Meaningful cognitive change for the Minimal Assessment of Cognitive Function in Multiple Sclerosis.

BACKGROUND: There is limited information on interpretation of cognitive changes over time in multiple sclerosis (MS). OBJECTIVE: This study aimed to provide normative data for the assessment of statistically meaningful change in all tests of the Minimal Assessment of Cognitive Function in MS (MACFIMS). METHODS: We applied the reliable change methodology to a healthy Italian cohort, assessed with two alternate versions of the MACFIMS 1 year apart. We calculated confidence intervals of retest score variance using the reliable change index (RCI). Moreover, multivariable linear regression models adjusted for age, sex, education, and baseline score were built to calculate the regression-based change index (RB-CI). RESULTS: Overall, 200 healthy individuals were enrolled. Thresholds for interpreting change in each test were calculated. In the multivariable models, baseline score was associated with retest score in all tests (B from 0.439 to 0.760; p < 0.001). RB-CI can be calculated with data of the multivariable models. CONCLUSION: We provide normative data for reliable cognitive change evaluation for all the tests of the MACFIMS, which includes the Symbol Digit Modalities Test and Brief International Cognitive Assessment in MS, two widely used tools for screening and monitoring cognition in MS. Our findings can significantly improve the interpretation of cognitive changes in MS.

Clinical effectiveness of different natalizumab interval dosing schedules in a large Italian population of patients with multiple sclerosis.

INTRODUCTION: Natalizumab (NTZ) is one of the most effective treatment options for multiple sclerosis (MS) treatment. Our study aimed to evaluate the effectiveness of NTZ when administered according to the extended dosing strategy compared with standard 4-weekly administration in a large Italian MS population. MATERIALS AND METHODS: This retrospective multicentre study included patients with relapsing-remitting MS (RR-MS) who received NTZ administrations between the 1 June 2012 and the 15 May 2018 and were followed by the 'Italian MS Register'. All patients with MS were stratified into two groups based on NTZ administration schedule: standard interval dosing (SID) patients who received infusions on average from 28 to 32 days (median 30) and extended interval dosing (EID) including patients who have been infused with interval between 33 and 49 days (median 43). Clinical data were assessed at baseline (before starting NTZ), after 12 (T1) and 24 months (T2) of treatment. RESULTS: Out of 5231 patients with RR-MS screened, 2092 (mean age 43.2±12.0, 60.6% women) were enrolled. A total of 1254 (59.9%) received NTZ according to SID, and 838 (40.1%) according to EID. At 12 and 24 months, no differences in terms of annualised relapse rate and disability status were found between the two groups. Progression index and confirmed disability worsening were similar between the two groups. DISCUSSION: The use of NTZ with an extended interval schedule showed similar effectiveness compared with SID. Unchanged clinical efficacy of EID schedule may raise the question of a possible advantage in terms of tolerability and safety.

The minimal neuropsychological assessment of MS patients (MACFIMS): normative data of the Italian population.

Cognitive impairment is common in multiple sclerosis (MS), and research has emphasized the crucial role of cognitive assessment in disease monitoring. The minimal neuropsychological assessment of MS (MACFIMS) represents one of the neuropsychological batteries most widely used throughout the world. To date, a complete validation, as well as normative values of an alternative form, is lacking in the Italian population, limiting the use of this tool in longitudinal assessment. A total of 200 healthy subjects (127 females and 73 males) were recruited from the community in 8 Italian cities and were evaluated with the MACFIMS at baseline and reassessed with an alternate form of the same battery after 12 months. Regression-based norms that account for demographic influences on test performance were calculated at each time point (baseline and follow-up). The study provides, for the first time, normative values of two forms of the MACFIMS battery for the Italian population. Data application allows clinicians to monitor the performance of cognitive functions over time and to better understand the efficacy of both pharmacological and non-pharmacological interventions in clinical practice and research.

Correction to: Aging with multiple sclerosis: prevalence and profile of cognitive impairment.

The above article was published online with an error in author name's affiliation. The Author Claudia Niccolai has changed her affiliation to IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy.

Reliability and Repeatability Analysis of Indices to Measure Gait Deterioration in MS Patients during Prolonged Walking.

Gait deterioration caused by prolonged walking represents one of the main consequences of multiple sclerosis (MS). This study aims at proposing quantitative indices to measure the gait deterioration effects. The experimental protocol consisted in a 6-min walking test and it involved nine patients with MS and twenty-six healthy subjects. Pathology severity was assessed through the Expanded Disability Status Scale. Seven inertial units were used to gather lower limb kinematics. Gait variability and asymmetry were assessed by coefficient of variation (CoV) and symmetry index (SI), respectively. The evolution of ROM (range of motion), CoV, and SI was computed analyzing data divided into six 60-s subgroups. Maximum difference among subgroups and the difference between the first minute and the remaining five were computed. The indices were analyzed for intra- and inter-day reliability and repeatability. Correlation with clinical scores was also evaluated. Good to excellent reliability was found for all indices. The computed standard deviations allowed us to affirm the good repeatability of the indices. The outcomes suggested walking-related fatigue leads to an always more variable kinematics in MS, in terms of changes in ROM, increase of variability and asymmetry. The hip asymmetry strongly correlated with the clinical disability.

Aging with multiple sclerosis: prevalence and profile of cognitive impairment.

BACKGROUND: The increase in life expectancy of patients with multiple sclerosis (MS) requires a better knowledge of disease features in the older patients group. OBJECTIVE: To describe the prevalence and profile of cognitive impairment (CI) in older patients with MS and perform a comparison with younger patients. METHODS: Patients were consecutively recruited for 6 months. Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop Test. CI was defined as impairment in ≥ 2 cognitive domains. RESULTS: We identified 111 patients older than 55 years (mean age 59.7 years). The prevalence of CI was 77.4%, which was significantly higher than in younger patients (42.8%; p < 0.01). Information processing speed was the most impaired domain (68.8%), followed by verbal learning (49.5%), executive function (47.7%), and visuospatial learning (26.6%). We found no significant differences in the prevalence of impairment in the distinct cognitive domains between older and younger patients with CI. Depression and fatigue were not associated with increased CI among patients in the older age group (p > 0.70). CONCLUSION: There is a remarkably high frequency of CI in older patients with MS. The similar profile of CI between older and younger patients suggests that CI is mostly directly related to MS itself and not to comorbid age-related disorders.

Patients with paediatric-onset multiple sclerosis are at higher risk of cognitive impairment in adulthood: An Italian collaborative study.

BACKGROUND: Patients with paediatric-onset multiple sclerosis (POMS) could be at an increased risk for cognitive impairment (CI), given the potential harmful effects of disease activity in neurodevelopment. However, there is scarce information on their long-term cognitive outcomes. OBJECTIVE: To compare the prevalence and profile of CI between adults with a history of POMS and those with classic, adult-onset multiple sclerosis (AOMS). METHODS: Cognitive performance was assessed through the Brief Repeatable Battery (BRB) and the Stroop Test in consecutive patients referred to six Italian MS centres. CI was defined as impairment in ⩾2 cognitive domains. RESULTS: In all, 119 patients with POMS and 712 with AOMS were included in this analysis. The prevalence of CI was 48.0% in AOMS, 44.5% in POMS; with similar neuropsychological profile between the two groups. However, when adjusting for current age, we found a significantly increased risk for CI (odds ratio (OR) = 1.71; p = 0.02) and for impairment in information processing speed (OR = 1.86; p < 0.01) in patients with POMS. A higher Expanded Disability Status Scale (EDSS) was also identified in POMS ( p = 0.03) compared with AOMS patients. CONCLUSION: Patients with a history of POMS appear to be at higher risk of physical and cognitive disability than AOMS patients, after correcting for age effects, with particular involvement of information processing speed.

Age and disability drive cognitive impairment in multiple sclerosis across disease subtypes.

BACKGROUND: There is limited and inconsistent information on the clinical determinants of cognitive impairment (CI) in multiple sclerosis (MS). OBJECTIVE: The aim of this study was to compare the prevalence and profile of CI across MS disease subtypes and assess its clinical determinants. METHODS: Cognitive performance was assessed through the Brief Repeatable Battery and the Stroop test in consecutive patients with MS referred to six Italian centers. CI was defined as impairment in ⩾ 2 cognitive domains. RESULTS: A total of 1040 patients were included, 167 with clinically isolated syndrome (CIS), 759 with relapsing remitting (RR), 74 with secondary progressive (SP), and 40 with primary progressive (PP) disease course. The overall prevalence of CI was 46.3%; 34.5% in CIS, 44.5% in RR, 79.4% in SP, and 91.3% in PP. The severity of impairment and the number of involved domains were significantly higher in SP and primary progressive multiple sclerosis (PPMS) than in CIS and RR. In multivariable logistic regression analysis, the presence of CI was significantly associated with higher Expanded Disability Status Scale (EDSS) and older age. CONCLUSION: CI is present in all MS subtypes since the clinical onset and its frequency is increased in the progressive forms, but these differences seem to be more associated with patient age and physical disability than to disease subtype per se.

[Prevalence of Obstructive Sleep Apnea Syndrome among holders of a category B driver's license and among professionals in the Province of Pesaro-Urbino (Italy)]. / Prevalenza di OSAS nella provincia di Pesaro-Urbino: dati derivati da uno screening su titolari di patente superiore e/o professionale afferenti alla CML dell'Area Vasta 1.

Obstructive Sleep Apnea Syndrome (OSAS) is a sleeping disorder caused by repeated episodes of partial or complete obstruction of the upper airways during sleep. During 2013, a pilot project was performed in the Marche region (Italy), co-jointly by the University "Politecnica delle Marche" and the Italian National Institute of Work Accident Insurance (INAIL), among holders of a category "B" driver's licence and among professionals undergoing screening at an Occupational Medicine Service covering the Province of Pesaro-Urbino (Italy). Nineteen percent of 553 subjects undergoing a screening examination were found to be affected by OSAS. The data collected is of great interest in the phase of implementation of new national laws.

Identifying the Distinct Cognitive Phenotypes in Multiple Sclerosis.

Importance: Cognitive impairment is a common and disabling feature of multiple sclerosis (MS), but a precise characterization of cognitive phenotypes in patients with MS is lacking. Objectives: To identify cognitive phenotypes in a clinical cohort of patients with MS and to characterize their clinical and magnetic resonance imaging (MRI) features. Design, Setting, and Participants: This multicenter cross-sectional study consecutively screened clinically stable patients with MS and healthy control individuals at 8 MS centers in Italy from January 1, 2010, to October 31, 2019. Patients with MS and healthy control individuals who were not using psychoactive drugs and had no history of other neurological or medical disorders, learning disability, severe head trauma, and alcohol or drug abuse were enrolled. Main Outcomes and Measures: Participants underwent a neurological examination and a cognitive evaluation with the Rao Brief Repeatable Battery and Stroop Color and Word Test. A subgroup of participants also underwent a brain MRI examination. Latent profile analysis was used on cognitive test z scores to identify cognitive phenotypes. Linear regression and mixed-effects models were used to define clinical and MRI features of each phenotype. Results: A total of 1212 patients with MS (mean [SD] age, 41.1 [11.1] years; 784 women [64.7%]) and 196 healthy control individuals (mean [SD] age, 40.4 [8.6] years; 130 women [66.3%]) were analyzed in this study. Five cognitive phenotypes were identified: preserved cognition (n = 235 patients [19.4%]), mild-verbal memory/semantic fluency (n = 362 patients [29.9%]), mild-multidomain (n = 236 patients [19.5%]), severe-executive/attention (n = 167 patients [13.8%]), and severe-multidomain (n = 212 patients [17.5%]) involvement. Patients with preserved cognition and mild-verbal memory/semantic fluency were younger (mean [SD] age, 36.5 [9.8] years and 38.2 [11.1] years) and had shorter disease duration (mean [SD] 8.0 [7.3] years and 8.3 [7.6] years) compared with patients with mild-multidomain (mean [SD] age, 42.6 [11.2] years; mean [SD] disease duration, 12.8 [9.6] years; P < .001), severe-executive/attention (mean [SD] age, 42.9 [11.7] years; mean [SD] disease duration, 12.2 [9.5] years; P < .001), and severe-multidomain (mean [SD] age, 44.0 [11.0] years; mean [SD] disease duration, 13.3 [10.2] years; P < .001) phenotypes. Severe cognitive phenotypes prevailed in patients with progressive MS. At MRI evaluation, compared with those with preserved cognition, patients with mild-verbal memory/semantic fluency exhibited decreased mean (SE) hippocampal volume (5.42 [0.68] mL vs 5.13 [0.68] mL; P = .04), patients with the mild-multidomain phenotype had decreased mean (SE) cortical gray matter volume (687.69 [35.40] mL vs 662.59 [35.48] mL; P = .02), patients with severe-executive/attention had higher mean (SE) T2-hyperintense lesion volume (51.33 [31.15] mL vs 99.69 [34.07] mL; P = .04), and patients with the severe-multidomain phenotype had extensive brain damage, with decreased volume in all the brain structures explored, except for nucleus pallidus, amygdala and caudate nucleus. Conclusions and Relevance: This study found that by defining homogeneous and clinically meaningful phenotypes, the limitations of the traditional dichotomous classification in MS can be overcome. These phenotypes can represent a more meaningful measure of the cognitive status of patients with MS and can help define clinical disability, support clinicians in treatment choices, and tailor cognitive rehabilitation strategies.

No evidence of JC virus reactivation in natalizumab treated multiple sclerosis patients: an 18 month follow-up study.

BACKGROUND AND AIM: Natalizumab, used as therapy for multiple sclerosis (MS), has been associated with progressive multifocal leucoencephalopathy (PML), a potentially fatal disease caused by JC virus (JCV), which is not predictable by specific markers. This study evaluated whether JCV reactivation occurred in the urine and/or plasma in 42 MS patients treated with natalizumab over 18 months, and followed by a thorough monitoring programme. METHODS: 42 patients (F/M: 24/18, mean age 34.4±8.9 years) were followed-up by: urine and plasma JCV-DNA PCR assay, immune cell subsets analysis, clinical and MRI evaluation, quality of life, fatigue and mood assessment. RESULTS: JCV data. At baseline, 11/42 (26%) patients had JCV viruria, persistent at serial controls. One patient acquired viruria at month 1 and one patient at month 12. No patient had JCV viraemia at baseline; three patients acquired viraemic (one at month 6, one at month 13 (both transiently) and one at month 12 (persistently viraemic)). The prevalence of JCV in both urine and plasma did not change significantly from baseline to months 12 and 18. No patient had clinical or MRI evidence of PML. Immunological data. Circulating B cells showed greater expansion (300% increase in absolute number) since the first infusion. NK cell count doubled with no change in percentage while T cell count increased with a reduced percentage, reflecting a clear redistribution in the lymphocyte compartment. CD4+ and CD8+ T cells increased proportionally, with no change in their percentage. Clinical data. 27 patients (64%) were disease free after 1 year. A marked improvement in quality of life was reported by 72% of patients. CONCLUSIONS: No evidence of subclinical JCV reactivation was found in our natalizumab treated MS patients up to 18 months of therapy, notwithstanding the marked increase in circulating B cells observed. Moreover, the efficacy of natalizumab, its tolerability and the positive impact on quality of life were confirmed in this study.

Basal ganglia and frontal/parietal cortical atrophy is associated with fatigue in relapsing-remitting multiple sclerosis.

BACKGROUND: Fatigue is one of the most frequent symptoms suffered by patients affected by multiple sclerosis. The patho-physiological basis of multiple sclerosis-related fatigue remains to be elucidated. OBJECTIVE: Our aim was to investigate whether a particular pattern of deep and/or cortical grey matter atrophy is associated with fatigue in patients with multiple sclerosis. METHODS: A total of 152 patients with relapsing-remitting multiple sclerosis were evaluated with the Expanded Disability Status Scale, the Fatigue Severity Status Scale (FSS), the Modified Fatigue Impact Scale and the Beck Depression Inventory. The thalamic and basal ganglia volume and the regional cortical thickness were analysed by means of FreeSurfer. RESULTS: Based on Fatigue Severity Status Scale score, patients were divided into fatigued (FSS ≥ 4, 71 patients, 46.6%) and non-fatigued (FSS < 4, 81 patients, 53.4%). A significant atrophy of striatum, thalamus, superior frontal gyrus and inferior parietal gyrus was observed in fatigued patients compared with non-fatigued patients. The cognitive domain of Modified Fatigue Impact Scale significantly correlated with the volume of the striatum and with the cortical thickness of the posterior parietal cortex and middle frontal gyrus (R = 0.51-0.61), while the physical domain of Modified Fatigue Impact Scale significantly correlated with striatum volume and superior frontal gyrus cortical thickness (R = 0.50-0.54). CONCLUSIONS: The regional analysis of deep and cortical grey matter atrophy suggests an association between the neurodegenerative process taking place in the striatum-thalamus-frontal cortex pathway and the development of fatigue in relapsing-remitting multiple sclerosis. The inclusion of the posterior parietal cortex as one of the best predictors of the Modified Fatigue Impact Scale cognitive domain suggests the major role of the posterior attentional system in determining cognitive fatigue in relapsing-remitting multiple sclerosis.

Neurofunctional modulation of brain regions by the observation of pointing and grasping actions.

Previous neuroimaging research on healthy humans has provided evidence for a neural system underlying the observation of another person's hand actions. However, whether the neural processes involved in this capacity are activated by the observation of other transitive hand actions such as pointing remains unknown. Therefore, using functional magnetic resonance imaging we investigated the neural mechanisms underlying the observation of static images representing the hand of a human model pointing to an object (pointing condition), grasping an object (grasping condition), or resting in proximity of an object (control condition). The results indicated that activity within portions of the lateral occipitotemporal and the somatosensory cortices modulates according to the type of observed transitive actions. Specifically, these regions were more activated for the grasping than for the pointing condition. In contrast, the premotor cortex, a neural marker of action observation, did not show any differential activity when contrasting the considered experimental conditions. Our findings may provide novel insights regarding a possible role of extrastriate and somatosensory brain areas for the perception of distinct types of human hand-object interactions.

Combined circulating epigenetic markers to improve mesothelin performance in the diagnosis of malignant mesothelioma.

OBJECTIVES: Malignant mesothelioma (MM) is a highly aggressive tumor with poor prognosis. A major challenge is the development and application of early and highly reliable diagnostic marker(s). Serum biomarkers, such as 'soluble mesothelin-related proteins' (SMRPs), is the most studied and frequently used in MM. However, the low sensitivity of SMRPs for early MM limits its value; therefore, additional biomarkers are required. In this study, two epigenetically regulated markers in MM (microRNA-126, miR-126, and methylated thrombomodulin promoter, Met-TM) were combined with SMRPs and evaluated as a potential strategy to detect MM at an early stage. MATERIALS AND METHODS: A total of 188 subjects, including 45 MM patients, 99 asbestos-exposed subjects, and 44 healthy controls were prospectively enrolled, serum samples collected, and serum levels of SMRPs, miR-126 and Met-TM evaluated. Logistic regression analysis was performed to evaluate the diagnostic value of the three biomarkers. Using this approach, the performance of the '3-biomarker classifier' was tested by calculating the overall probability score of the MM and control samples, respectively, and the ROC curve was generated. RESULTS AND CONCLUSION: The combination of the three biomarkers was the best predictor to differentiate MM patients from asbestos-exposed subjects and healthy controls. The accuracy and cancer specificity was confirmed in a second validation cohort and lung cancer population. We propose that the combination of the two epigenetic biomarkers with SMRPs as a diagnosis for early MM overcomes the limitations of using SMRPs alone.

Cortical pathology and cognitive impairment in multiple sclerosis.

Cognitive impairment constitutes a relevant clinical aspect of multiple sclerosis (MS). Depending on the disease phase and type, 40-65% of MS patients develop various degrees of cognitive dysfunction. Pathological and MRI studies have failed to demonstrate the existence of a strict relationship between cognitive impairment and subcortical white matter pathology. The correlation is also poor when MRI metrics of whole brain (white plus gray matter) atrophy are considered. Over the last decade, increasing observations have provided evidence of a primary role of cortical pathology - that is, inflammatory focal lesions (cortical lesions) and atrophy (cortical thickness) - in determining global and/or selective cognitive disability in MS. By applying a new semi-automated software (Freesurfer) to analyze the global and regional cortical thickness and the double inversion recovery sequence to identify cortical lesions, it has been observed that specific cognitive deficits, such as memory impairment, attention deficits and reduced mental processing speed, could be better explained by cortical structural abnormalities rather than subcortical white matter lesions. Therefore, MRI evaluation of cortical pathology should be included in the routine examination of MS patients, especially those with initial signs/symptoms of cognitive dysfunctions.

Investigation of the neural correlates underlying action observation in multiple sclerosis patients.

Recent fMRI evidence indicates that both the execution and the observation of hand actions in multiple sclerosis (MS) patients increase recruitment of a portion of the so-called mirror neuron system. However, it remains unclear whether this is the expression of a compensatory mechanism for the coding of observed action or whether such a mechanism represents a rather unspecific functional adaptation process. Here we used fMRI on early relapsing remitting MS (RRMS) patients to clarify this issue. Functional images of 15 right-handed early RRMS patients and of 15 sex- and age-matched right-handed healthy controls were acquired using a 1.5 T scanner. During scanning, participants simply observed images depicting a human hand either grasping an object or resting alongside an object. As shown by a between-group analysis, when compared to controls, RRMS patients revealed a robust increase of activation in an extensive network of brain regions including frontal, parietal, temporal and visual areas usually activated during action observation. However, this pattern of hemodynamic activity was completely independent of the type of observed hand-object interaction as revealed by the lack of any significant between-group interaction. Our findings are in line with previous fMRI evidence demonstrating cortical reorganization in MS patients during action observation. However, based on our findings we go one step further and suggest that such functional cortical changes may be the expression of a generalized and unspecific compensatory mechanism, that is not necessarily involved in action understanding.

Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis.

BACKGROUND: Neuropsychological deficits in patients with multiple sclerosis (MS) have been shown to be associated with the major pathological substrates of the disease, ie, inflammatory demyelination and neurodegeneration. Double inversion recovery sequences allow cortical lesions (CLs) to be detected in the brain of patients with MS. Modern postprocessing techniques allow cortical atrophy to be assessed reliably. OBJECTIVE: To investigate the contribution of cortical gray matter lesions and tissue loss to cognitive impairment in patients with relapsing-remitting MS. DESIGN: Cross-sectional survey. SETTING: Referral, hospital-based MS clinic. Patients Seventy patients with relapsing-remitting MS. MAIN OUTCOME MEASURES: Neuropsychological performance was tested using the Rao Brief Repeatable Battery of Neuropsychological Tests, version A. Patients who scored 2 SDs below the mean normative values on at least 1 test of the Rao Brief Repeatable Battery of Neuropsychological Tests, version A, were considered to be cognitively impaired. A composite cognitive score (the cognitive impairment index) was computed. T2 hyperintense white matter lesion volume, contrast-enhancing lesion number, CL number and volume, normalized brain volume, and normalized neocortical gray matter volume were also assessed. RESULTS: Twenty-four patients with relapsing-remitting MS (34.3%) were classified as cognitively impaired. T2 hyperintense white matter lesion volume and contrast-enhancing lesion number were not different between cognitively impaired and cognitively unimpaired patients. Cognitively impaired patients had a higher CL number (P = .01) and volume (P < .001) and decreased normalized brain volume (P = .02) and normalized neocortical gray matter volume (P = .002) when compared with cognitively unimpaired patients. Multivariate analysis revealed that age (beta = 0.228; P = .02), CL volume (beta = 0.452; P < .001), and normalized neocortical gray matter volume (beta = 0.349; P < .001) were independent predictors of the cognitive impairment index (r(2) = 0.55; F = 23.903; P < .001). CONCLUSION: The burden of CLs and tissue loss are among the major structural changes associated with cognitive impairment in relapsing-remitting MS.