Brain microstructure is linked to cognitive fatigue in early multiple sclerosis.

Cognitive fatigue is a major symptom of Multiple Sclerosis (MS), from the early stages of the disease. This study aims to detect if brain microstructure is altered early in the disease course and is associated with cognitive fatigue in people with MS (pwMS) compared to matched healthy controls (HC). Recently diagnosed pwMS (N = 18, age < 45 years old) with either a Relapsing-Remitting or a Clinically Isolated Syndrome course of the disease, and HC (N = 19) matched for sex, age and education were analyzed. Quantitative multiparameter maps (MTsat, PD, R1 and R2*) of pwMS and HC were calculated. Parameters were extracted within the normal appearing white matter, cortical grey matter and deep grey matter (NAWM, NACGM and NADGM, respectively). Bayesian T-test for independent samples assessed between-group differences in brain microstructure while associations between score at a cognitive fatigue scale and each parameter in each tissue class were investigated with Generalized Linear Mixed Models. Patients exhibited lower MTsat and R1 values within NAWM and NACGM, and higher R1 values in NADGM compared to HC. Cognitive fatigue was associated with PD measured in every tissue class and to MTsat in NAWM, regardless of group. Disease-specific negative correlations were found in pwMS in NAWM (R1, R2*) and NACGM (R1). These findings suggest that brain microstructure within normal appearing tissues is already altered in the very early stages of the disease. Moreover, additional microstructure alterations (e.g. diffuse and widespread demyelination or axonal degeneration) in pwMS may lead to disease-specific complaint of cognitive fatigue.

Effect of cognitive reserve on the association between slow wave sleep and cognition in community-dwelling older adults.

Sleep, especially slow wave sleep (SWS), is essential for cognitive functioning and is reduced in aging. The impact of sleep quality on cognition is variable, especially in aging. Cognitive reserve (CR) may be an important modulator of these effects. We aimed at investigating this question to better identify individuals in whom sleep disturbances might have greater behavioral consequences. Polysomnography and neuropsychological assessments were performed in 135 cognitively intact older adults (mean age ± SD: 69.4 ± 3.8y) from the Age-Well randomized controlled trial (baseline data). Two measures of cognitive engagement throughout life were used as CR proxies. Linear regression analyses were performed between the proportion of SWS, and executive function and episodic memory composite scores. Then, interaction analyses between SWS and CR proxies on cognition were conducted to assess the possible impact of CR on these links. SWS was positively associated with episodic memory, but not with executive function. CR proxies modulated the associations between SWS and both executive and episodic memory performance. Specifically, individuals with higher CR were able to maintain cognitive performance despite low amounts of SWS. This study provides the first evidence that CR may protect against the deleterious effects of age-related sleep changes on cognition.

Effects of Meditation Training and Non-Native Language Training on Cognition in Older Adults: A Secondary Analysis of a Randomized Clinical Trial.

Importance: Nonpharmacological interventions are a potential strategy to maintain or promote cognitive functioning in older adults. Objective: To investigate the effects of 18 months' meditation training and 18 months' non-native language training on cognition in older adults. Design, Setting, and Participants: This study was a secondary analysis of the Age-Well trial, an 18-month, observer-masked, randomized clinical trial with 3 parallel arms. Eligible participants were community-dwelling adults aged 65 years and older residing in Caen, France. Participants were enrolled from November 24, 2016, to March 5, 2018, and randomly assigned (1:1:1) to meditation training, non-native language (English) training, or no intervention arms. Final follow-up was completed on February 6, 2020. Data were analyzed between December 2021 and November 2022. Interventions: The 18-month meditation and non-native language training interventions were structurally equivalent and included 2-hour weekly group sessions, daily home practice of 20 minutes or longer, and 1 day of more intensive home practice. The no intervention group was instructed not to change their habits and to continue living as usual. Main Outcomes and Measures: Cognition (a prespecified secondary outcome of the Age-Well trial) was assessed preintervention and postintervention via the Preclinical Alzheimer Cognitive Composite 5 (PACC5), and composites assessing episodic memory, executive function, and attention. Results: Among 137 randomized participants, 2 were excluded for not meeting eligibility criteria, leaving 135 (mean [SD] age, 69.3 [3.8] years; 83 female [61%]) eligible for analysis. One participant among the remaining 135 did not complete the trial. In adjusted mixed effects models, no interaction effects were observed between visit and group for PACC5 (F2,131.39 = 2.58; P = .08), episodic memory (F2,131.60 = 2.34; P = .10), executive function (F2,131.26 = 0.89; P = .41), or attention (F2,131.20 = 0.34; P = .79). Results remained substantively unchanged across sensitivity and exploratory analyses. Conclusions and Relevance: In this secondary analysis of an 18-month randomized trial, meditation and non-native language training did not confer salutary cognitive effects. Although further analyses are needed to explore the effects of these interventions on other relevant outcomes related to aging and well-being, these findings did not support the use of these interventions for enhancing cognition in cognitively healthy older adults. Trial Registration: ClinicalTrials.gov Identifier: NCT02977819.

The Effect of Meditation-Based Interventions on Patients with Fatigue Symptoms: A Systematic Review and Meta-Analysis.

Persistent fatigue constitutes a prevalent and debilitating symptom in several diseases. The symptom is not effectively alleviated by pharmaceutical treatments, and meditation has been proposed as a non-pharmacological intervention. Indeed, meditation has been shown to reduce inflammatory/immune problems, pain, stress, anxiety and depression which are associated with pathological fatigue. This review synthesizes data from randomized control trials (RCTs) that explored the effect of meditation-based interventions (MeBIs) on fatigue in pathological conditions. Eight databases were searched from inception to April 2020. Thirty-four RCTs met eligibility criteria and covered six conditions (68% cancer), 32 of which were included in the meta-analysis. The main analysis showed an effect in favor of MeBIs compared to control groups (g = 0.62). Separate moderator analyses assessing control group, pathological condition, and MeBI type, highlighted a significantly moderating role of the control group. Indeed, compared to actively controlled studies, studies using a passive control group were associated with a statistically significantly more beneficial impact of the MeBIs (g = 0.83). These results indicate that MeBIs alleviate pathological fatigue and it seems that the studies with a passive control group showed a greater effect of MeBI on the reduction of fatigue compared to studies using active control groups. However, the specific effect of meditation type and pathological condition should be analyzed with more studies, and there remains a need to assess meditation effects on different types of fatigue (i.e., physical and mental) and in additional conditions (e.g., post-COVID-19).

Using quantitative magnetic resonance imaging to track cerebral alterations in multiple sclerosis brain: A longitudinal study.

INTRODUCTION: Quantitative MRI quantifies tissue microstructural properties and supports the characterization of cerebral tissue damages. With an MPM protocol, 4 parameter maps are constructed: MTsat, PD, R1 and R2*, reflecting tissue physical properties associated with iron and myelin contents. Thus, qMRI is a good candidate for in vivo monitoring of cerebral damage and repair mechanisms related to MS. Here, we used qMRI to investigate the longitudinal microstructural changes in MS brain. METHODS: Seventeen MS patients (age 25-65, 11 RRMS) were scanned on a 3T MRI, in two sessions separated with a median of 30 months, and the parameters evolution was evaluated within several tissue classes: NAWM, NACGM and NADGM, as well as focal WM lesions. An individual annual rate of change for each qMRI parameter was computed, and its correlation to clinical status was evaluated. For WM plaques, three areas were defined, and a GLMM tested the effect of area, time points, and their interaction on each median qMRI parameter value. RESULTS: Patients with a better clinical evolution, that is, clinically stable or improving state, showed positive annual rate of change in MTsat and R2* within NAWM and NACGM, suggesting repair mechanisms in terms of increased myelin content and/or axonal density as well as edema/inflammation resorption. When examining WM lesions, qMRI parameters within surrounding NAWM showed microstructural modifications, even before any focal lesion is visible on conventional FLAIR MRI. CONCLUSION: The results illustrate the benefit of multiple qMRI data in monitoring subtle changes within normal appearing brain tissues and plaque dynamics in relation with tissue repair or disease progression.

Effects of a mindfulness-based versus a health self-management intervention on objective cognitive performance in older adults with subjective cognitive decline (SCD): a secondary analysis of the SCD-Well randomized controlled trial.

BACKGROUND: Older individuals with subjective cognitive decline (SCD) perceive that their cognition has declined but do not show objective impairment on neuropsychological tests. Individuals with SCD are at elevated risk of objective cognitive decline and incident dementia. Non-pharmacological interventions (including mindfulness-based and health self-management approaches) are a potential strategy to maintain or improve cognition in SCD, which may ultimately reduce dementia risk. METHODS: This study utilized data from the SCD-Well randomized controlled trial. One hundred forty-seven older adults with SCD (MAge = 72.7 years; 64% female) were recruited from memory clinics in four European countries and randomized to one of two group-based, 8-week interventions: a Caring Mindfulness-based Approach for Seniors (CMBAS) or a health self-management program (HSMP). Participants were assessed at baseline, post-intervention (week 8), and at 6-month follow-up (week 24) using a range of cognitive tests. From these tests, three composites were derived-an "abridged" Preclinical Alzheimer's Cognitive Composite 5 (PACC5Abridged), an attention composite, and an executive function composite. Both per-protocol and intention-to-treat analyses were performed. Linear mixed models evaluated the change in outcomes between and within arms and adjusted for covariates and cognitive retest effects. Sensitivity models repeated the per-protocol analyses for participants who attended ≥ 4 intervention sessions. RESULTS: Across all cognitive composites, there were no significant time-by-trial arm interactions and no measurable cognitive retest effects; sensitivity analyses supported these results. Improvements, however, were observed within both trial arms on the PACC5Abridged from baseline to follow-up (Δ [95% confidence interval]: CMBAS = 0.34 [0.19, 0.48]; HSMP = 0.30 [0.15, 0.44]). There was weaker evidence of an improvement in attention but no effects on executive function. CONCLUSIONS: Two non-pharmacological interventions conferred small, non-differing improvements to a global cognitive composite sensitive to amyloid-beta-related decline. There was weaker evidence of an effect on attention, and no evidence of an effect on executive function. Importantly, observed improvements were maintained beyond the end of the interventions. Improving cognition is an important step toward dementia prevention, and future research is needed to delineate the mechanisms of action of these interventions and to utilize clinical endpoints (i.e., progression to mild cognitive impairment or dementia). TRIAL REGISTRATION: ClinicalTrials.gov, NCT03005652.

Pupil response speed as a marker of cognitive fatigue in early Multiple Sclerosis☆.

CONTEXT: Cognitive fatigue (CF) is a disabling symptom frequently reported by patients with Multiple Sclerosis (pwMS). Whether pwMS in the early disease stages present an increased sensitivity to fatigue induction remains debated. Objective measures of CF have been validated neither for clinical nor research purposes. This study aimed at (i) assessing how fatigue induction by manipulation of cognitive load affects subjective fatigue and behavioural performance in newly diagnosed pwMS and matched healthy controls (HC); and (ii) exploring the relevance of eye metrics to describe CF in pwMS. METHODS: Nineteen pwMS with disease duration < 5 years and 19 matched HC participated to this study. CF was induced with a dual-task in two separate sessions with varying cognitive load (High and Low cognitive load conditions, HCL and LCL). Accuracy, reaction times (RTs), subjective fatigue and sleepiness states were assessed. Bayesian Analyses of Variance for repeated measures (rmANOVA) explored the effects of time, group and load condition on the assessed variables. Eye metrics (number of long blinks, pupil size and pupil response speed: PRS) were obtained during the CF task for a sub-sample (16 pwMS and 15 HC) and analysed with Generalized Linear Mixed Models (GLMM). RESULTS: Performance (accuracy and RTs) was lower in the HCL condition and accuracy decreased over time (BFsincl > 100) while RTs did not significantly vary. Performance over task and conditions followed the same pattern of evolution across groups (BFsincl < 0.08) suggesting that pwMS did not show increased alteration of performance during fatigue induction. Regarding subjective state, both fatigue and sleepiness increased following the task (BFsincl > 15), regardless of condition and group (BFsincl < 3). CF in pwMS seems to be associated with PRS, as PRS decreased during the task amongst pwMS only and especially in the HCL condition (all p < .05). A significant Condition*Group interaction was observed regarding long blinks (p < .0001) as well as an expected effect of cognitive load condition on pupil diameter (p < .01). CONCLUSION: These results suggest that newly diagnosed pwMS and HC behave similarly during fatigue induction, in terms of both performance decrement and accrued fatigue sensation. Eye metric data further reveal a susceptibility to CF in pwMS, which can be objectively measured.