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.
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.
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.
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 numbertime 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.
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.
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