Multiple sclerosis (MS) is a chronic, progressive disease of the central nervous system that is characterised by inflammatory damage to the myelin sheath. Though often neglected, cognitive impairment is a common feature of MS that affects 43-70% of patients. It has a sophisticated neuroanatomic and pathophysiologic background and disturbs such vital cognitive domains as speed of information processing, memory, attention, executive functions and visual perceptual functions. In recent years there has been growing interest in neuroimaging findings with regard to cognitive impairment in MS. The possible options of managing cognitive dysfunction in MS are pharmacologic interventions, cognitive rehabilitation and exercise training; however, not enough evidence has been presented in this field. The aim of our article is to provide current knowledge on cognitive impairment in MS based on the most recent scientific results and conclusions with regard to affected cognitive domains, neuropsychological assessment, underlying mechanisms of this disturbance, neuroimaging findings and therapeutic options.

Cognitive impairment in multiple sclerosis - a review of current knowledge and recent research.

Background Cognitive impairment is experienced by about 50% of patients with Multiple Sclerosis (MS) worldwide and affects their employment, disease management and quality of life in general. The Brief International Cognitive assessment for MS (BICAMS) is a brief, practical and potentially universal battery for cognitive impairment in MS patients. It consists of three tests: the Symbol Digit Modalities Test (SDMT), the California Verbal Learning Test-2 (CVLT-2) and the Brief Visuospatial Memory Test-Revised (BVMT-R). Objective The objective of this study was to validate the BICAMS in Greek MS patients and controls. Methods Forty four MS patients and seventy nine healthy control (HC) participants were recruited and tested. They were group matched for age, education, gender and also premorbid cognitive reserve. All of them completed the three tests of the BICAMS battery. Instead of CVLT-2, the Greek validated form (Greek Verbal Learning Test, GVLT), was used. In addition, cognitive reserve was assessed using the Cognitive Reserve Index questionnaire (CRIq) standardized for the Greek population. Results Significant difference was found in the performance of the two groups in all tests (p Conclusions The study provides validation of BICAMS in Greek population and therefore facilitates the use of this battery in clinical practice and in future studies of MS patients in Greece.

Validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) in Greek population with multiple sclerosis.

Background Numerous factors can affect multiple sclerosis (MS) patients' quality of life (QoL). We investigated how physical impairment, upper extremity function, cognitive impairment, cognitive reserve, symptoms of psychological distress, depression, fatigue as well as age and disease duration contribute to patient-reported measures of QoL in relapse-remitting MS (RRMS) and progressive MS (PMS). Methods 39 patients with RRMS and 16 patients with PMS were evaluated for physical impairment (EDSS assessed by a neurologist), upper extremity function (9-hole peg test), cognitive deficits (broad neuropsychological test battery), cognitive reserves (highest obtained degree of education and vocabulary), symptoms of psychological distress (Symptom Checklist-90-R), depression (Beck Depression Inventory) and fatigue (Fatigue Scale for Motor and Cognitive Functions). The effects of these variables on QoL, as measured with the EQ-5D-3L, were tested with a multivariate analysis of variance. Results Degree of education, MS disease type, disease duration, BDI and SCL-90-R-scores affected significantly the EQ-5D index. Post-hoc analysis revealed that patients with university education, RRMS, shorter disease duration as well as less depression and psychological distress symptoms had significantly higher EQ-5D indices. No significant effects were observed for measures of physical disability, cognitive impairment or fatigue. Conclusions Depression and psychological distress symptoms are among the factors with the most essential impact on subjective well-being in MS patients. Since they can be targeted by both psychopharmacological and psychotherapeutic treatment, focusing on mental comorbidity could substantially increase QoL in MS.

Determinants of quality of life in relapsing-remitting and progressive multiple sclerosis

Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS): Canadian contribution to the international validation project.

Aim. To explore the efficacy of home-based, computerised, cognitive rehabilitation in patients with multiple sclerosis using neuropsychological assessment and advanced structural and functional magnetic resonance imaging (fMRI). Methods. 38 patients with MS and cognitive impairment on the Brief International Cognitive Assessment for MS (BICAMS) were enrolled. Patients were randomised to undergo 45 minutes of computerised cognitive rehabilitation using RehaCom software ( ) three times weekly for six weeks or to a control condition ( ). Neuropsychological and MRI data were obtained at baseline (time 1), following the 6-week intervention (time 2), and after a further twelve weeks (time 3). Cortical activations were explored using fMRI and microstructural changes were explored using quantitative magnetisation transfer (QMT) imaging. Results. The treatment group showed a greater improvement in SDMT gain scores between baseline and time 2 compared to the control group ( ). The treatment group exhibited increased activation in the bilateral prefrontal cortex and right temporoparietal regions relative to control group at time 3 ( ). No significant changes were observed on QMT. Conclusion. This study supports the hypothesis that home-based, computerised, cognitive rehabilitation may be effective in improving cognitive performance in patients with MS. Clinical trials registration is ISRCTN54901925 .

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A Randomised Controlled Trial of Efficacy of Cognitive Rehabilitation in Multiple Sclerosis: A Cognitive, Behavioural, and MRI Study

Background Multiple Sclerosis (MS) causes not only somatic, but also cognitive impairment regardless of the patients׳ age or the course of the disease. The Brief International Cognitive Assessment for MS (BICAMS) test, published in 2011, is a short cognitive questionnaire: a fast, reliable, sensitive and specific tool for the evaluation of the patients׳ cognitive state. Objectives Our primary objective was to assess the validity of the Hungarian version of the BICAMS test. Our secondary objective was to evaluate the impact of the cognitive impairment on the patient׳s quality of life and fatigue׳s impact on the patients׳ cognitive state. Methods 65 RR-MS patients and 65 age, sex and education matched healthy control (HC) subjects completed the test and were retested after 3 weeks. The patients also completed the MS Quality of Life 54 (MSQoL54) and the Fatigue Impact Scale (FIS) assessments. Group differences were calculated by paired sample T-tests. The test-retest reliability was measured by intraclass correlation coefficients. To analyze the difference between the test-retest performances of the two groups we used two-way repeated measures ANOVA where the BICAMS battery was the single composite outcome and one-way repeated measures ANOVA. To assess the impact of the cognitive decline on the patients׳ quality of life and fatigue׳s impact on the cognitive state, we examined the correlations between results in the BICAMS and the MSQoL54 and FIS. Results We found significant difference ( p ≤0.001, p =0.017 in the first CVLT-II assessment) between MS patients and members of the HC group in all four evaluated parameters of BICAMS test in both sessions. The correlation coefficients were very strong between the tests and retests ( r >0.8; p r =0.678, p p =0.020) better in the retest sessions as compared to their original performance than the patients did and this difference is solely due to the difference between the CVLT-II performances. We have found significant negative correlation between the patients׳ cognitive function and the fatigue score ( r p r >0.3; p Conclusions The Hungarian version of the BICAMS test is a valid and reliable method for the evaluation of MS patients׳ cognitive function. It seems that because of the short retest period, the members of the HC group remembered the CVLT-II words thus performed better than the patients did. Also apparently fatigue can have a negative impact on the patients׳ cognitive state, and cognitive impairment could worsen the patients׳ quality of life.

The Hungarian validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery and the correlation of cognitive impairment with fatigue and quality of life

Our aim was to study the possible relationship between psychological stress and granulocyte activation primarily in healthy students during an examination period (n = 11) and also in chronically anxious patients (n = 15). We employed cell surface markers: lactoferrin, L-selectin, alphaMbeta2-integrin and CD15s and flow cytometry to detect changes in the activation state of granulocytes, with the start of the stressed state in students at the beginning of an examination period, which was associated with elevated blood plasma cortisol level, and following relaxation hypnosis in both students, during their examination term, and patients. The ratios of all four types of marker-carrier granulocytes increased at the start of the examination period in students; an especially dramatic (ca. 5-fold) enhancement was observed in the proportion of lactoferrin-bearing cells relatively to the pre-examination term value. After hypnosis, the percentage of lactoferrin-exposing granulocytes decreased considerably both in students and in patients, by about half; a similar decrease was observed in the ratio of CD15s-carrier cells in patients. No significant alteration was observed during the study in state or trait anxiety levels, and in total or differential leukocyte counts. Thus, granulocyte activation could be associated with stress, while relaxation may facilitate reducing activation of these cells. In both groups of subjects, granulocyte surface lactoferrin appeared to be a sensitive "stress indicator". This needs further evaluation.

Granulocyte activation in humans is modulated by psychological stress and relaxation.

Star-crossed? The association of the 5-HTTLPR s allele with season of birth in a healthy female population, and possible consequences for temperament, depression and suicide

Tibor Rudisch

Papers

The Hungarian validation of the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) battery and the correlation of cognitive impairment with fatigue and quality of life

Granulocyte activation in humans is modulated by psychological stress and relaxation.

Star-crossed? The association of the 5-HTTLPR s allele with season of birth in a healthy female population, and possible consequences for temperament, depression and suicide