological biomarker of disability level in MS, especially when assessed in the hemisphere corresponding to the weaker body side. Interventions aimed at increasing cortical excitation or reducing inhibition may restore E/I balance potentially stalling progression or improving function in MS.

Effect of Aerobic Exercise versus Non-Invasive Brain Stimulation on Cognitive Function in Multiple Sclerosis: A Systematic Review and Meta-Analysis.

In this study, we investigated the effects of noninvasive brain stimulation (NIBS) and exercise on cognition in patients with multiple sclerosis (pwMS). A literature search was performed using the Cochrane Library, Scopus, PubMed and Web of Science. The time interval used for database construction was up to February 2024; the collected trials were subsequently screened, and the data were extracted. We identified 12 studies with 208 pwMS treated with noninvasive brain stimulation. Seven of the twelve studies concluded that NIBS was effective in improving reaction time, attention and processing speed. Additionally, 26 articles investigated the effect of various types of exercise on cognition among 708 pwMS. Twelve studies used aerobic exercise only, three studies used resistance only, one used yoga, and ten studies used mixed forms of exercise, such as Pilates, resistance and Frenkel coordination. Aerobic exercise was effective in improving at least one cognitive domain in ten studies. Resistance exercise was found to improve cognition in three studies. Yoga failed to show any improvement in one study. NIBS might be an effective intervention for cognition improvement among pwMS. Aerobic exercise and combined forms of exercise are the most frequently investigated and applied and found to be effective. Further studies are needed, especially for resistance, balance and stretching exercises.

Digital symbol-digit modalities test with modified flexible protocols in patients with CNS demyelinating diseases

Cognitive impairment (CI) is prevalent in central nervous system demyelinating diseases, such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We developed a novel tablet-based modified digital Symbol Digit Modalities Test (MD-SDMT) with adjustable protocols that feature alternating symbol-digit combinations in each trial, lasting one or two minutes. We assessed 144 patients (99 with MS and 45 with NMOSD) using both MD-SDMT protocols and the traditional paper-based SDMT. We also gathered participants’ feedback through a questionnaire regarding their preferences and perceived reliability. The results showed strong correlations between MD-SDMT and paper-based SDMT scores (Pearsons correlation: 0.88 for 2 min; 0.85 for 1 min, both p < 0.001). Among the 120 respondents, the majority preferred the digitalized SDMT (55% for the 2 min, 39% for the 1 min) over the paper-based version (6%), with the 2 min MD-SDMT reported as the most reliable test. Notably, patients with NMOSD and older individuals exhibited a preference for the paper-based test, as compared to those with MS and younger patients. In summary, even with short test durations, the digitalized SDMT effectively evaluates cognitive function in MS and NMOSD patients, and is generally preferred over the paper-based method, although preferences may vary with patient characteristics.

Monitoring cognitive functioning in multiple sclerosis will trigger anxiety in patients: Commentary

Monitoring cognitive functioning in multiple sclerosis will trigger anxiety in patients: Commentary

The influence of depression and anxiety on cognition in people with multiple sclerosis: a cross-sectional analysis.

There are conflicting findings about the relationships between depression, anxiety, and cognitive dysfunction in people with multiple sclerosis (MS), and a paucity of research has examined the cumulative influence on cognition of depression plus anxiety. This study aimed to determine whether elevated symptoms of depression and anxiety alone or in combination are associated with worse cognition in people with MS. In this cross-sectional analysis, people with MS consecutively seen at a tertiary neuropsychiatry clinic completed the Hospital Anxiety and Depression Scale for symptoms of depression (HADS-D) and anxiety (HADS-A), and the Minimal Assessment of Cognitive Function in MS for cognitive indices. Accounting for covariates, regression models predicted cognitive indices from scores for HADS-D, HADS-A, and the interaction. Of 831 people with MS, 72% were female, mean age was 43.2years, and median Expanded Disability Status Scale score was 2.0. Depressive symptoms were independently predictive of lower verbal fluency (Controlled Oral Word Association Test, p < 0.01), verbal learning (California Verbal Learning Test-II (CVLT-II) total learning, p = 0.02), verbal delayed recall (CVLT-II delayed recall, p < 0.01), and processing speed (Symbol Digit Modalities Test, p < 0.01; three-second Paced Auditory Serial Addition Test (PASAT), p = 0.05; two-second PASAT, p = 0.01). Anxiety in people with depression predicted decreased visuospatial function (Judgment of Line Orientation, p = 0.05), verbal learning (p < 0.01), verbal delayed recall (p < 0.01), visuospatial recall (Brief Visuospatial Memory Test-Revised, p = 0.02), and executive function (Delis-Kaplan Executive Function System, p < 0.01). Anxiety alone was not independently predictive of cognition. In conclusion, depression, especially with comorbid anxiety, is associated with cognitive dysfunction in people with MS.

Meaningful cognitive change for the Minimal Assessment of Cognitive Function in Multiple Sclerosis

Background: There is limited information on interpretation of cognitive changes over time in multiple sclerosis (MS). Objective: This study aimed to provide normative data for the assessment of statistically meaningful change in all tests of the Minimal Assessment of Cognitive Function in MS (MACFIMS). Methods: We applied the reliable change methodology to a healthy Italian cohort, assessed with two alternate versions of the MACFIMS 1 year apart. We calculated confidence intervals of retest score variance using the reliable change index (RCI). Moreover, multivariable linear regression models adjusted for age, sex, education, and baseline score were built to calculate the regression-based change index (RB-CI). Results: Overall, 200 healthy individuals were enrolled. Thresholds for interpreting change in each test were calculated. In the multivariable models, baseline score was associated with retest score in all tests (B from 0.439 to 0.760; p < 0.001). RB-CI can be calculated with data of the multivariable models. Conclusion: We provide normative data for reliable cognitive change evaluation for all the tests of the MACFIMS, which includes the Symbol Digit Modalities Test and Brief International Cognitive Assessment in MS, two widely used tools for screening and monitoring cognition in MS. Our findings can significantly improve the interpretation of cognitive changes in MS.

Free-living ambulatory physical activity and cognitive function in multiple sclerosis: the significance of step rate vs. step volume.

Physical activity (PA) represents a promising behavioral approach for managing cognitive dysfunction in multiple sclerosis (MS). However, there is a lack of information on the pattern of free-living PA intensity (e.g., step rate) and its unique association with cognition. Such information is essential for informing clinical trials in MS. We examined associations among PA volume and intensity with cognitive function in persons with MS, and intensity was derived from steps-based metrics (peak 30-min cadence [Peak-30CAD], and time spent in incremental cadence bands). We included data from 147 persons with MS who underwent assessments of cognitive function (via Brief International Cognitive Assessment in MS) and wore an ActiGraph GT3X + accelerometer for 7days. We performed bivariate and partial correlations and regression analyses examining associations among PA metrics and cognitive outcomes. Higher Peak-30CAD was significantly associated with better performance in cognitive processing speed and verbal learning and memory (rs = 0.19-0.38), and the associations remained significant when controlling for daily steps, age, sex, and years of education (p < 0.05). By comparison, daily steps was only correlated with cognitive processing speed (rs = 0.26), and the association was non-significant when controlling for Peak-30CAD and covariates. There were stronger correlations among time spent in higher intensity cadence bands with cognitive performance (rs = 0.18-0.38). Our results highlight the important role of PA intensity for cognition in MS, and may inform future development of focal PA interventions that focusing on step rate patterns for improving cognition in persons with MS.

Cognitive function and brain magnetic resonance imaging profiles in neuromyelitis optica spectrum disorder and multiple sclerosis.

The objective of this study was to investigate cognitive performance and brain volume profile in patients with neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). In a historical cohort study, 29 MS patients, 31 NMOSD patients, and 20 healthy controls (HCs) underwent neuropsychological assessment using the Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS). Patients with MS and NMOSD also underwent a 1.5-tesla magnetic resonance imaging scan and high-resolution three-dimensional T1-weighted MPRAGE sequence. The Symbol Digit Modalities Test scores were significantly lower in MS (mean [standard deviation (SD)] =44.1 [14]) and NMOSD (mean [SD] =45.5 [14.3]) patients compared to HCs (mean [SD] =57 [9.5], P < 0.001). Scores of the Controlled Oral Word Association Test were also lower in MS (mean [SD] =25.9 [9.8]) and NMOSD (mean [SD] =24.6 [10.2]) patients compared to HCs (mean [SD] =36.6 [9.8], P < 0.001). Additionally, the MS group performed worse on the Brief Visuospatial Memory Test (BVMT) compared to the NMOSD group (9.4 ± 3.4 vs. 7.1 ± 3.7 P < 0.001). In MS patients, there was a significant correlation between all cognition scores and total brain lesions, as well as between every test except BVMT-Revised with thalamic volumes. In NMOSD patients, a correlation was found between gray matter volume and the learning phase of the California Verbal Learning Test-II as well as between total lesion percentage and verbal memory and information processing speed. Both NMOSD and MS patients experienced impairment of information processing speed, working memory, and verbal fluency, whereas visuospatial memory impairment was only observed in MS patients. Despite lower total brain lesion and less thalamic atrophy, patients with NMOSD are at risk of cognitive impairment. Microscopic structural abnormalities may be a possible cause.

Peering further into the mind's eye: combining visual evoked potential and optical coherence tomography measures enhances insight into the variance in cognitive functioning in multiple sclerosis.

Spectral Optical Coherence Tomography (OCT) and Visual Evoked Potentials (VEPs) have both emerged as potentially useful biomarkers of cognitive decline in people with multiple sclerosis (PwMS). Their combined use may provide additional predictive value for identifying disease impact, progression, and remyelination capacity above-and-beyond what is captured using either approach alone. We examined the relationship between OCT/VEP measures and cognitive functioning in 205 PwMS. OCT measures included Retinal Nerve Fiber Layer Volume (RNFLV), Papillo-Macular Bundle Volume (PBMV), and Macular Volume (MV). VEP measures included latency of the P100, and inter-ocular latency. Cognitive performance was evaluated across seven separate domains of performance, and for overall cognition, using the NeuroTrax computerized testing battery. Both OCT and VEP measures were significantly correlated with cognitive performance across several domains. Linear regression models that controlled for the influence of visual acuity revealed (1) that reduced MV was significantly predictive of poorer visual-spatial functioning, and (2) that delayed VEP latency was significantly predictive of performance in global cognitive functioning and visual-spatial functioning, after controlling for multiple comparisons. Among PwMS with normal visual acuity, PwMS with a combination of both relatively low MV and delayed VEP latency tended to have poorer performance in the domains of global, executive, and visual-spatial functioning compared to PwMS with both high MV and normal VEP latency. Approaches that combine the use of OCT and VEP measures can enhance insight into underlying factors that contribute to variance in cognitive functioning in PwMS.

Multi-modal neuroimaging signatures predict cognitive decline in multiple sclerosis: A 5-year longitudinal study

BackgroundCognitive impairment is a hallmark of multiple sclerosis (MS) but is usually an under-recorded symptom of disease progression. Identifying the predictive signatures of cognitive decline in people with MS (pwMS) over time is important to ensure effective preventative treatment strategies. Structural and functional brain characteristics as measured by various magnetic resonance (MR) methods have been correlated with variation in cognitive function in MS, but typically these studies are limited to a single MR modality and/or are cross-sectional designs. Here we assess the predictive value of multiple different MR modalities in relation to cognitive decline in pwMS over 5 years. MethodsA cohort of 43 pwMS was assessed at baseline and 5 years follow-up. Baseline (input) data consisted of 70 multi-modal MRI measures for different brain regions including magnetic resonance spectroscopy (MRS), diffusion tensor imaging (DTI) and standard volumetrics. Age, sex, disease duration and treatment were included as clinical inputs. Cognitive function was assessed using the Audio Recorded Cognitive Screen (ARCS) and the Symbol Digit Modalities Test (SDMT). Prediction modelling was performed using the machine learning package - GLMnet, where a penalised regression was applied to identify multi-modal signatures with the most predictive value (and the least error) for each outcome. ResultsThe multi-modal approach to neuroimaging was able to accurately predict cognitive decline in pwMS. The best performing model for change in total ARCS (tARCS) included 16 features from across the various MR modalities and explained 54 % of the variation in change over time (R2=0.54, 95 % CI=0.48–0.51). The features included nine MRS, four volumetric and two DTI parameters. The model also selected disease duration, but not treatment, as a predictive feature. By comparison, the best model for SDMT included several of the same above features and explained 39 % of the change over time (R2=0.39, 95 % CI=0.48–0.51). Conventional volumetric measures were about half as good at predicting change in tARCS score compared to the best multi-modal model (R2=0.26 95 % CI:0.22–0.29). The clinical interpretation of the best predictive model for change in tARCS showed that cognitive decline could be predicted with >90 % accuracy in this cohort (AUC=0.92, SE=0.86 - 0.94). ConclusionMulti-modal MRI signatures can predict cognitive decline in a cohort of pwMS over 5 years with high accuracy. Future studies will benefit from the inclusion of even more MR modalities e.g., functional MRI, quantitative susceptibility mapping, magnetisation transfer imaging, as well as other potential predictors e.g., genetic and environmental factors. With further validation, this signature could be used in future trials with high-risk patients to personalise the management of cognitive decline in pwMS, even in the absence of relapses.

The correlation of conventional and advanced MRI findings with cognitive function in multiple sclerosis: A systematic review and meta-analysis

There are limited data on the possible association between conventional and advanced magnetic resonance imaging (MRI) findings and cognitive function in patients with multiple sclerosis (MS). Therefore, this systematic review and meta-analysis aimed to explore the correlation between MRI-derived metrics and cognitive tests in patients with MS. An electronic literature search of the PubMed, Web of Sciences, Embase, and Scopus databases was performed to identify related studies. The correlation coefficients of the MRI indices and cognitive tests were pooled. Thirteen studies were selected for inclusion of 824 patients diagnosed with MS. Most evaluated patients (60.44%) had relapsing-remitting MS (RRMS). The Paced Auditory Serial Addition Test (PASAT-3), Brief Visuospatial Memory Test (BVMT), and Symbol Digit Modalities Test (SDMT) were inversely correlated with the mean diffusivity (MD) of the brain with pooled correlation coefficient of -0.225, -0.361, and -0.438, respectively (P&lt;0.0001). The SDMT test positively correlated with fractional anisotropy (FA) with a correlation coefficient of 0.351 (P&lt;0.0001) and inversely correlated with T2 lesion volume with a correlation coefficient of -0.367 (P&lt;0.0001). In the case of other tests, there was low number of studies with significant correlations being reported. We found significant correlations between some neuropsychological tests and MRI findings in patients with MS. Brain atrophy might disrupt the process of correct registration between anatomical and MRI diffusion scans. However, we did not have enough studies with exactly matched anatomical areas to evaluate correlations and we recommend that histological validation of diffusion tensor imaging (DTI) findings for brain atrophy is needed as a basis for picture processing procedures and correlation with cognition status.

Does multilingualism act as a protective factor (cognitive reserve) against cognitive impairment in multiple sclerosis?: A retrospective cohort study

BackgroundCognitive impairment (CI) is common in multiple sclerosis (MS), affecting half of persons with MS (PwMS). Cognitive reserve has been associated with delaying the onset and slowing the progression of CI in PwMS. Multilingualism has been demonstrated to be a protective factor against CI in Alzheimer's disease (AD) but has never been studied in PwMS. ObjectiveTo explore if multilingualism is a protective factor against CI in PwMS. MethodsThis is a retrospective cohort study of PwMS aged 18–59, with a confirmed diagnosis of relapsing MS, fluent in English, who completed the Minimal Assessment of Cognitive Function in MS (MACFIMS) at the London (ON) MS Clinic. Any PwMS with a history of dementia or developmental delay, daily marijuana use, a major psychiatric disorder, or less than grade 9 education was excluded. We focused on the Brief Visuospatial Memory Test (BVMTR), immediate recall (-IR) and delayed recall (-DR) as it would be the least affected by language, as well as the Symbol Digit Modalities Test (SDMT), as information processing speed is the most commonly affected domain in PwMS. One-way ANOVA was used to compare raw scores on the BVMTR and SDMT between groups (uni- vs. multillingual), while chi-square was used to compare impairment on BVMTR and SDMT between groups. ResultsThe cohort consisted of 678 subjects. The mean age was 39.7 (± 9.6) years with 501 (73.9 %) females (sex at birth), the mean duration of disease of 5.9 (± 6.9) years, and mean years of education was 13.9 (±2.2). The majority of subjects (563, 83 %) were unilingual and (115, 17 %) were multilingual; 102 subjects were bilingual and 13 subjects fluent in ≥ three languages. English was the first language was in most of subjects (614, 90.6 %). There was no significant difference on the BVMTR-IR scores (p = 0.189) or BVMTR-DR (p = 0.096) between groups. Similarly, there was no difference in the number of subjects impaired on the BVMTR-IR (X2 (1, N = 678) = 3.167, p = 0.057) or BVMT-DR between groups (X2 (1, N = 678) = 2.996, p = 0.083). Further, there was no significant difference on the SDMT (p = 0.506) between groups, or in number of subjects impaired on the SDMT between groups (X2 (1, N = 678) = 1.023, p = 0.312). ConclusionThis study shows that multilingualism does not have a protective effect against CI in PwMS and does not play a role in enriching the cognitive reserve, in contrast to studies in AD. This difference may be explained by a different underlying pathological mechanism in these diseases and warrants further study.

The effect of atomoxetine on cognitive function in patients with multiple sclerosis.

Background: Recent research shows that most of the patients with multiple sclerosis (MS) have cognitive-like disorders. Due to the beneficial effects of atomoxetine on improving cognition in limited animal and human surveys, the aim of the present study was to investigate the effect of the atomoxetine on improving cognitive disorders of MS. Methods: This study was a parallel, randomized clinical trial, designed to investigate the effect of atomoxetine drug on the improvement of cognitive impairment (CI) in MS, from April 2021 to March 2022. According to the inclusion and exclusion criteria, a total of 52 participants were involved in the study and then randomly divided in two groups of 26. Experimental group was treated with atomoxetine and the control group was treated with placebo. The Minimal Assessment of Cognitive Function in Multiple Sclerosis (MACFIMS) test was performed for assessment at the beginning and after 3 months. The California Verbal Learning Test (CVLT), the CVLT-delay, the Brief Visuospatial Memory Test-Revised (BVMT-R), and the Symbol Digit Modalities Test (SDMT) were used to evaluate the CI and changes following medication. Finally, data were analyzed by SPSS software at significance level of 0.05. Results: The mean age of patients in the experimental group was 37.7 ± 8.5 and in the placebo group was 37.8 ± 7.6 (P = 0.32). The results showed significant changes in cognitive levels before and after the use of atomoxetine and also in comparison to the placebo group (P < 0.05). Conclusion: This study showed that atomoxetine improved the cognitive domains after administration compared to placebo.

One-year regional brain volume changes as potential predictors of cognitive function in multiple sclerosis: a pilot study

BackgroundThe most reliable magnetic resonance imaging (MRI) marker of cognitive dysfunction in multiple sclerosis (MS) is brain atrophy. However, 1-year volumetric changes prior to cognitive assessment were never studied as potential predictors of cognition, which we aim to assess with this pilot work.MethodsTwenty-two MS patients were submitted to a baseline measure of 83 regional brain volumes with MRI and re-evaluated 1 year later; they were also tested with the Brief International Cognitive Assessment for MS (BICAMS): sustained attention and processing speed were examined with the Symbol Digit Modalities Test (SDMT), verbal and visuo-spatial learning and memory with the learning trials from the California Verbal Learning Test-II (CVLT) and the Brief Visuo-spatial Memory Test-revised (BVMT), respectively. Controlling for age, sex, and years of education, a multivariate linear regression model was created for each cognitive score at 1-year follow-up in a backward elimination manner, considering cross-sectional regional volumes and 1-year volume changes as potential predictors.ResultsDecreases in the volumes of the left amygdala and the right lateral orbitofrontal cortex in the year prior to assessment were identified as possible predictors of worse performance in verbal memory (P = 0.009) and visuo-spatial memory (P = 0.001), respectively, independently of cross-sectional brain regional volumes at time of testing.ConclusionOur work reveals novel 1-year regional brain volume changes as potential predictors of cognitive deficits in MS. This suggests a possible role of these regions in such deficits and might contribute to uncover cognitively deteriorating patients, whose detection is still unsatisfying in clinical practice.

The spectral slope as a marker of excitation/inhibition ratio and cognitive functioning in multiple sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease characterized by neuronal and synaptic loss, resulting in an imbalance of excitatory and inhibitory synaptic transmission and potentially cognitive impairment. Current methods for measuring the excitation/inhibition (E/I) ratio are mostly invasive, but recent research combining neurocomputational modeling with measurements of local field potentials has indicated that the slope with which the power spectrum of neuronal activity captured by electro- and/or magnetoencephalography rolls off, is a non-invasive biomarker of the E/I ratio. A steeper roll-off is associated with a stronger inhibition. This novel method can be applied to assess the E/I ratio in people with multiple sclerosis (pwMS), detect the effect of medication such as benzodiazepines, and explore its utility as a biomarker for cognition. We recruited 44 healthy control subjects and 95 pwMS who underwent resting-state magnetoencephalographic recordings. The 1/f spectral slope of the neural power spectra was calculated for each subject and for each brain region. As expected, the spectral slope was significantly steeper in pwMS treated with benzodiazepines (BZDs) compared to pwMS not receiving BZDs (p = .01). In the sub-cohort of pwMS not treated with BZDs, we observed a steeper slope in cognitively impaired pwMS compared to cognitively preserved pwMS (p = .01) and healthy subjects (p = .02). Furthermore, we observed a significant correlation between 1/f spectral slope and verbal and spatial working memory functioning in the brain regions located in the prefrontal and parietal cortex. In this study, we highlighted the value of the spectral slope in MS by quantifying the effect of benzodiazepines and by putting it forward as a potential biomarker of cognitive deficits in pwMS.

Accelerometry measures of physical activity and sedentary behavior: Associations with cognitive functioning in MS

BackgroundCognitive dysfunction is a pervasive symptom of multiple sclerosis (MS). Correlational evidence on the relationships between physical activity, sedentary behavior, and cognition has been mixed and limited to a few activity measures. The collinearity of accelerometry-based metrics has precluded an assessment of the full activity spectrum. Here, we aimed to examine the rich set of activity measures using analytic approaches suitable for collinear metrics. We investigated the combination of physical activity, sedentary, and clinicodemographic measures that explain the most variance in composite scores of working memory/processing speed, visual memory, and verbal memory. MethodsWe analyzed baseline accelerometry and neuropsychological data (n = 80) from a randomized controlled trial of pedometer tracking. Using partial least squares regression (PLSR), we built three models to predict latent scores on the three domains of cognition using 12 activity metrics, sex, education, and Expanded Disability Status Scale (EDSS) scores. Significance was assessed using linear regression models with model component scores as predictors and cognitive composites as outcomes. ResultsThe latent component was significant for working memory/processing speed but was not significant for visual memory and verbal memory after Bonferroni correction. Working memory/processing speed was positively associated with average kilocalories, moderate-to-vigorous physical activity (MVPA), steps, and sex (i.e., higher scores in males) and negatively related to duration of long sedentary bouts and EDSS. ConclusionsThese findings suggest that increasing overall energy expenditure through walking and MVPA, while decreasing prolonged sedentary time may positively benefit working memory/processing speed in people with MS. Trial RegistrationThis RCT #NCT03244696 was registered on Clinicaltrials.gov (https://www.clinicaltrials.gov/ct2/show/NCT03244696).

The potential therapeutic effect of statins in multiple sclerosis: beneficial or detrimental effects.

Multiple sclerosis (MS) is a chronic progressive disabling disease of the central nervous system (CNS) characterized by demyelination and neuronal injury. Dyslipidemia is observed as one of the imperative risk factors involved in MS neuropathology. Also, chronic inflammation in MS predisposes to the progress of dyslipidemia. Therefore, treatment of dyslipidemia in MS by statins may attenuate dyslipidemia-induced MS and avert MS-induced metabolic changes. Therefore, the present review aimed to elucidate the possible effects of statins on the pathogenesis and outcomes of MS. Statins adversely affect the cognitive function in MS by decreasing brain cholesterol CoQ10, which is necessary for the regulation of neuronal mitochondrial function. However, statins could be beneficial in MS by shifting the immune response from pro-inflammatory Th17 to an anti-inflammatory regulatory T cell (Treg). The protective effect of statins against MS is related to anti-inflammatory and immunomodulatory effects with modulation of fibrinogen and growth factors. In conclusion, the effects of statins on MS neuropathology seem to be conflicting, as statins seem to be protective in the acute phase of MS through anti-inflammatory and antioxidant effects. However, statins lead to detrimental effects in the chronic phase of MS by reducing brain cholesterol and inhibiting the remyelination process.

Cognitive performance in multiple sclerosis: what is the role of the gamma-aminobutyric acid system?

Cognitive impairment occurs in 40-65% of persons with multiple sclerosis and may be related to alterations in glutamatergic and GABAergic neurotransmission. Therefore, the aim of this study was to determine how glutamatergic and GABAergic changes relate to cognitive functioning in multiple sclerosis in vivo. Sixty persons with multiple sclerosis (mean age 45.5 ± 9.6 years, 48 females, 51 relapsing-remitting multiple sclerosis) and 22 age-matched healthy controls (45.6 ± 22.0 years, 17 females) underwent neuropsychological testing and MRI. Persons with multiple sclerosis were classified as cognitively impaired when scoring at least 1.5 standard deviations below normative scores on ≥30% of tests. Glutamate and GABA concentrations were determined in the right hippocampus and bilateral thalamus using magnetic resonance spectroscopy. GABA-receptor density was assessed using quantitative [11C]flumazenil positron emission tomography in a subset of participants. Positron emission tomography outcome measures were the influx rate constant (a measure predominantly reflecting perfusion) and volume of distribution, which is a measure of GABA-receptor density. Twenty persons with multiple sclerosis (33%) fulfilled the criteria for cognitive impairment. No differences were observed in glutamate or GABA concentrations between persons with multiple sclerosis and healthy controls, or between cognitively preserved, impaired and healthy control groups. Twenty-two persons with multiple sclerosis (12 cognitively preserved and 10 impaired) and 10 healthy controls successfully underwent [11C]flumazenil positron emission tomography. Persons with multiple sclerosis showed a lower influx rate constant in the thalamus, indicating lower perfusion. For the volume of distribution, persons with multiple sclerosis showed higher values than controls in deep grey matter, reflecting increased GABA-receptor density. When comparing cognitively impaired and preserved patients to controls, the preserved group showed a significantly higher volume of distribution in cortical and deep grey matter and hippocampus. Positive correlations were observed between both positron emission tomography measures and information processing speed in the multiple sclerosis group only. Whereas concentrations of glutamate and GABA did not differ between multiple sclerosis and control nor between cognitively impaired, preserved and control groups, increased GABA-receptor density was observed in preserved persons with multiple sclerosis that was not seen in cognitively impaired patients. In addition, GABA-receptor density correlated to cognition, in particular with information processing speed. This could indicate that GABA-receptor density is upregulated in the cognitively preserved phase of multiple sclerosis as a means to regulate neurotransmission and potentially preserve cognitive functioning.

A multimodal marker for cognitive functioning in multiple sclerosis: the role of NfL, GFAP and conventional MRI in predicting cognitive functioning in a prospective clinical cohort

BackgroundCognitive impairment in people with MS (PwMS) has primarily been investigated using conventional imaging markers or fluid biomarkers of neurodegeneration separately. However, the single use of these markers do only partially explain the large heterogeneity found in PwMS.ObjectiveTo investigate the use of multimodal (bio)markers: i.e., serum and cerebrospinal fluid (CSF) levels of neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and conventional imaging markers in predicting cognitive functioning in PwMS.MethodsEighty-two PwMS (56 females, disease duration = 14 ± 9 years) underwent neuropsychological and neurological examination, structural magnetic resonance imaging, blood sampling and lumbar puncture. PwMS were classified as cognitively impaired (CI) if scoring ≥ 1.5SD below normative scores on ≥ 20% of test scores. Otherwise, PwMS were defined as cognitively preserved (CP). Association between fluid and imaging (bio)markers were investigated, as well as binary logistics regression to predict cognitive status. Finally, a multimodal marker was calculated using statistically important predictors of cognitive status.ResultsOnly higher NfL levels (in serum and CSF) correlated with worse processing speed (r = − 0.286, p = 0.012 and r = − 0.364, p = 0.007, respectively). sNfL added unique variance in the prediction of cognitive status on top of grey matter volume (NGMV), p = 0.002). A multimodal marker of NGMV and sNfL yielded most promising results in predicting cognitive status (sensitivity = 85%, specificity = 58%).ConclusionFluid and imaging (bio)markers reflect different aspects of neurodegeneration and cannot be used interchangeably as markers for cognitive functioning in PwMS. The use of a multimodal marker, i.e., the combination of grey matter volume and sNfL, seems most promising for detecting cognitive deficits in MS.