Slowing processing speed is associated with cognitive fatigue in newly diagnosed multiple sclerosis patients.

OBJECTIVE: To further investigate objective measures of cognitive fatigue (CF), defined as the inability to sustain performance over time, in newly diagnosed multiple sclerosis (MS) patients, by conducting a performance analysis on the Paced Auditory Serial Addition Test (PASAT) based on the type of errors (omissions vs. incorrect responses) committed. METHOD: Sixty-two newly diagnosed patients with MS (pwMS) and 41 healthy controls (HC) completed the PASAT. Analysis of the change in performance during the test was performed by comparing the number of correct responses, incorrect responses, and omissions in the 1st versus the 3rd tertile of the PASAT. RESULTS: A significant decline in accuracy over time was observed to be related to an increment in the number of omissions, significantly more pronounced in pwMS than in HC. No change in the number of incorrect responses throughout the PASAT was observed for either group. CONCLUSIONS: CF can be detected even in newly diagnosed pwMS and might objectively manifest as a progressive increase in omissions during a sustained highly demanding task (i.e., PASAT). This pattern may reflect slowed processing speed and increased fatigue in pwMS. Focusing on omissions on the PASAT instead of correct responses only may improve its specificity as an objective measure of CF.

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.

Unraveling the MRI-Based Microstructural Signatures Behind Primary Progressive and Relapsing-Remitting Multiple Sclerosis Phenotypes.

BACKGROUND: The mechanisms driving primary progressive and relapsing-remitting multiple sclerosis (PPMS/RRMS) phenotypes are unknown. Magnetic resonance imaging (MRI) studies support the involvement of gray matter (GM) in the degeneration, highlighting its damage as an early feature of both phenotypes. However, the role of GM microstructure is unclear, calling for new methods for its decryption. PURPOSE: To investigate the morphometric and microstructural GM differences between PPMS and RRMS to characterize GM tissue degeneration using MRI. STUDY TYPE: Prospective cross-sectional study. SUBJECTS: Forty-five PPMS (26 females) and 45 RRMS (32 females) patients. FIELD STRENGTH/SEQUENCE: 3T scanner. Three-dimensional (3D) fast field echo T1-weighted (T1-w), 3D turbo spin echo (TSE) T2-w, 3D TSE fluid-attenuated inversion recovery, and spin echo-echo planar imaging diffusion MRI (dMRI). ASSESSMENT: T1-w and dMRI data were employed for providing information about morphometric and microstructural features, respectively. For dMRI, both diffusion tensor imaging and 3D simple harmonics oscillator based reconstruction and estimation models were used for feature extraction from a predefined set of regions. A support vector machine (SVM) was used to perform patients' classification relying on all these measures. STATISTICAL TESTS: Differences between MS phenotypes were investigated using the analysis of covariance and statistical tests (P < 0.05 was considered statistically significant). RESULTS: All the dMRI indices showed significant microstructural alterations between the considered MS phenotypes, for example, the mode and the median of the return to the plane probability in the hippocampus. Conversely, thalamic volume was the only morphometric feature significantly different between the two MS groups. Ten of the 12 features retained by the selection process as discriminative across the two MS groups regarded the hippocampus. The SVM classifier using these selected features reached an accuracy of 70% and a precision of 69%. DATA CONCLUSION: We provided evidence in support of the ability of dMRI to discriminate between PPMS and RRMS, as well as highlight the central role of the hippocampus. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Cerebrospinal fluid inflammatory profile of cognitive impairment in newly diagnosed multiple sclerosis patients.

BACKGROUND: The cerebrospinal fluid (CSF) molecular milieu is a marker of diffuse intrathecal inflammation in the meninges that, in turn, targets the grey matter (GM) in multiple sclerosis (MS). Cognitive impairment (CI) is associated with brain damage in MS and is often present early in people with MS (pwMS). OBJECTIVE: To investigate whether a specific CSF inflammatory profile is associated with different degrees of CI in newly diagnosed pwMS. METHODS: Sixty-nine pwMS and 43 healthy controls (HCs) underwent neuropsychological testing. The presence and levels of 57 inflammatory mediators in the CSF were assessed. RESULTS: Apparently cognitively normal (ACN) pwMS had impaired executive functioning compared to HCs but performed better than pwMS with mild and severe CI (mCI and sCI) in all tests. CSF mediators involving innate immunity and immune activation and recruitment, differentiate ACN from pwMS with mCI, while CSF mediators related to B- and T-cell immunity and chemotaxis differentiate both ACN and mCI from those with sCI. CXCL13 was the only molecule that differentiated sCI from mCI pwMS. CONCLUSION: Specific CSF molecular patterns, reflecting the involvement of both innate and adaptive immune responses, are associated with the severity of CI in newly diagnosed pwMS.

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.

Pitch height and brightness both contribute to elicit the SMARC effect: a replication study with expert musicians.

Pitch-height can be represented in a spatial format. Reaction times (RTs) to lower pitch-heights are faster when responses are executed in the lower side of space, whereas RTs to higher pitch-heights are faster when responses are executed in the upper side of space. This effect is called the Spatial-Music Association of Response Codes (SMARC) effect. We investigated how pitch-height and the brightness of a tone's timbre might contribute in eliciting the SMARC effect as a function of music expertise by comparing the results of 24 musicians with the results we gathered previously (Pitteri et al., 2017) with 24 non-musicians. Three experimental conditions were used: pitch-height varied, brightness varied; pitch-height varied, brightness fixed; pitch-height fixed, brightness varied. We found that the coherent modulation of both pitch-height and brightness elicited the strongest SMARC effect, independently of music expertise. These results add evidence to the hypothesis that the strongest SMARC effect does not belong to pitch-height or brightness, but to pitch-height and brightness together.

Inflammatory intrathecal profiles and cortical damage in multiple sclerosis.

OBJECTIVE: Gray matter (GM) damage and meningeal inflammation have been associated with early disease onset and a more aggressive disease course in multiple sclerosis (MS), but can these changes be identified in the patient early in the disease course? METHODS: To identify possible biomarkers linking meningeal inflammation, GM damage, and disease severity, gene and protein expression were analyzed in meninges and cerebrospinal fluid (CSF) from 27 postmortem secondary progressive MS and 14 control cases. Combined cytokine/chemokine CSF profiling and 3T magnetic resonance imaging (MRI) were performed at diagnosis in 2 independent cohorts of MS patients (35 and 38 subjects) and in 26 non-MS patients. RESULTS: Increased expression of proinflammatory cytokines (IFNγ, TNF, IL2, and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTα, IL6, and IL10) was detected in the meninges and CSF of postmortem MS cases with high levels of meningeal inflammation and GM demyelination. Similar proinflammatory patterns, including increased levels of CXCL13, TNF, IFNγ, CXCL12, IL6, IL8, and IL10, together with high levels of BAFF, APRIL, LIGHT, TWEAK, sTNFR1, sCD163, MMP2, and pentraxin III, were detected in the CSF of MS patients with higher levels of GM damage at diagnosis. INTERPRETATION: A common pattern of intrathecal (meninges and CSF) inflammatory profile strongly correlates with increased cortical pathology, both at the time of diagnosis and at death. These results suggest a role for detailed CSF analysis combined with MRI as a prognostic marker for more aggressive MS. Ann Neurol 2018 Ann Neurol 2018;83:739-755.

Spatial grounding of symbolic arithmetic: an investigation with optokinetic stimulation.

Growing evidence suggests that mental calculation might involve movements of attention along a spatial representation of numerical magnitude. Addition and subtraction on nonsymbolic numbers (numerosities) seem to induce a "momentum" effect, and have been linked to distinct patterns of neural activity in cortical regions subserving attention and eye movements. We investigated whether mental arithmetic on symbolic numbers, a cornerstone of abstract mathematical reasoning, can be affected by the manipulation of overt spatial attention induced by optokinetic stimulation (OKS). Participants performed additions or subtractions of auditory two-digit numbers during horizontal (experiment 1) or vertical OKS (experiment 2), and eye movements were concurrently recorded. In both experiments, the results of addition problems were underestimated, whereas results of subtractions were overestimated (a pattern that is opposite to the classic Operational Momentum effect). While this tendency was unaffected by OKS, vertical OKS modulated the occurrence of decade errors during subtractions (i.e., fewer during downward OKS and more frequent during upward OKS). Eye movements, on top of the classic effect induced by OKS, were affected by the type of operation during the calculation phase, with subtraction consistently leading to a downward shift of gaze position and addition leading to an upward shift. These results highlight the pervasive nature of spatial processing in mental arithmetic. Furthermore, the preeminent effect of vertical OKS is in line with the hypothesis that the vertical dimension of space-number associations is grounded in universal (physical) constraints and, thereby, more robust than situated and culture-dependent associations with the horizontal dimension.

Increased cortical lesion load and intrathecal inflammation is associated with oligoclonal bands in multiple sclerosis patients: a combined CSF and MRI study.

BACKGROUND: Although IgG oligoclonal bands (OCBs) in the cerebrospinal fluid (CSF) are a frequent phenomenon in multiple sclerosis (MS) patients, their relationship with grey matter lesions, intrathecal/meningeal inflammation and clinical evolution has not been clarified yet. The aim of our study was to assess the relationship between the OCBs, the inflammatory/neurodegenerative CSF profile at diagnosis, the cortical lesion load and the clinical evolution after 10 years. METHODS: This is a 10-year observational, cross-sectional study based on a combined MRI, cognitive and CSF profiling of the examined patients. Forty consecutive OCB-negative (OCB-) and 50 OCB-positive (OCB+) MS patients were included in this study. Both groups had mean disease duration of 10 years and were age and gender matched. Each patient underwent neurological and neuropsychological evaluation and 3-T MRI. Analysis of the presence and levels of 28 inflammatory mediators was performed in the CSF obtained from 10 OCB- MS, 11 OCB+ MS and 10 patients with other neurological conditions. RESULTS: Increased number of CLs was found in OCB+ compared to OCB- patients (p < 0.0001), whereas no difference was found in white matter lesion (WML) load (p = 0.36). The occurrence of OCB was also associated with increased levels of neurofilament light chains and of several inflammatory mediators linked to B lymphocyte activity and lymphoid-neogenesis (CXCL13, CXCL12, CXCL10, TNFSF13, TNFSF13B, IL6, IL10) and other pro-inflammatory molecules, such as IFN-γ, TNF, MMP2, GM-CSF, osteopontin and sCD163. Finally, the occurrence of OCB was found associated with poor prognosis, from both physical and cognitive points of view. CONCLUSIONS: OCB at MS onset are associated with more severe GM pathology and with a more severe physical disability and cognitive impairment after 10 years. Increased levels of cytokines linked to B cell activation, lymphoid-neogenesis, and pro-inflammatory immune response in the CSF of OCB+ patients support the hypothesis of crucial role played by compartmentalized, intrathecal B cell response in the pathogenesis of CLs and OCB production.

Dimethyl fumarate: a possible exit strategy from natalizumab treatment in patients with multiple sclerosis at risk for severe adverse events.

INTRODUCTION: Among disease-modifying treatments for multiple sclerosis, natalizumab (NTZ) is highly effective, well tolerated and generally safe. Major concerns regard the risk of developing progressive multifocal leukoencephalopathy (PML), and the occurrence of rebounds or disease activity after its discontinuation. The aim of this study was to explore the efficacy of dimethyl fumarate (DMF) in preventing disease reactivation after NTZ discontinuation. METHODS: Thirty-nine patients with relapsing remitting multiple sclerosis, at high risk of PML, were switched from NTZ to DMF and underwent neurological and 3T MRI monitoring for 2 years. Clinical and MRI data regarding the 2-year period preceding NTZ treatment, the 2 years of NTZ treatment and the 2 years of DMF were collected. RESULTS: During the DMF phase, among the 39 patients, one or more relapses occurred in five patients (12.8%), increased disability progression in 4 (10.3%) and MRI activity in 8 (20.5%). Post-NTZ rebound effect was observed only in one patient. Overall, only two dropouts (one rebound activity and one gastrointestinal side effect) were registered and almost 80% of the patients have still no evidence of disease activity at the end of DMF treatment. The multiple linear regression model revealed that the number of relapses and MRI parameters before DMF treatment were good predictors of disease activity during treatment with DMF. DISCUSSION: DMF appeared generally safe and no carryover PML among investigated cases was observed. Although DMF did not eliminate the possibility of disease reactivation, it seems anyway a promising drug for those patients who shall discontinue NTZ. The clinical and radiological activity preceding the DMF treatment might be used as a prognostic marker of therapy response.

Cognitive impairment predicts disability progression and cortical thinning in MS: An 8-year study.

BACKGROUND: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS). Although cognitive impairment (CI) affects a large proportion of MS patients, only few data are available about its prognostic value associated with advanced magnetic resonance imaging (MRI) metrics. OBJECTIVES: We aimed at investigating the relationship between the early CI and the disease progression over 8-year follow-up in MS patients. METHODS: We conducted a retrospective 8-year longitudinal study involving 78 patients with relapsing-remitting MS, who completed neuropsychological examination and structural MRI at the time of diagnosis. Each patient was clinically evaluated every 6 months, and cortical thickness was quantified at baseline and at the end of the follow-up. Patients were classified as having normal cognition and mild or severe CI. RESULTS: The results show that CI at the time of diagnosis is a good predictor of conversion to definite MS ( p < 0.001), disability progression ( p < 0.001), as well as of transition to secondary progressive phase ( p < 0.001) and of cortical thinning ( p < 0.001). CONCLUSION: We confirmed and extended the evidence that early CI might be helpful in the identification of MS patients at high risk of disability progression and poor clinical outcome and should be considered as a marker of most aggressive pathology.

Naturally together: pitch-height and brightness as coupled factors for eliciting the SMARC effect in non-musicians.

Pitch-height is often labeled spatially (i.e., low or high) as a function of the fundamental frequency of the tone. This correspondence is highlighted by the so-called Spatial-Musical Association of Response Codes (SMARC) effect. However, the literature suggests that the brightness of the tone's timbre might contribute to this spatial association. We investigated the SMARC effect in a group of non-musicians by disentangling the role of pitch-height and the role of tone-brightness. In three experimental conditions, participants were asked to judge whether the tone they were listening to was (or was not) modulated in amplitude (i.e., vibrato). Participants were required to make their response in both the horizontal and the vertical axes. In a first condition, tones varied coherently in pitch (i.e., manipulation of the tone's F0) and brightness (i.e., manipulation of the tone's spectral centroid); in a second condition, pitch-height varied whereas brightness was fixed; in a third condition, pitch-height was fixed whereas brightness varied. We found the SMARC effect only in the first condition and only in the vertical axis. In contrast, we did not observe the effect in any of the remaining conditions. The present results suggest that, in non-musicians, the SMARC effect is not due to the manipulation of the pitch-height alone, but arises because of a coherent change of pitch-height and brightness; this effect emerges along the vertical axis only.

Pure left neglect for Arabic numerals.

Arabic numerals are diffused and language-free representations of number magnitude. To be effectively processed, the digits composing Arabic numerals must be spatially arranged along a left-to-right axis. We studied one patient (AK) to show that left neglect, after right hemisphere damage, can selectively impair the computation of the spatial frames underpinning recognition and understanding of Arabic numerals, without impairing the spatial frames for coding alphabetic strings or for coding environmental spatial information. The presence in our brain of these specific and precise spatial frames must be rooted in the paramount importance of Arabic numerals processing in our everyday activities.

Social Cognition in Multiple Sclerosis: A 3-Year Follow-Up MRI and Behavioral Study.

Social cognition (SC) has become a topic of widespread interest in the last decade. SC deficits were described in multiple sclerosis (MS) patients, in association with amygdala lesions, even in those without formal cognitive impairment. In this 3-year follow-up study, we aimed at longitudinally investigating the evolution of SC deficits and amygdala damage in a group of cognitive-normal MS patients, and the association between SC and psychological well-being. After 3 years (T3) from the baseline examination (T0), 26 relapsing-remitting MS patients (RRMS) were retested with a neuropsychological battery and SC tasks (theory of mind, facial emotion recognition, empathy). A SC composite score (SCcomp) was calculated for each patient. Emotional state, fatigue, and quality of life (QoL) were also evaluated. RRMS patients at T3 underwent a 3T-MRI as performed at T0, from which were calculated both volume and cortical lesion volume (CLV) of the amygdalae. Compared to T0, at T3 all RRMS patients were still cognitive-normal and remained stable in their global SC impaired performance. At T0, SCcomp correlated with amygdala CLV (p = 0.002) while, at T3, was more associated with amygdala volume (p = 0.035) rather than amygdala CLV (p = 0.043). SCcomp change T3-T0 correlated with global emotional state (p = 0.043), depression (p = 0.046), anxiety (p = 0.034), fatigue (p = 0.025), and QoL-social functioning (p = 0.033). We showed the longitudinal stability of SC deficits in cognitive-normal RRMS patients, mirroring the amygdala structural damage and the psychological well-being. These results highlight that SC exerts a key role in MS.

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.

Microstructural MRI Correlates of Cognitive Impairment in Multiple Sclerosis: The Role of Deep Gray Matter.

Although cognitive impairment (CI) is frequently observed in people with multiple sclerosis (pwMS), its pathogenesis is still controversial. Conflicting results emerged concerning the role of microstructural gray matter (GM) damage especially when involving the deep GM structures. In this study, we aimed at evaluating whether differences in cortical and deep GM structures between apparently cognitively normal (ACN) and CI pwMS (36 subjects in total) are present, using an extensive set of diffusion MRI (dMRI) indices and conventional morphometry measures. The results revealed increased anisotropy and restriction over several deep GM structures in CI compared with ACN pwMS, while no changes in volume were present in the same areas. Conversely, reduced anisotropy/restriction values were detected in cortical regions, mostly the pericalcarine cortex and precuneus, combined with reduced thickness of the superior frontal gyrus and insula. Most of the dMRI metrics but none of the morphometric indices correlated with the Symbol Digit Modality Test. These results suggest that deep GM microstructural damage can be a strong anatomical substrate of CI in pwMS and might allow identifying pwMS at higher risk of developing CI.

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.

False memories in relapsing remitting multiple sclerosis patients: A preliminary investigation with the DRM paradigm.

BACKGROUND: Memory impairment is one of the most frequently and early detected impairment in multiple sclerosis (MS) patients. Several authors have argued that when a failure occurs in the retrieval of lexical information, this might be due to a reduction of the lexical pool, related to semantic memory. Here we further investigated memory alteration in MS patients, by focusing on memory distortions (i.e., false memories) for semantically-related material. METHODS: A group of 40 consecutive relapsing remitting MS (RRMS) patients and a matched control group of 40 healthy controls performed the Deese-Roediger-McDermott (DRM), a false memory task for lists of associated words. RESULTS: At recall, RRMS patients reported a reduced number of false recalls for semantically-related but non-presented items (i.e., critical false recalls) compared to HCs; at recognition, RRMS patients showed a reduced level of confidence for false recognitions of critical items. CONCLUSION: We found a reduced susceptibility to false memories in RRMS patients compared to HCs. The potential mechanisms underlying this effect are discussed in light of the alterations in the structure of semantic memory.