Longitudinal fibre-specific white matter damage predicts cognitive decline in multiple sclerosis.

During the course of multiple sclerosis, many patients experience cognitive deficits which are not simply driven by lesion number or location. By considering the full complexity of white matter structure at macro- and microstructural levels, our understanding of cognitive impairment in multiple sclerosis may increase substantially. Accordingly, this study aimed to investigate specific patterns of white matter degeneration, the evolution over time, the manifestation across different stages of the disease and their role in cognitive impairment using a novel fixel-based approach. Neuropsychological test scores and MRI scans including 30-direction diffusion-weighted images were collected from 327 multiple sclerosis patients (mean age = 48.34 years, 221 female) and 95 healthy controls (mean age = 45.70 years, 55 female). Of those, 233 patients and 61 healthy controls had similar follow-up assessments 5 years after. Patients scoring 1.5 or 2 standard deviations below healthy controls on at least two out of seven cognitive domains (from the Brief Repeatable Battery of Neuropsychological Tests, BRB-N) were classified as mildly cognitively impaired or cognitively impaired, respectively, or otherwise cognitively preserved. Fixel-based analysis of diffusion data was used to calculate fibre-specific measures (fibre density, reflecting microstructural diffuse axonal damage; fibre cross-section, reflecting macrostructural tract atrophy) within atlas-based white matter tracts at each visit. At baseline, all fixel-based measures were significantly worse in multiple sclerosis compared with healthy controls (P < 0.05). For both fibre density and fibre cross-section, a similar pattern was observed, with secondary progressive multiple sclerosis patients having the most severe damage, followed by primary progressive and relapsing-remitting multiple sclerosis. Similarly, damage was least severe in cognitively preserved (n = 177), more severe in mildly cognitively impaired (n = 63) and worst in cognitively impaired (n = 87; P < 0.05). Microstructural damage was most pronounced in the cingulum, while macrostructural alterations were most pronounced in the corticospinal tract, cingulum and superior longitudinal fasciculus. Over time, white matter alterations worsened most severely in progressive multiple sclerosis (P < 0.05), with white matter atrophy progression mainly seen in the corticospinal tract and microstructural axonal damage worsening in cingulum and superior longitudinal fasciculus. Cognitive decline at follow-up could be predicted by baseline fixel-based measures (R2 = 0.45, P < 0.001). Fixel-based approaches are sensitive to white matter degeneration patterns in multiple sclerosis and can have strong predictive value for cognitive impairment. Longitudinal deterioration was most marked in progressive multiple sclerosis, indicating that degeneration in white matter remains important to characterize further in this phenotype.

Relative aerobic load of walking in people with multiple sclerosis.

OBJECTIVE: To examine the energy demand of walking relative to aerobic capacity in people with multiple sclerosis. DESIGN: Cross-sectional cohort study. PATIENTS: A total of 45 people with multiple sclerosis (32 females), median disease duration 15 years (interquartile range (IQR) 9; 20), median Expanded Disability Status Scale 4 (min-max range: 2.0; 6.0). METHODS: Aerobic capacity, derived from a cardiopulmonary exercise test and gas exchange measurements, assessed during a 6-min overground walk test at comfortable speed, were analysed. The relative aerobic load of walking was determined as the energy demand of walking relative to oxygen uptake at peak and at the first ventilatory threshold. Healthy reference data were used for clinical inference. RESULTS: People with multiple sclerosis walk at a mean relative aerobic load of 60.0% (standard deviation 12.8%) relative to peak aerobic capacity, and 89.1% (standard deviation 19.9%) relative to the first ventilatory threshold. Fourteen participants walked above the first ventilatory threshold (31%). Peak aerobic capacity was reduced in 45% of participants, and energy demands were increased in 52% of participants. CONCLUSION: People with multiple sclerosis walk at a relative aerobic load close to their first ventilatory threshold. A high relative aerobic load can guide clinicians to improve aerobic capacity or reduce the energy demands of walking.

Identifying and understanding cognitive profiles in multiple sclerosis: a role for visuospatial memory functioning.

BACKGROUND: The heterogeneous nature of cognitive impairment in people with multiple sclerosis (PwMS) hampers understanding of the underlying mechanisms and developing patient-tailored interventions. We aim to identify and classify cognitive profiles in PwMS, comparing these to cognitive status (preserved versus impaired). METHODS: We included 1213 PwMS (72% female, age 45.4 ± 10.7 years, 83% relapsing-remitting MS). Cognitive test scores were converted to Z-scores compared to healthy controls for the functions: attention, inhibition, information processing speed (IPS), verbal fluency and verbal/visuospatial memory. Concerning cognitive status, impaired cognition (CI) was defined as performing at Z ≤ - 1.5 SD on ≥ 2 functions. Cognitive profiles were constructed using latent profile analysis on all cognitive functions. Cognitive profiles or status was classified using gradient boosting decision trees, providing the importance of each feature (demographics, clinical, cognitive and psychological functioning) for the overall classification. RESULTS: Six profiles were identified, showing variations in overall performance and specific deficits (attention, inhibition, IPS, verbal fluency, verbal memory and visuospatial memory). Across the profiles, IPS was the most impaired function (%CI most preserved profile, Profile 1 = 22.4%; %CI most impaired profile, Profile 6 = 76.6%). Cognitive impairment varied from 11.8% in Profile 1 to 95.3% in Profile 6. Of all cognitive functions, visuospatial memory was most important in classifying profiles and IPS the least (area under the curve (AUC) = 0.910). For cognitive status, IPS was the most important classifier (AUC = 0.997). CONCLUSIONS: This study demonstrated that cognitive heterogeneity in MS reflects a continuum of cognitive severity, distinguishable by distinct cognitive profiles, primarily explained by variations in visuospatial memory functioning.

Don't be late! Timely identification of cognitive impairment in people with multiple sclerosis: a study protocol.

BACKGROUND: Cognitive impairment occurs in up to 65% of people with multiple sclerosis (PwMS), negatively affecting daily functioning and health-related quality of life. In general, neuropsychological testing is not part of standard MS-care due to insufficient time and trained personnel. Consequently, a baseline assessment of cognitive functioning is often lacking, hampering early identification of cognitive decline and change within a person over time. To assess cognitive functioning in PwMS in a time-efficient manner, a BICAMS-based self-explanatory digital screening tool called the Multiple Screener©, has recently been developed. The aim of the current study is to validate the Multiple Screener© in a representative sample of PwMS in the Netherlands. Additionally, we aim to investigate how cognitive functioning is related to psychological factors, and both work and societal participation. METHODS: In this cross-sectional multicentre study, 750 PwMS (aged 18-67 years) are included. To obtain a representative sample, PwMS are recruited via 12 hospitals across the Netherlands. They undergo assessment with the Minimal Assessment of Cognitive Functioning in MS (MACFIMS; reference-standard) and the Multiple Screener©. Sensitivity, specificity, and predictive values for identifying (mild) cognitive impairment are determined in a subset of 300 participants. In a second step, the identified cut-off values are tested in an independent subset of at least 150 PwMS. Moreover, test-retest reliability for the Multiple Screener© is determined in 30 PwMS. Information on psychological and work-related factors is assessed with questionnaires. DISCUSSION: Validating the Multiple Screener© in PwMS and investigating cognition and its determinants will further facilitate early identification and adequate monitoring of cognitive decline in PwMS.

Don't be late! Postponing cognitive decline and preventing early unemployment in people with multiple sclerosis: a study protocol.

BACKGROUND: Up to 65% of people with multiple sclerosis (PwMS) develop cognitive deficits, which hampers their ability to work, participating in day-to-day life and ultimately reducing quality of life (QoL). Early cognitive symptoms are often less tangible to PwMS and their direct environment and are noticed only when symptoms and work functioning problems become more advanced, i.e., when (brain) damage is already advanced. Treatment of symptoms at a late stage can lead to cognitive impairment and unemployment, highlighting the need for preventative interventions in PwMS. AIMS: This study aims to evaluate the (cost-) effectiveness of two innovative preventative interventions, aimed at postponing cognitive decline and work functioning problems, compared to enhanced usual care in improving health-related QoL (HRQoL). METHODS: Randomised controlled trial including 270 PwMS with mild cognitive impairment, who have paid employment ≥ 12 h per week and are able to participate in physical exercise (Expanded Disability Status Scale < 6.0). Participants are randomised across three study arms: 1) 'strengthening the brain' - a lifestyle intervention combining personal fitness, mental coaching, dietary advice, and cognitive training; 2) 'strengthening the mind' - a work-focused intervention combining the capability approach and the participatory approach in one-on-one coaching by trained work coaches who have MS themselves; 3) Control group-receiving general information about cognitive impairment in MS and receiving care as usual. Intervention duration is four months, with short-term and long-term follow-up measurements at 10 and 16 months, respectively. The primary outcome measure of the Don't be late! intervention study will be HRQoL as measured with the 36-item Short Form. Secondary outcomes include cognition, work related outcomes, physical functioning, structural and functional brain changes, psychological functioning, and societal costs. Semi-structured interviews and focus groups with stakeholders will be organised to qualitatively reflect on the process and outcome of the interventions. DISCUSSION: This study seeks to prevent (further) cognitive decline and job loss due to MS by introducing tailor-made interventions at an early stage of cognitive symptoms, thereby maintaining or improving HRQoL. Qualitative analyses will be performed to allow successful implementation into clinical practice. TRIAL REGISTRATION: Retrospectively registered at ClinicalTrials.gov with reference number NCT06068582 on 10 October 2023.

Isolated cognitive impairment in people with multiple sclerosis: frequency, MRI patterns and its development over time.

OBJECTIVES: To study the frequency of isolated (i.e., single-domain) cognitive impairments, domain specific MRI correlates, and its longitudinal development in people with multiple sclerosis (PwMS). METHODS: 348 PwMS (mean age 48 ± 11 years, 67% female, 244RR/52SP/38PP) underwent neuropsychological testing (extended BRB-N) at baseline and at five-year follow-up. At baseline, structural MRI was acquired. Isolated cognitive impairment was defined as a Z-score of at least 1.5 SD below normative data in one domain only (processing speed, memory, executive functioning/working memory, and attention). Multi-domain cognitive impairment was defined as being affected in ≥ 2 domains, and cognitively preserved otherwise. For PwMS with isolated cognitive impairment, MRI correlates were explored using linear regression. Development of isolated cognitive impairment over time was evaluated based on reliable change index. RESULTS: At baseline, 108 (31%) PwMS displayed isolated cognitive impairment, 148 (43%) PwMS displayed multi-domain cognitive impairment. Most PwMS with isolated cognitive impairment were impaired on executive functioning/working memory (EF/WM; N = 37), followed by processing speed (IPS; N = 25), memory (N = 23), and attention (N = 23). Isolated IPS impairment was explained by a model of cortical volume and fractional anisotropy (adj. R2 = 0.539, p < 0.001); memory by a model with cortical volume and hippocampal volume (adj. R2 = 0.493, p = 0.002); EF/WM and attention were not associated with any MRI measure. At follow-up, cognitive decline was present in 11/16 (69%) of PwMS with isolated IPS impairment at baseline. This percentage varied between 18 and 31% of PwMS with isolated cognitive impairment in domains other than IPS at baseline. CONCLUSION: Isolated cognitive impairment is frequently present in PwMS and can serve as a proxy for further decline, particularly when it concerns processing speed. Cortical and deep grey matter atrophy seem to play a pivotal role in isolated cognitive impairment. Timely detection and patient-tailored intervention, predominantly for IPS, may help to postpone further cognitive decline.

Neurophysiological brain function predicts response to cognitive rehabilitation and mindfulness in multiple sclerosis: a randomized trial.

BACKGROUND: Cognitive treatment response varies highly in people with multiple sclerosis (PwMS). Identification of mechanisms is essential for predicting response. OBJECTIVES: This study aimed to investigate whether brain network function predicts response to cognitive rehabilitation therapy (CRT) and mindfulness-based cognitive therapy (MBCT). METHODS: PwMS with cognitive complaints completed CRT, MBCT, or enhanced treatment as usual (ETAU) and performed three measurements (baseline, post-treatment, 6-month follow-up). Baseline magnetoencephalography (MEG) measures were used to predict treatment effects on cognitive complaints, personalized cognitive goals, and information processing speed (IPS) using mixed models (secondary analysis REMIND-MS study). RESULTS: We included 105 PwMS (96 included in prediction analyses; 32 CRT, 31 MBCT, 33 ETAU), and 56 healthy controls with baseline MEG. MEG did not predict reductions in complaints. Higher connectivity predicted better goal achievement after MBCT (p = 0.010) and CRT (p = 0.018). Lower gamma power (p = 0.006) and higher connectivity (p = 0.020) predicted larger IPS benefits after MBCT. These MEG predictors indicated worse brain function compared to healthy controls (p < 0.05). CONCLUSIONS: Brain network function predicted better cognitive goal achievement after MBCT and CRT, and IPS improvements after MBCT. PwMS with neuronal slowing and hyperconnectivity were most prone to show treatment response, making network function a promising tool for personalized treatment recommendations. TRIAL REGISTRATION: The REMIND-MS study was prospectively registered in the Dutch Trial registry (NL6285; https://trialsearch.who.int/Trial2.aspx?TrialID=NTR6459 ).

Cognitive phenotypes predict response to restorative cognitive rehabilitation in multiple sclerosis.

BACKGROUND: Cognitive phenotyping may be useful for predicting rehabilitation response in multiple sclerosis. OBJECTIVE: To evaluate the association between cognitive phenotype(s) and response to restorative cognitive rehabilitation (RRCR). METHODS: In a post hoc retrospective analysis of the RRCR study including 51 multiple sclerosis patients, we evaluated both impairment within specific cognitive domains as well as overall global impairment severity to investigate their relationship to improvement following rehabilitation. RESULTS: Greater improvement in executive function was predicted by impairment within this domain as well as by having fewer impaired cognitive domains overall. Similar results were observed for visuospatial memory. CONCLUSIONS: Patients most likely to benefit from restorative cognitive rehabilitation may exhibit impairment within the domain of interest yet lower cognitive burden overall.

Neurobiological basis and risk factors of persistent fatigue and concentration problems after COVID-19: study protocol for a prospective case-control study (VeCosCO).

INTRODUCTION: The risk factors for persistent fatigue and cognitive complaints after infection with SARS-CoV-2 and the underlying pathophysiology are largely unknown. Both clinical factors and cognitive-behavioural factors have been suggested to play a role in the perpetuation of complaints. A neurobiological aetiology, such as neuroinflammation, could be the underlying pathophysiological mechanism for persisting complaints.To unravel factors associated with persisting complaints, VeCosCO will compare individuals with and without persistent fatigue and cognitive complaints >3 months after infection with SARS-CoV-2. The study consists of two work packages. The first work package aims to (1) investigate the relation between persisting complaints and neuropsychological functioning; (2) determine risk factors and at-risk phenotypes for the development of persistent fatigue and cognitive complaints, including the presence of postexertional malaise and (3) describe consequences of persistent complaints on quality of life, healthcare consumption and physical functioning. The second work package aims to (1) determine the presence of neuroinflammation with [18F]DPA-714 whole-body positron emission tomography (PET) scans in patients with persisting complaints and (2) explore the relationship between (neuro)inflammation and brain structure and functioning measured with MRI. METHODS AND ANALYSIS: This is a prospective case-control study in participants with and without persistent fatigue and cognitive complaints, >3 months after laboratory-confirmed SARS-CoV-2 infection. Participants will be mainly included from existing COVID-19 cohorts in the Netherlands covering the full spectrum of COVID-19 acute disease severity. Primary outcomes are neuropsychological functioning, postexertional malaise, neuroinflammation measured using [18F]DPA-714 PET, and brain functioning and structure using (f)MRI. ETHICS AND DISSEMINATION: Work package 1 (NL79575.018.21) and 2 (NL77033.029.21) were approved by the medical ethical review board of the Amsterdam University Medical Centers (The Netherlands). Informed consent is required prior to participation in the study. Results of this study will be submitted for publication in peer-reviewed journals and shared with the key population.

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.

BACKGROUND: Cognitive 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. OBJECTIVE: To 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. METHODS: Eighty-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. RESULTS: Only 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%). CONCLUSION: Fluid 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.

Neurophysiological MEG markers of cognitive impairment and performance validity in multiple sclerosis.

BACKGROUND: Suboptimal performance during neuropsychological testing frequently occurs in multiple sclerosis (MS), leading to unreliable cognitive outcomes. Neurophysiological alterations correlate with MS-related cognitive impairment, but studies have not yet considered performance validity. OBJECTIVES: To investigate neurophysiological markers of cognitive impairment in MS, while explicitly addressing performance validity. METHODS: Magnetoencephalography recordings, neuropsychological assessments, and performance validity testing were obtained from 90 MS outpatients with cognitive complaints. Spectral and resting-state functional connectivity (rsFC) properties were compared between cognitively impaired (CI), cognitively preserved (CP), and suboptimally performing (SUB) patients using regression models and permutation testing. RESULTS: CI had higher power in low-frequency bands and lower power in high bands compared to CP, indicating neuronal slowing. CI also showed lower beta power compared to SUB. Overall power spectra visually differed between CI and CP, and SUB showed overlap with both groups. CI had lower rsFC than CP and SUB patients. CP and SUB patients showed no differences. CONCLUSION: Neuronal slowing and altered rsFC can be considered cognitive markers in MS. Patients who performed suboptimally showed resemblance with patients with and without cognitive impairments, and although their overall neurophysiological profile was more similar to patients without impairments, it suggests heterogeneity regarding their pathophysiology.

Brain-derived neurotrophic factor, neurofilament light and glial fibrillary acidic protein do not change in response to aerobic training in people with MS-related fatigue - a secondary analysis of a randomized controlled trial.

BACKGROUND: Neuroinflammation and neurodegeneration are pathological hallmarks of multiple sclerosis (MS). Brain-derived neurotrophic factor (BDNF), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) are blood-based biomarkers for neurogenesis, axonal damage and astrocyte reactivity, respectively. We hypothesize that exercise has a neuroprotective effect on MS reflected by normalization of BDNF, NfL and GFAP levels. OBJECTIVES: To investigate the neuroprotective effect of aerobic training (AT) compared to a control intervention on blood-based biomarkers (i.e. BDNF, NfL, GFAP) in people with MS (pwMS). METHODS: In the TREFAMS-AT (Treating Fatigue in Multiple Sclerosis - Aerobic Training) study, 89 pwMS were randomly allocated to either a 16-week AT intervention or a control intervention (3 visits to a MS nurse). In this secondary analysis, blood-based biomarker concentrations were measured in 55 patients using Simoa technology. Changes in pre- and post-intervention concentrations were compared and between-group differences were assessed using analysis of covariance (ANCOVA). Confounding effects of age, sex, MS-related disability assessed using the Expanded Disability Status Scale (EDSS), MS duration, use of disease-modifying medication, and Body Mass Index were considered. RESULTS: Blood samples were available for 30 AT and 25 control group participants (mean age 45.6 years, 71% female, median disease duration 8 years, median EDSS score 2.5). Within-group changes in both study groups were small and non-significant, with the exception of BDNF in the control group (median (interquartile range) -2.1 (-4.7; 0)). No between-group differences were found for any biomarker: BDNF (ß = 0.11, 95%CI (-3.78 to 4.00)), NfL (ß = -0.04, 95%CI (-0.26 to 0.18)), and GFAP (ß = -0.01, 95%CI (-0.16 to 0.15)), adjusted for confounders. CONCLUSION: Aerobic exercise therapy did not result in statistically significant changes in the tested neuro-specific blood-based biomarkers in people with MS. TRIAL REGISTRATION: this study is registered under number ISRCTN69520623 (https://www.isrctn.com/ISRCTN695206).

Inhibitory synaptic loss drives network changes in multiple sclerosis: An ex vivo to in silico translational study.

BACKGROUND: Synaptic and neuronal loss contribute to network dysfunction and disability in multiple sclerosis (MS). However, it is unknown whether excitatory or inhibitory synapses and neurons are more vulnerable and how their losses impact network functioning. OBJECTIVE: To quantify excitatory and inhibitory synapses and neurons and to investigate how synaptic loss affects network functioning through computational modeling. METHODS: Using immunofluorescent staining and confocal microscopy, densities of glutamatergic and GABAergic synapses and neurons were compared between post-mortem MS and non-neurological control cases. Then, a corticothalamic biophysical model was employed to study how MS-induced excitatory and inhibitory synaptic loss affect network functioning. RESULTS: In layer VI of normal-appearing MS cortex, excitatory and inhibitory synaptic densities were significantly lower than controls (reductions up to 14.9%), but demyelinated cortex showed larger losses of inhibitory synapses (29%). In our computational model, reducing inhibitory synapses impacted the network most, leading to a disinhibitory increase in neuronal activity and connectivity. CONCLUSION: In MS, excitatory and inhibitory synaptic losses were observed, predominantly for inhibitory synapses in demyelinated cortex. Inhibitory synaptic loss affected network functioning most, leading to increased neuronal activity and connectivity. As network disinhibition relates to cognitive impairment, inhibitory synaptic loss seems particularly relevant in MS.

A randomized trial predicting response to cognitive rehabilitation in multiple sclerosis: Is there a window of opportunity?

BACKGROUND: Cognitive training elicits mild-to-moderate improvements in cognitive functioning in people with multiple sclerosis (PwMS), although response heterogeneity limits overall effectiveness. OBJECTIVE: To identify patient characteristics associated with response and non-response to cognitive training. METHODS: Eighty-two PwMS were randomized into a 7-week attention training (n = 58, age = 48.4 ± 10.2 years) or a waiting-list control group (n = 24, age = 48.5 ± 9.4 years). Structural and functional magnetic resonance imaging (MRI) was obtained at baseline and post-intervention. Twenty-one healthy controls (HCs, age = 50.27 ± 10.15 years) were included at baseline. Responders were defined with a reliable change index of 1.64 on at least 2/6 cognitive domains. General linear models and logistic regression were applied. RESULTS: Responders (n = 36) and non-responders (n = 22) did not differ on demographics, clinical variables and baseline cognition and structural MRI. However, non-responders exhibited a higher baseline functional connectivity (FC) between the default-mode network (DMN) and the ventral attention network (VAN), compared with responders (p = 0.018) and HCs (p = 0.001). Conversely, responders exhibited no significant baseline differences in FC compared with HCs. Response to cognitive training was predicted by lower DMN-VAN FC (p = 0.004) and DMN-frontoparietal FC (p = 0.029) (Nagelkerke R2 = 0.25). CONCLUSION: An intact pre-intervention FC is associated with cognitive training responsivity in pwMS, suggesting a window of opportunity for successful cognitive interventions.

miR-150-5p and let-7b-5p in Blood Myeloid Extracellular Vesicles Track Cognitive Symptoms in Patients with Multiple Sclerosis.

Cognitive deficits strongly affect the quality of life of patients with multiple sclerosis (MS). However, no cognitive MS biomarkers are currently available. Extracellular vesicles (EVs) contain markers of parental cells and are able to pass from the brain into blood, representing a source of disease biomarkers. The aim of this study was to investigate whether small non-coding microRNAs (miRNAs) targeting synaptic genes and packaged in plasma EVs may reflect cognitive deficits in MS patients. Total EVs were precipitated by Exoquick from the plasma of twenty-six cognitively preserved (CP) and twenty-three cognitively impaired (CI) MS patients belonging to two independent cohorts. Myeloid EVs were extracted by affinity capture from total EVs using Isolectin B4 (IB4). Fourteen miRNAs targeting synaptic genes were selected and measured by RT-PCR in both total and myeloid EVs. Myeloid EVs from CI patients expressed higher levels of miR-150-5p and lower levels of let-7b-5p compared to CP patients. Stratification for progressive MS (PMS) and relapsing-remitting MS (RRMS) and correlation with clinical parameters suggested that these alterations might be attributable to cognitive deficits rather than disease progression. This study identifies miR-150-5p and let-7b-5p packaged in blood myeloid EVs as possible biomarkers for cognitive deficits in MS.

A more unstable resting-state functional network in cognitively declining multiple sclerosis.

Cognitive impairment is common in people with multiple sclerosis and strongly affects their daily functioning. Reports have linked disturbed cognitive functioning in multiple sclerosis to changes in the organization of the functional network. In a healthy brain, communication between brain regions and which network a region belongs to is continuously and dynamically adapted to enable adequate cognitive function. However, this dynamic network adaptation has not been investigated in multiple sclerosis, and longitudinal network data remain particularly rare. Therefore, the aim of this study was to longitudinally identify patterns of dynamic network reconfigurations that are related to the worsening of cognitive decline in multiple sclerosis. Resting-state functional MRI and cognitive scores (expanded Brief Repeatable Battery of Neuropsychological tests) were acquired in 230 patients with multiple sclerosis and 59 matched healthy controls, at baseline (mean disease duration: 15 years) and at 5-year follow-up. A sliding-window approach was used for functional MRI analyses, where brain regions were dynamically assigned to one of seven literature-based subnetworks. Dynamic reconfigurations of subnetworks were characterized using measures of promiscuity (number of subnetworks switched to), flexibility (number of switches), cohesion (mutual switches) and disjointedness (independent switches). Cross-sectional differences between cognitive groups and longitudinal changes were assessed, as well as relations with structural damage and performance on specific cognitive domains. At baseline, 23% of patients were cognitively impaired (≥2/7 domains Z < -2) and 18% were mildly impaired (≥2/7 domains Z < -1.5). Longitudinally, 28% of patients declined over time (0.25 yearly change on ≥2/7 domains based on reliable change index). Cognitively impaired patients displayed more dynamic network reconfigurations across the whole brain compared with cognitively preserved patients and controls, i.e. showing higher promiscuity (P = 0.047), flexibility (P = 0.008) and cohesion (P = 0.008). Over time, cognitively declining patients showed a further increase in cohesion (P = 0.004), which was not seen in stable patients (P = 0.544). More cohesion was related to more severe structural damage (average r = 0.166, P = 0.015) and worse verbal memory (r = -0.156, P = 0.022), information processing speed (r = -0.202, P = 0.003) and working memory (r = -0.163, P = 0.017). Cognitively impaired multiple sclerosis patients exhibited a more unstable network reconfiguration compared to preserved patients, i.e. brain regions switched between subnetworks more often, which was related to structural damage. This shift to more unstable network reconfigurations was also demonstrated longitudinally in patients that showed cognitive decline only. These results indicate the potential relevance of a progressive destabilization of network topology for understanding cognitive decline in multiple sclerosis.

Functional network dynamics and decreased conscientiousness in multiple sclerosis.

BACKGROUND: Conscientiousness is a personality trait that declines in people with multiple sclerosis (PwMS) and its decline predicts worse clinical outcomes. This study aims to investigate the neural underpinnings of lower Conscientiousness in PwMS by examining MRI anomalies in functional network dynamics. METHODS: 70 PwMS and 50 healthy controls underwent personality assessment and resting-state MRI. Associations with dynamic functional network properties (i.e., eigenvector centrality) were evaluated, using a dynamic sliding-window approach. RESULTS: In PwMS, lower Conscientiousness was associated with increased variability of centrality in the left insula (tmax = 4.21) and right inferior parietal lobule (tmax = 3.79); a relationship also observed in regressions accounting for handedness, disease duration, disability, and tract disruption in relevant structural networks (ΔR2 = 0.071, p = 0.003; ΔR2 = 0.094, p = 0.004). Centrality dynamics of the observed regions were not associated with Neuroticism (R2 < 0.001, p = 0.956; R2 < 0.001, p = 0.945). As well, higher Conscientiousness was associated with greater variability in connectivity for the left insula with the default-mode network (F = 3.92, p = 0.023) and limbic network (F = 5.66, p = 0.005). CONCLUSION: Lower Conscientiousness in PwMS was associated with increased variability in network centrality, most prominently for the left insula and right inferior parietal cortex. This effect, specific to Conscientiousness and significant after accounting for disability and structural network damage, could indicate that overall stable network centrality is lost in patients with low Conscientiousness, especially for the insula and right parietal cortex. The positive relationship between Conscientiousness and variability of connectivity between left insula and default-mode network potentially affirms that dynamics between the salience and default-mode networks is related to the regulation of behavior.