Cortical lesions at diagnosis predict long-term cognitive impairment in multiple sclerosis: A 20-year study.

BACKGROUND AND PURPOSE: Although cognitive impairment (CI) is frequent in multiple sclerosis (MS) patients, few studies (and with conflicting results) have evaluated early predictors of CI in the long term. We aimed at determining associations between early clinical/neuroradiological variables with reference to CI after 20 years of MS. METHODS: We investigated in 170 MS patients the relationship between clinical/magnetic resonance imaging (MRI) data at diagnosis and cognitive status almost 20 years after MS onset. Among others, number and volume of both white matter lesions (WMLs) and cortical lesions (CLs) were evaluated at diagnosis and after 2 years. All MS patients were followed over time and underwent a comprehensive neuropsychological assessment at the end of study. Advanced statistical methods (unsupervised cluster analysis and random forest model) were conducted. RESULTS: CI patients showed higher focal cortical pathology at diagnosis compared to cognitively normal subjects (p < 0.001). Volumes of both WMLs and CLs emerged as the MRI metrics most associated with long-term CI. Moreover, number of CLs (especially ≥3) was also strongly associated with long-term CI (≥3 CLs: odds ratio [OR] = 3.7, 95% confidence interval = 1.8-7.5, p < 0.001), more than number of WMLs; the optimal cutoff of three CLs (area under the curve = 0.67, specificity = 75%, sensitivity = 55%) was estimated according to the risk of developing CI. CONCLUSIONS: These results highlight the impact of considering both white and gray matter focal damage from early MS stages. Given the low predictive value of WML number and the poor clinical applicability of lesion volume estimation in the daily clinical context, the evaluation of number of CLs could represent a reliable prognostic marker of CI.

Prominent role of executive functioning on the Phonemic Fluency Test in people with multiple sclerosis.

OBJECTIVE: Executive functioning (EF) can be one of the earliest, despite under-detected, impaired cognitive domains in patients with multiple sclerosis (pwMS). However, it is still not clear the role of EF on verbal fluency tests given the presence of information processing speed (IPS) deficits in pwMS. METHOD: Performance of a group of 43 pwMS without IPS impairment as measured with the Symbol Digit Modalities Test (SDMT) and a group of 32 healthy controls (HC) was compared on the Phonemic and Semantic Fluency Tests. For each group, we scored the number of words generated (i) in the early time interval (i.e., first 15 sec, semi-automatic process) and (ii) in the late time interval (i.e., from 15 to 60 sec, controlled process). RESULTS: Globally, pwMS produced significantly fewer words than HC on the Phonemic but not on the Semantic Fluency Test. Crucially, in the Phonemic Fluency Test pwMS generated significantly fewer words than HC in the late time interval, whereas no significant difference between the two groups emerged in the early time interval. CONCLUSIONS: These findings suggest that executive dysfunction is the core element on the Phonemic Fluency Test also in pwMS and it deserves attention in both research and clinical practice.

The CSF Profile Linked to Cortical Damage Predicts Multiple Sclerosis Activity.

OBJECTIVE: Intrathecal inflammation correlates with the grey matter damage since the early stages of multiple sclerosis (MS), but whether the cerebrospinal fluid (CSF) profile can help to identify patients at risk of disease activity is still unclear. METHODS: We evaluated the association between CSF levels of 18 cytokines, previously found to be associated to grey matter damage, and the disease activity, among 99 patients with relapsing-remitting MS, who underwent blinded clinical and 3 T magnetic resonance imaging (MRI) evaluations for 4 years. Groups with evidence of disease activity (EDA) or no evidence of disease activity (NEDA; occurrence of relapses, new white matter lesions, and Expanded Disability Status Scale [EDSS] change) were identified. Cortical lesions and the annualized cortical thinning were also evaluated. RESULTS: Forty-one patients experienced EDA and, compared to the NEDA group, had at diagnosis higher CSF levels of CXCL13, CXCL12, IFNγ, TNF, sCD163, LIGHT, and APRIL (p < 0.001). In the multivariate analysis, CXCL13 (hazard ratio [HR] = 1.35; p = 0.0002), LIGHT (HR = 1.22; p = 0.005) and APRIL (HR = 1.78; p = 0.0001) were the CSF molecules more strongly associated with the risk of EDA. The model, including CSF variables, predicted more accurately the occurrence of disease activity than the model with only clinical/MRI parameters (C-index at 4 years = 71% vs 44%). Finally, higher CSF levels of CXCL13 (ß = 4.7*10-4 ; p < 0.001), TNF (ß = 3.1*10-3 ; p = 0.004), LIGHT (ß = 2.6*10-4 ; p = 0.003), sCD163 (ß = 4.3*10-3 ; p = 0.009), and TWEAK (ß = 3.4*10-3 ; p = 0.024) were associated with more severe cortical thinning. INTERPRETATION: A specific CSF profile, mainly characterized by elevated levels of B-cell related cytokines, distinguishes patients at high risk of disease activity and severe cortical damage. The CSF analysis may allow stratifications of patients at diagnosis for optimizing therapeutic approaches. ANN NEUROL 2020;88:562-573.

The neural substrates of social cognition deficits in newly diagnosed multiple sclerosis patients.

OBJECTIVE: Cognitive and affective symptoms in multiple sclerosis (MS) can be independently impaired and have different pathways of progression. Cognitive alterations have been described since the earliest MS stages; by contrast, the social cognition (SC) domain has never been investigated in the first year from MS diagnosis. We aimed to evaluate SC and unravel its neural bases in newly diagnosed MS patients. METHODS: Seventy MS patients underwent at diagnosis a 3 T-MRI and a neuropsychological/SC assessment (median time between diagnosis and MRI/cognitive evaluation = 0 months). We tested two matched reference samples: 31 relapsing-remitting MS patients with longer course (mean ± SD disease duration = 7.0 ± 4.5 years) and 38 healthy controls (HCs). Cortical thicknesses (CTh) and volumes of brain regions were calculated. RESULTS: Newly diagnosed MS patients performed significantly lower than HCs in facial emotion recognition (global: p < 0.001; happiness: p = 0.041, anger: p = 0.007; fear: p < 0.001; disgust: p = 0.004) and theory of mind (p = 0.005), while no difference was found between newly diagnosed and longer MS patients. Compared to lower performers, higher performers in facial emotion recognition showed greater volume of amygdala (p = 0.032) and caudate (p = 0.036); higher performers in theory of mind showed greater CTh in lingual gyrus (p = 0.006), cuneus (p = 0.024), isthmus cingulate (p = 0.038), greater volumes of putamen (p = 0.016), pallidum (p = 0.029), and amygdala (p = 0.032); patients with higher empathy showed lower cuneus CTh (p = 0.042) and putamen volume (p = 0.007). INTERPRETATIONS: SC deficits are present in MS patients since the time of diagnosis and remain persistent along the disease course. Specific basal, limbic, and occipital areas play a significant role in the pathogenesis of these alterations.

Ocrelizumab reduces cortical and deep grey matter loss compared to the S1P-receptor modulator in multiple sclerosis.

INTRODUCTION: Ocrelizumab (OCR) and Fingolimod (FGL) are two high-efficacy treatments in multiple sclerosis which, besides their strong anti-inflammatory activity, may limit neurodegeneration. AIM: To compare the effect of OCR and FGL on clinical and MRI endpoints. METHODS: 95 relapsing-remitting patients (57 OCR, 38 FGL) clinically followed for 36 months underwent a 3-Tesla MRI at baseline and after 24 months. The annualized relapse rate, EDSS, new cortical/white matter lesions and regional cortical and deep grey matter volume loss were evaluated. RESULTS: OCR reduced the relapse rate from 0.48 to 0.04, FGL from 0.32 to 0.05 (both p < 0.001). Compared to FGL, OCR-group experienced fewer new white matter lesions (12% vs 32%, p = 0.005), no differences in new cortical lesions, lower deep grey matter volume loss (- 0.12% vs - 0.66%; p = 0.002, Cohen's d = 0.54), lower global cortical thickness change (- 0.45% vs - 0.70%; p = 0.036; d = 0.42) and reduced cortical thinning/volume loss in several regions of interests, including those of parietal gyrus (d-range = 0.65-0.71), frontal gyrus (d-range = 0.47-0.60), cingulate (d-range = 0.41-0.72), insula (d = 0.36), cerebellum (cortex d = 0.72, white matter d = 0.44), putamen (d = 0.35) and thalamus (d = 0.31). The effect on some regional thickness changes was confirmed in patients without focal lesions. CONCLUSIONS: When compared with FGL, patients receiving OCR showed greater suppression of focal MRI lesions accumulation and lower cortical and deep grey matter volume loss.

CSF levels of Chitinase3like1 correlate with early response to cladribine in multiple sclerosis.

Background: Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. Aim: To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Methods: Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Results: Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). Conclusions: CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Association of Levels of CSF Osteopontin With Cortical Atrophy and Disability in Early Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS). METHODS: CSF levels of osteopontin (OPN) and 66 inflammatory markers were assessed using an immune-assay multiplex technique in 107 patients with RRMS (82 F/25 M, mean age 35.7 ± 11.8 years). All patients underwent regular clinical assessment and yearly 3T MRI scans for 2 years while 39 patients had a 4-year follow-up. White matter lesion number and volume, cortical lesions (CLs) and volume, and global cortical thickness (CTh) were evaluated together with the 'no evidence of disease activity' (NEDA-3) status, defined by no relapses, no disability worsening, and no MRI activity, including CLs. RESULTS: The random forest algorithm selected OPN, CXCL13, TWEAK, TNF, IL19, sCD30, sTNFR1, IL35, IL16, and sCD163 as significantly associated with changes in global CTh. OPN and CXCL13 were most related to accumulation of atrophy after 2 and 4 years. In a multivariate linear regression model on CSF markers, OPN (p < 0.001), CXCL13 (p = 0.001), and sTNFR1 (p = 0.024) were increased in those patients with accumulating atrophy (adjusted R-squared 0.615). The 10 markers were added in a model that included all clinical, demographic, and MRI variables: OPN (p = 0.002) and IL19 (p = 0.022) levels were confirmed to be significantly increased in patients developing more CTh change over the follow-up (adjusted R-squared 0.619). CXCL13 and OPN also revealed the best association with NEDA-3 after 2 years, with OPN significantly linked to disability accumulation (OR 2.468 [1.46-5.034], p = 0.004) at the multivariate logistic regression model. DISCUSSION: These data confirm and expand our knowledge on the prognostic role of the CSF inflammatory profile in predicting changes in cortical pathology and disease activity in early MS. The data emphasize a crucial role of OPN.

Making Visible the Invisible: Automatically Measured Global and Regional Brain Volume Is Associated with Cognitive Impairment and Fatigue in Multiple Sclerosis.

In multiple sclerosis (MS), the transition from relapsing-remitting to the secondary-progressive phase is characterized by a progression independent of relapse activity (PIRA), resulting in physical disability accumulation and invisible symptoms, i.e., fatigue and cognitive impairment (CI). These symptoms are related to neurodegenerative processes and have been correlated with MRI measures of brain atrophy only at a group level; however, the application in clinical practice of atrophy-based measurements for single-patient evaluation is yet to be fully investigated. In the present study, we aimed to evaluate the association between brain atrophy, measured with easy-to-use automatic software, and the "invisible" MS symptoms of cognition and fatigue. A total of 69 MS patients were included in the study; cognitive impairment and fatigue (FSS) (in addition to neurological disability, EDSS) were assessed and correlated with brain volumes calculated using the automated software QyScore® which is validated for single-patient use in the clinical setting. Results showed that the cognitive status was accurately reflected by measures of atrophy, with a sensitivity of up to 90%. CI patients showed a lower volume compared to cognitively normal patients in the whole brain (p = 0.017), gray matter (p = 0.042), insula (p = 0.035), cerebellum (p = 0.008), and limbic lobe (p = 0.049). FSS was associated with temporal lobe (r = -0.37, p = 0.013) and insular (r = -0.36, p = 0.019) volumes. The volumes of the same regions were also associated with EDSS. The global/regional atrophy results, assessed with automatic and easy-to-use software, correlated with cognitive and fatigue symptoms, thus supporting the clinical application in routine patient management.

Immune Response after COVID-19 mRNA Vaccination in Multiple Sclerosis Patients Treated with DMTs.

The impact of disease-modifying therapies (DMTs) on the immune response to coronavirus disease-2019 (COVID-19) vaccines in persons with multiple sclerosis (pwMS) needs further elucidation. We investigated BNT162b2 mRNA COVID-19 vaccine effects concerning antibody seroconversion, inflammatory mediators' level and immunophenotype assessment in pwMS treated with cladribine (c-pwMS, n = 29), fingolimod (f-pwMS, n = 15) and ocrelizumab (o-pwMS, n = 54). Anti-spike immunoglobulin (Ig)-G detection was performed by an enzyme immunoassay; molecular mediators (GrB, IFN-γ and TNF-α) were quantified using the ELLA platform, and immunophenotype was assessed by flow cytometry. ANCOVA, Student's t-test and Pearson correlation analyses were applied. Only one o-pwMS showed a mild COVID-19 infection despite most o-pwMS lacking seroconversion and showing lower anti-spike IgG titers than c-pwMS and f-pwMS. No significant difference in cytokine production and lymphocyte count was observed in c-pwMS and f-pwMS. In contrast, in o-pwMS, a significant increase in GrB levels was detected after vaccination. Considering non-seroconverted o-pwMS, a significant increase in GrB serum levels and CD4+ T lymphocyte count was found after vaccination, and a negative correlation was observed between anti-spike IgG production and CD4+ T cells count. Differences in inflammatory mediators' production after BNT162b2 vaccination in o-pwMS, specifically in those lacking anti-spike IgG, suggest a protective cellular immune response.

A Videogame-Based Approach to Measuring Information Processing Speed in Multiple Sclerosis Patients.

Objective: Slowing information processing speed (IPS) is a biomarker of neuronal damage in patients with multiple sclerosis (pwMS). A focus on IPS might be the ideal solution in the perspective of promptly detecting cognitive changes over time. We developed a tablet-based home-made videogame to test the sensitivity of this device in measuring subclinical IPS in pwMS. Materials and Methods: Forty-three pwMS without cognitive impairment and 20 healthy controls (HCs) were administered the videogame task with a tablet. Response times (RTs) and accuracy were recorded. Results: PwMS (mean RTs = 505.5 ± 73.9 ms) were significantly slower than HCs (mean RTs = 462.3 ± 40.3 ms, P = 0.014) on the videogame task. A moderate but significant correlation (r = -0.35, P = 0.03) between mean RTs and the Symbol Digit Modalities Test was observed. Conclusion: Our videogame showed good sensitivity in measuring IPS in apparently cognitive normal pwMS. Computerized testing might be useful in screening initial cognitive dysfunction that should be monitored as a marker of underlying disease progression. IRB approval Number is 2332CESC.

Coping Strategies and Their Impact on Quality of Life and Physical Disability of People with Multiple Sclerosis.

The aim of the study is to investigate the impact of coping strategies on Health-Related Quality of Life (HRQoL) and physical disability assessed with the Expanded Disability Status Scale (EDSS) of people with multiple sclerosis (pwMS). PwMS were asked to focus on "MS diagnosis" as the core stressor. One hundred eight pwMS completed the Coping Responses Inventory-Adult form (CRI-Adult), the Multiple Sclerosis Quality of Life-29 (MSQoL-29), and the Depression Anxiety Stress Scale-21 (DASS-21). Multiple regression analyses (first block: EDSS, disease duration, and DASS-21) revealed that physical MSQoL-29 was positively associated with Alternative Rewards and negatively with Resigned Acceptance of the CRI-Adult. The mental MSQoL-29 was positively associated with Problem-Solving and negatively with Emotional Discharge. The Expanded Disability Status Scale (EDSS; first block: disease duration and general distress) was negatively associated with Positive Reappraisal. The Analysis of covariance (ANCOVA) revealed that pwMS with lower physical disability showed higher scores in Positive Reappraisal and lower scores in Emotional Discharge than pwMS with a higher physical disability. Coping strategies can play a role on HRQoL and physical disability in pwMS above and beyond EDSS, disease duration, and general distress. Psychological interventions should be considered in pwMS since the time of diagnosis to promote engagement in adaptive coping strategies and contrast the maladaptive ones.

CSF parvalbumin levels reflect interneuron loss linked with cortical pathology in multiple sclerosis.

INTRODUCTION AND METHODS: In order to verify whether parvalbumin (PVALB), a protein specifically expressed by GABAergic interneurons, could be a MS-specific marker of grey matter neurodegeneration, we performed neuropathology/molecular analysis of PVALB expression in motor cortex of 40 post-mortem progressive MS cases, with/without meningeal inflammation, and 10 control cases, in combination with cerebrospinal fluid (CSF) assessment. Analysis of CSF PVALB and neurofilaments (Nf-L) levels combined with physical/cognitive/3TMRI assessment was performed in 110 naïve MS patients and in 32 controls at time of diagnosis. RESULTS: PVALB gene expression was downregulated in MS (fold change = 3.7 ± 1.2, P < 0.001 compared to controls) reflecting the significant reduction of PVALB+ cell density in cortical lesions, to a greater extent in MS patients with high meningeal inflammation (51.8, P < 0.001). Likewise, post-mortem CSF-PVALB levels were higher in MS compared to controls (fold change = 196 ± 36, P < 0.001) and correlated with decreased PVALB+ cell density (r = -0.64, P < 0.001) and increased MHC-II+ microglia density (r = 0.74, P < 0.01), as well as with early age of onset (r = -0.69, P < 0.05), shorter time to wheelchair (r = -0.49, P < 0.05) and early age of death (r = -0.65, P < 0.01). Increased CSF-PVALB levels were detected in MS patients at diagnosis compared to controls (P = 0.002). Significant correlation was found between CSF-PVALB levels and cortical lesion number on MRI (R = 0.28, P = 0.006) and global cortical thickness (R = -0.46, P < 0.001), better than Nf-L levels. CSF-PVALB levels increased in MS patients with severe cognitive impairment (mean ± SEM:25.2 ± 7.5 ng/mL) compared to both cognitively normal (10.9 ± 2.4, P = 0.049) and mild cognitive impaired (10.1 ± 2.9, P = 0.024) patients. CONCLUSIONS: CSF-PVALB levels reflect loss of cortical interneurons in MS patients with more severe disease course and might represent an early, new MS-specific biomarker of cortical neurodegeneration, atrophy, and cognitive decline.

Visual-Attentional Load Unveils Slowed Processing Speed in Multiple Sclerosis Patients: A Pilot Study with a Tablet-Based Videogame.

Slowing in information processing speed (IPS) is the key cognitive deficit in multiple sclerosis (MS). Testing IPS in different cognitive load conditions by using computerized tools might reveal initial IPS slowness underestimated by classic paper-and-pencil tests. To investigate the extent to which IPS can be affected by increased task demands, we developed three tasks based on the manipulation of the visual-attentional load, delivered with a home-made, tablet-based videogame. Fifty-one patients with MS (pwMS), classified as having no cognitive impairment in classic paper-and-pencil tests, and 20 healthy controls (HC) underwent the videogame tasks; reaction times (RTs) and accuracy were recorded. A significant reduced performance of pwMS as compared with HC was found on the videogame tasks, with pwMS being on average slower and less accurate than HC. Furthermore, pwMS showed a significantly more pronounced decrement in accuracy as a function of the visual-attentional load, suggesting a higher susceptibility to increased task demands. Significant correlations among the Symbol Digit Modalities Test (SDMT) and the videogame mean RTs and accuracy were found, providing evidence for the concurrent validity of the videogame as a valid tool to test IPS in pwMS. The high potential that might derive from the adoption of computerized assessment tools in clinical practice should be taken into consideration and investigated further.

Executive functioning affects verbal learning process in multiple sclerosis patients: Behavioural and imaging results.

Verbal learning and memory deficits are among the most frequent in people with multiple sclerosis (pwMS) and have been shown to be affected by deficits in other cognitive domains, such as information processing speed and executive functioning (EF). In the present study, we aimed to further investigate the differential impact that EF may exert on verbal learning and memory on both behavioural and neural levels. Seventy pwMS were assessed with a comprehensive battery of neuropsychological tests, including tests of verbal memory (Selective Reminding Test; SRT) and EF (Stroop test; Phonemic and Alternate Verbal Fluency; Modified Five-Point Test). Structural 3Tesla magnetic resonance imaging (MRI) scans were available for 68 patients; cortical thickness of several frontal, pre-frontal, and hippocampal regions was calculated. Multivariable linear regression analysis showed that patients' performance on Alternate Fluency Test predicted both their immediate (SRT-LTS: R2  = .38; p < .001; SRT-CLTR: R2  = .42; p < .001) and delayed (SRT-D: R2  = .39; p < .001) verbal memory performance. In addition, we found a significant relationship between the cortical thickness of the hippocampus and several bilateral frontal areas (i.e., anterior cingulate gyrus, superior and inferior frontal gyrus, medial frontal cortex, and frontal pole) with verbal memory tests scores (SRT-LTS: R2  = .45; p < .001; SRT-CLTR: R2  = .52; p < .001; SRT-D: R2  = .49; p < .001). These behavioural and MRI results suggest that EF significantly impacts verbal memory performance in pwMS. The understanding of the complex interaction between these distinct cognitive domains can help foster the development of memory rehabilitation paradigms that take into account also the role of executive functioning.

Lost in Classification: Lower Cognitive Functioning in Apparently Cognitive Normal Newly Diagnosed RRMS Patients.

Cognitive functioning in multiple sclerosis (MS) patients is usually related to the classic, dichotomic classification of impaired vs. unimpaired cognition. However, this approach is far from mirroring the real efficiency of cognitive functioning. Applying a different approach in which cognitive functioning is considered as a continuous variable, we aimed at showing that even newly diagnosed relapsing-remitting MS (RRMS) patients might suffer from reduced cognitive functioning with respect to a matched group of neurologically healthy controls (HCs), even if they were classified as having no cognitive impairment (CI). Fifty newly diagnosed RRMS patients and 36 HCs were tested with an extensive battery of neuropsychological tests. By using Z-scores applied to the whole group of RRMS and HCs together, a measure of cognitive functioning (Z-score index) was calculated. Among the 50 RRMS patients tested, 36 were classified as cognitively normal (CN). Even though classified as CN, RRMS patients performed worse than HCs at a global level (p = 0.004) and, more specifically, in the domains of memory (p = 0.005) and executive functioning (p = 0.006). These results highlight that reduced cognitive functioning can be present early in the disease course, even in patients without an evident CI. The current classification criteria of CI in MS should be considered with caution.