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.

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.

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.

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.

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.

The Prognostic Value of White-Matter Selective Double Inversion Recovery MRI Sequence in Multiple Sclerosis: An Exploratory Study.

Using a white-matter selective double inversion recovery sequence (WM-DIR) that suppresses both grey matter (GM) and cerebrospinal fluid (CSF) signals, some white matter (WM) lesions appear surrounded by a dark rim. These dark rim lesions (DRLs) seem to be specific for multiple sclerosis (MS). They could be of great usefulness in clinical practice, proving to increase the MRI diagnostic criteria specificity. The aims of this study are the identification of DRLs on 1.5 T MRI, the exploration of the relationship between DRLs and disease course, the characterization of DRLs with respect to perilesional normal-appearing WM using magnetization transfer imaging, and the investigation of possible differences in the underlying tissue properties by assessing WM-DIR images obtained at 3.0 T MRI. DRLs are frequent in primary progressive MS (PPMS) patients. Amongst relapsing-remitting MS (RRMS) patients, DRLs are associated with a high risk of the disease worsening and secondary progressive MS (SPMS) conversion after 15 years. The mean magnetization transfer ratio (MTR) of DRLs is significantly different from the lesion without the dark rim, suggesting that DRLs correspond to more destructive lesions.

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.

Comparing learning performance on the open trial selective reminding test with the California verbal learning test II in traumatic brain injury.

Introduction: Learning and memory deficits are prevalent following moderate to severe traumatic brain injury (TBI), affecting between 54% and 84% of impacted individuals.Objective: The current study examined learning performance on two tests of verbal memory: the OT-SRT and the CVLT-II.Methods: Sixty-eight participants with TBI performed the OT-SRT and the CVLT-II on two different days. Additionally, all participants completed cognitive tests assessing processing speed, working memory and executive functions. By definition, all participants with TBI were identified as having impaired learning on the OT-SRT, however only 38 were also identified as impaired on the CVLT-II. The sample was thus divided into two groups, those who failed both tests (Fail-2) and those who failed only the OT-SRT (Fail-1).Results: The Failed-1 group showed significantly better performance in processing speed, working memory and executive functions compared to the Fail-2 group. On the CVLT-II, the Fail-1 group performed significantly better on the number of words recalled on trials 1 and 5 compared to the Fail-2 group. Both groups performed similarly the OT-SRT.Discussion: The CVLT-II and the OT-SRT are not equivalent tests and should not be used interchangeably.

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.

Can Implicit or Explicit Time Processing Impact Numerical Representation? Evidence From a Dual Task Paradigm.

Whether the human brain processes various types of magnitude, such as numbers and time, through a shared representation or whether there are different representations for each type of magnitude is still debated. Here, we investigated two aspects of number-time interaction: the effects of implicit and explicit processing of time on numbers and the bi-directional interaction between time and number processing. Thirty-two participants were randomly assigned into two experimental groups that performed, respectively, a Single task (number comparison, with implicit time processing) and a Dual task (number comparison as a primary task, with explicit time processing as a secondary task). Results showed that participants, only in the Dual task, were faster and more accurate when processing large numbers paired with long rather than short durations, whereas the opposite pattern was not evident for small numbers. Moreover, participants were more accurate when judging long durations after having processed large rather than small numbers, whereas the opposite pattern emerged for short durations. We propose that number processing influences time processing more than vice versa, suggesting that numbers and time might be at least partially independently represented. This finding can pave the way for investigating the hierarchical representation of space, numbers, and time.