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Cortical atrophy, lesion burden and cognitive impairment in MS. Coronal (A, C, E, F) and axial (B, D) views of MRI brain scans from RRMS patients without cognitive impairment (patient 1—A, B; patient 2—C, D) and with cognitive decline (patient 3—E, F). Patient 1 demonstrates relatively preserved brain parenchymal volume (A) despite moderately significant WM lesion burden (B). Conversely, patient 2 has evidence of significant globalized cerebral atrophy (C) in the absence of a significant WM lesion load (D). Patient 3 shows radiographic evidence of progressively worsening global cerebral atrophy over 18 months despite disease-modifying therapy and relative stability of WM lesion burden. These images highlight the complex relationships between GM and WM pathology and cognitive impairment in MS. A, C. T1-weighted sequences; B, D, E, F. T2-FLAIR sequence.
Source publication
Cognitive impairment is a common and debilitating feature of multiple sclerosis (MS) that has only recent gained considerable attention. Clinical neuropsychological studies have made apparent the multifaceted nature of cognitive troubles often encountered in MS and continue to broaden our understanding of its complexity. Radiographic studies have s...
Context in source publication
Context 1
... atrophy of both WM and GM are noted over time, MRI studies support GM atrophy as the driving force behind whole brain atrophy. Cross-sectional studies compar- ing early MS patients to healthy controls confirm a significant brain volume reduction compared with healthy controls, but also find a greater reduction in GM than WM when controlling for age and gender, as well as a lack of correlation between brain atrophy measures and T 2 lesion load (50, 202) ( Figure 1). Early MS patients followed for 4 years were found to have GM atrophy occurring at a 3.4× greater rate in the group of first demyelinating event patients who converted to MS vs. those who did not. ...
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Lay summary:
Habit learning, action selection and performance are modulated by the basal ganglia, a collection of groups of neurons located below the cerebral cortex in the brain. In autism, there is emerging evidence that parts of the basal ganglia are structurally and functionally altered disrupting normal information flow. The basal ganglia thr...
Citations
... Between 40 and 70 percent of MS patients experience cognitive impairment (CI) even in the early stages of the disease [5]. Cognitive abnormality in MS has been associated with both white matter (demyelinated lesions and white matter that appears normal) and grey matter (cerebral cortex, deep nuclei), with white matter loss being associated with deficits in working memory and mental speed of processing and grey matter atrophy being associated with deficits in verbal memory [6]. ...
Background
Grey matter loss is thought to be the primary reason of cognitive disability in MS, with trans-synaptic axonal degeneration acting a supportive role. This research sought to evaluate cognitive profile of Egyptian multiple sclerosis patients and find out if it has a correlation with serum neurofilament or not.
Methods
This was a cross-sectional research performed on a total of 60 patients with MS and 30 healthy controls. BICAMS battery of neuropsychological tests was used which includes SDMT, CVLT and BVMT. Serum NFLs using ELISA technique.
Results
Mean ± SD of NFL in RRMS was 82.25 ± 170.9, in PPMS was 22.08 ± 7.26, in SPMS was 95.82 ± 187.5, and in control group was 56.65 ± 125.4, there was high statistical substantial variations among the different groups while there was non-statistical variation between RRMS and PPMS groups, also there was no variation between PPMS and SPMS with regard to serum level of NFL. There is no significant correlation between the NFL and different cognitive tests.
Conclusion
Since sNfL did not strongly connect with cognitive function in MS patients, it is possible that it cannot be used as a substitute indicator for neuropsychological state in these groups.
... Dorsal prefrontal lesions have been linked to problems regarding theory of mind deficits, reduced initiation, apathy, lack of drive, loss of interest, lethargy, slowness, inattentiveness, reduced spontaneity, unconcern, lack of emotional reactivity, dullness, poor grooming and perseveration (ylvisaker et al., 2005). Multiple studies showed that Ms pathology is multifaceted, with cortical, deep grey matter and white matter structures being significantly impacted (Deluca et al., 2015;calabrese et al., 2013;pirko et al., 2007;popescu & lucchinetti, 2012). lesions are present in the gray matter, including the cortex, the basal ganglia, brain stem and the gray matter of the spinal cord. ...
Although multiple sclerosis (MS) is a common disease of the central nervous system, little is known about behavioral problems, like signs of rigidity, increased disinhibition and apathy. The aim of the present study is to examine whether people with MS (PwMS) report more behavioral problems compared to people with a non-CNS-involved chronic disease (people with rheumatoid arthritis (PwRA)) and the relationship with depression, anxiety, coping and fatigue. Forty-five PwMS and thirty PwRA and informants filled in questionnaires assessing behavioral problems (NPI-Q, BRIEF-A), depression and anxiety (HADS), acceptance (ICQ) and fatigue (CIS-20). Compared to PwRA, PwMS reported significantly more apathy, irritability and aimless repetitive behavior. PwMS also reported higher levels of fatigue and more helplessness. Higher levels of depressive symptoms and lower levels of acceptance were related to higher levels of self-reported apathy. Higher levels of irritability were related to more helplessness and less acceptance. This study indicates that there is a specific pattern of self-reported behavioral problems in PwMS regarding apathy, irritability and repetitive behavior. These results may not solely be explained by psychological factors, but it is hypothesized that this could result from MS related executive disorders.
... White matter lesions have been considered the dominant hallmark of inflammatory disease activity in MS; though, grey matter (GM) involvement is more recently recognized to occur early on and throughout the disease course. Disability progression and worsening of cognitive functioning cannot be strongly predicted by a single MRI marker, as white matter lesion volume [3]. ...
Background
Cognitive impairment, a common and debilitating symptom in people with multiple sclerosis (MS), is especially related to cortical damage. However, the impact of regional cortical damage remains poorly understood. Our aim was to evaluate structural (network) integrity in lesional and non-lesional cortex in people with MS, and its relationship with cognitive dysfunction.
Methods
In this cross-sectional study, 176 people with MS and 48 healthy controls underwent MRI, including double inversion recovery and diffusion-weighted scans, and neuropsychological assessment. Cortical integrity was assessed based on fractional anisotropy (FA) and mean diffusivity (MD) within 212 regions split into lesional or non-lesional cortex, and grouped into seven cortical networks. Integrity was compared between people with MS and controls, and across cognitive groups: cognitively-impaired (CI; ≥ two domains at Z ≤ − 2 below controls), mildly CI (≥ two at − 2 < Z ≤ − 1.5), or cognitively-preserved (CP).
Results
Cortical lesions were observed in 87.5% of people with MS, mainly in ventral attention network, followed by limbic and default mode networks. Compared to controls, in non-lesional cortex, MD was increased in people with MS, but mean FA did not differ. Within the same individual, MD and FA were increased in lesional compared to non-lesional cortex. CI-MS exhibited higher MD than CP-MS in non-lesional cortex of default mode, frontoparietal and sensorimotor networks, of which the default mode network could best explain cognitive performance.
Conclusion
Diffusion differences in lesional cortex were more severe than in non-lesional cortex. However, while most people with MS had cortical lesions, diffusion differences in CI-MS were more prominent in non-lesional cortex than lesional cortex, especially within default mode, frontoparietal and sensorimotor networks.
... Since cognitive impairment occurs with signs of decline in thinking, attention, or memory and can be gradual or sudden, it can reduce MS patients' quality of life (DeLuca et al., 2015;Karalı et al., 2022). A healthy lifestyle including and consequently social isolation of pwMS (Hosseini et al., 2022). ...
The present study aims to investigate the relationships between indices of cognitive reserve and cognitive impairment in patients with multiple sclerosis (pwMS). In this descriptive-correlational study, the statistical population included all pwMS who visited the MS Clinic of Isfahan, (Iran) in 2022. The convenience sampling method was employed to select 106 patients. The research instruments included the Cognitive Reserve Index Questionnaire (CRIq) and Multiple Sclerosis Neuropsychological Questionnaire (MSNQ). Multiple regression and analysis of variance (ANOVA) were adopted for data analysis in SPSS. Regression analysis revealed that CRI-education and CRI-working activity had significant relationships with cognitive impairment (p < 0.01). The coefficient of determination indicated that cognitive reserve explained 16% of changes in cognitive impairment in pwMS. Considered an index of cognitive reserve, leisure time (CRI-leisure time) had no significant relationships with cognitive impairment in pwMS. Although there were no confirmed relationships between gender and cognitive impairment in pwMS, there was a significant difference in the degree of cognitive impairment based on marital status (p < 0.01).
... MS affects over 2 million people, imposing a significant global health burden [2]. Some studies have reported that approximately 40-70% of MS patients experience cognitive dysfunction [3,4], and up to 60% have neuropsychiatric symptoms [5,6]. These neuropsychiatric abnormalities may be related to changes in brain connectivity. ...
Background
Observational studies have suggested an association between multiple sclerosis (MS) and cortical structure, but the results have been inconsistent.
Objective
We used two-sample Mendelian randomization (MR) to assess the causal relationship between MS and cortical structure.
Methods
MS data as the exposure trait, including 14,498 cases and 24,091 controls, were obtained from the International Multiple Sclerosis Genetics Consortium. Genome-wide association study (GWAS) data for cortical surface area (SAw/nw) and thickness (THw/nw) in 51,665 individuals of European ancestry were obtained from the ENIGMA Consortium. The inverse-variance weighted (IVW) method was used as the primary analysis for MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. Enrichment analysis was performed on MR analyses filtered by sensitivity analysis.
Results
After IVW and sensitivity analysis filtering, only six surviving MR results provided suggestive evidence supporting a causal relationship between MS and cortical structure, including lingual SAw ( p = .0342, beta (se) = 5.7127 (2.6969)), parahippocampal SAw ( p = .0224, beta (se) = 1.5577 (0.6822)), rostral middle frontal SAw ( p = .0154, beta (se) = − 9.0301 (3.7281)), cuneus THw ( p = .0418, beta (se) = − 0.0020 (0.0010)), lateral orbitofrontal THw ( p = .0281, beta (se) = 0.0025 (0.0010)), and lateral orbitofrontal THnw ( p = .0417, beta (se) = 0.0029 (0.0014)). Enrichment analysis suggested that leukocyte cell-related pathways, JAK-STAT signaling pathway, NF-kappa B signaling pathway, cytokine-cytokine receptor interaction, and prolactin signaling pathway may be involved in the effect of MS on cortical morphology.
Conclusion
Our results provide evidence supporting a causal relationship between MS and cortical structure. Enrichment analysis suggests that the pathways mediating brain morphology abnormalities in MS patients are mainly related to immune and inflammation-driven pathways.
... The extent and the time of depletion of the cognitive reserve show a high individual variability, although this is occasionally considered in the assessment of cognitive tests (as the "Cognitive Reserve Index"). 35,45,46 A further reason for the diversity of our results is apparent in the variations on detection of DSI. As mentioned previously, there is and will continue to be a very intense international debate about exactly which CD is being measured by the NPTs that are becoming more widely available. ...
Objective
Methods of cognitive measurements in multiple sclerosis (MS) are not standardized. We aimed to identify the prevalence of cognitive domain‐specific impairment (DSI) in MS by using subtests of the Brief Repeatable Battery of Neuropsychological Tests (BRB‐N) with analyzing different cutoff values.
Methods
The systematic review and meta‐analysis were registered on PROSPERO (ID: CRD42021287004). The systematic literature search was performed via PubMed, Embase, and CENTRAL on 24 October 2021. Inclusion criteria were adults of different MS subtypes (CIS, RRMS, PPMS, and SPMS) with the condition of distinct DSI measured by BRB‐N. Pediatric MS, computerized versions of BRB‐N, and patients receiving steroids were excluded. Primary outcome was pooled prevalence rates of impaired patients within each cutoff and MS subtype, with 95% confidence interval, I‐squared statistics for heterogeneity, and chi‐squared test for subgroup differences. Risk of bias was assessed using the “JBI Quality Assessment Tool for Prevalence Studies.”
Results
In 48 eligible observational studies ( n = 3431 patients), the three most prevalent thresholds were the 2.0 SD and 1.5 SD below the mean of normative values, and the score below the fifth percentile of the normative values. A progressively increasing worsening of the overall DSI was observed from CIS, moving toward RRMS, PPMS, and SPMS.
Interpretation
Cognitive impairment is observed in all MS phenotypes, with varying degrees. Due to several potential influencing factors, our comprehensive literature review has not revealed consistent findings, and we, therefore, recommend considering a more sophisticated, “ individual referencing ” approach, acknowledging the diverse clinical and sociodemographic characteristics among populations and disparities in cognitive testing.
... A key aspect of rehabilitation for MS patients is cognitive rehabilitation. In people with MS (PwMS), areas such as attention, memory, learning, planning, mental flexibility, problem-solving, and language recall are commonly affected [3], with direct consequences on self-esteem, participation in social activities, and withdrawal from work and relationships [4]. In recent years, technological advances have made it possible to integrate novel computerized systems into the standard rehabilitation practice. ...
Rehabilitation is essential for individuals with multiple sclerosis (MS) to improve their quality of life and mitigate the progression of the disease. Cognitive deficits, which commonly affect MS patients, significantly impact daily functioning and well-being. This paper focuses on the development of a digital version of the Tangram puzzle using virtual reality (VR) to promote logical reasoning, attention, and social interactions to enhance engagement in cognitive rehabilitation for MS patients. The developed simulation integrates social presence in the form of a non-playable character (NPC) intending to improve player performance and motivation to ultimately promote engagement and adherence to treatment. A user study involving different game modes with the NPC in either a supporting or interfering role, was conducted to evaluate the effectiveness and usability of the Tangram VR exergame. After collecting and analyzing questionnaire scores and performance data, our results suggest that the application was well-received by users, and the introduction of an NPC had an impact in terms of execution times and sense of frustration, depending on its behaviour. Nonetheless, only a limited set of significant differences between modes was found, suggesting that further study is necessary to validate the results fully.
... Importantly, this disabling disease affects 2.3 million people worldwide, representing the most common cause of nontraumatic disability in young adults [3]. Although MS is usually recognized by typical presentations that include visual loss, diplopia, ataxia, weakness, sensory disturbances, or urge incontinence [1], cognitive impairment is also now recognized as a common feature of the disease, with an estimated prevalence of 40-70% [4], including deficits on processing speed, attention, learning, and memory as frequently affected domains [5]. Importantly, cognitive dysfunction decreases adherence to treatment and further impacts quality of life of patients with increased unemployment and rates of divorces [2,4]. ...
... Although MS is usually recognized by typical presentations that include visual loss, diplopia, ataxia, weakness, sensory disturbances, or urge incontinence [1], cognitive impairment is also now recognized as a common feature of the disease, with an estimated prevalence of 40-70% [4], including deficits on processing speed, attention, learning, and memory as frequently affected domains [5]. Importantly, cognitive dysfunction decreases adherence to treatment and further impacts quality of life of patients with increased unemployment and rates of divorces [2,4]. However, the underpinnings of these cognitive deficits are still largely unknown and health professionals are poor at detecting them in routine clinical consultation [6]. ...
... Our work suggests that other measures of brain regional volumes should be taken into account when considering MRI as a potentially powerful tool to predictive cognition in MS. Such dysfunction is still poorly detected although highly impactful [2,4,6]. ...
Background
The 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.
Methods
Twenty-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.
Results
Decreases 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.
Conclusion
Our 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.
... Dementia observed in MS patients is mostly subcortical in origin, thus affecting executive functioning, information processing speed and recall. Studies have shown that cognitive impairment in MS patients can lead to a significant decrease in quality of life with increased rates of divorce and reduced labour force participation rates [25][26][27][28]. On the other hand, the gold standard treatment modalities in MS, collectively known as disease modifying drugs (DMDs), exert cognitive sparing effects, hence acting as promising agents [29][30][31]. ...
Neurosteroids (NSs) are endogenous steroid hormones, which are synthesised and metabolised within the central nervous system (CNS). NSs aid myelination and glial differentiation and modulate cognitive functions. Herein, we aim to investigate the relationship between NS levels, 5-alpha-dihydroxyprogesterone (5-α-DHP) and allopregnanolone (ALPG), and their relationship with cognitive changes in relapsing remitting MS patients.
A total of 43 cases with well controlled, relapsing remitting MS composed the study group. The control group included 21 age and gender matched healthy controls (HC). MS patients were assessed by calculating Expanded Disability Status Scale (EDSS) scores, and the Brief Repeatable Battery of Neuropsychological Tests (BRBNT) was performed in both MS group and HC. Levels of 5-α-DHP and ALPG levels were also evaluated for each participant.
The median level of 5-α-DHP was 48 [IQR: 39.2–144.2] pg/mcgL in the MS group and 68.4 [IQR: 57.1–365.9] pg/mcgL in HC (p = 0.02). The median ALPG level was found to be 56.5 [IQR: 37.7–75.4] pg/mcgL in the MS group and 43.9 [IQR: 29.4–70.2] pg/mcgL in HC (p = 0.1). In both groups 5-α-DHP levels were positively correlated with Symbol Digit Modalities Test (SDMT) scores (HC: p = 0.01, r = 0.3 and MS: p = 0.03, r = 0.3). In the MS group, higher EDSS scores were associated with lower scores on Spatial Recall Test (SPART)-Delayed (p = 0.009, r= −0.4) and SDMT (p = 0.01, r= −0.4). The disease duration was negatively correlated with the scores on SPART-Immediate, SPART-Delayed and SDMT (p = 0.02, r= −0.4; p = 0.005, r= −0.4 and p = 0.05, r= −0.3).
5-α-DHP may be lower even in well-controlled cases. 5-α-DHP may contribute to better perceptual processing and attention in cases with MS.
... It is thought that both spontaneous and event-related theta activity are broadly distributed across the brain 37 and associated with active operations of the brain cortex, particularly during high-level cognitive processes (i.e., cognitive top-down control) 38 control. 38,44 The frontal and parietal cortex are necessary for sustaining and mediating attention. [45][46][47] This suggests that the breakdown propagation of theta reactivity may be related to the lack of cognitive processes and attention in DOC patients. ...
Introduction
Combining transcranial magnetic stimulation with electroencephalography (TMS‐EEG), oscillatory reactivity can be measured, allowing us to investigate the interaction between local and distant cortical oscillations. However, the extent to which human consciousness is related to these oscillatory effective networks has yet to be explored.
Aims
We tend to investigate the link between oscillatory effective networks and brain consciousness, by monitoring the global transmission of TMS‐induced oscillations in disorders of consciousness (DOC).
Results
A cohort of DOC patients was included in this study, which included 28 patients with a minimally conscious state (MCS) and 20 patients with vegetative state/unresponsive wakefulness syndrome (VS/UWS). Additionally, 25 healthy controls were enrolled. The oscillatory reactivity to single‐pulse TMS of the frontal, sensorimotor and parietal cortex was measured using event‐related spectral perturbation of TMS‐EEG. The temporal–spatial properties of the oscillatory reactivity were illustrated through life time, decay gradients and accumulative power. In DOC patients, an oscillatory reactivity was observed to be temporally and spatially suppressed. TMS‐EEG of DOC patients showed that the oscillations did not travel as far in healthy controls, in terms of both temporal and spatial dimensions. Moreover, cortical theta reactivity was found to be a reliable indicator in distinguishing DOC versus healthy controls when TMS of the parietal region and in distinguishing MCS versus VS/UWS when TMS of the frontal region. Additionally, a positive correlation was observed between the Coma Recovery Scale‐Revised scores of the DOC patients and the cortical theta reactivity.
Conclusions
The findings revealed a breakdown of oscillatory effective networks in DOC patients, which has implications for the use of TMS‐EEG in DOC evaluation and offers a neural oscillation viewpoint on the neurological basis of human consciousness.
