Peripheral blood B cell subset ratios and expression levels of B cell-associated genes are altered in benign multiple sclerosis.

The interplay between the immune system, sleep dysfunction and cognitive impairment participates in the progression of disability in multiple sclerosis (MS). Our aim was to identify molecular pathways and B cell associated with separate components of MS disability. Benign MS, non-benign MS patients and healthy controls were recruited. Patients underwent polysomnography and cognitive studies. Microarray and bioinformatics analysis performed using peripheral blood mononuclear cell samples identified B cell-associated genes with the most significantly altered expression. Expression levels of these genes were validated by real-time PCR and peripheral blood cell subsets were examined by flow cytometry. Putative correlations among clinical and laboratory parameters were investigated by correlation network analysis. Sleep and cognitive functions were equally impaired in BMS and NBMS. BMS patients showed significantly reduced memory B cell and increased regulatory B cell percentages than NBMS patients. Among genes that were selected by bioinformatics, levels of BLK, BLNK, BANK1, FCRL2, TGFB1 and KCNS3 genes were significantly different among study subgroups. Correlation network analysis showed associations among physical-cognitive disability and sleep dysfunction measures of MS versus expression levels of selected genes. BMS and NBMS differ by physical disability but not cognitive and sleep dysfunction. Different components of disability in MS are associated with peripheral blood B cell ratios and B cell related gene expression levels. Thus, it is likely that altered B cell functions participate in the progression of disability in MS.

Cytokine-chemokine and cognitive profile of multiple sclerosis patients with predominant optic nerve and spinal cord involvement.

Context/Objective: Clinical disease activity in multiple sclerosis (MS) may manifest as predominant involvement of optic nerves and spinal cord, as exemplified by opticospinal multiple sclerosis (OSMS) often encountered in Asian countries. Our aim was to compare the clinical features, neuropsychological profile and cytokine/chemokine levels of patients with conventional MS (CMS) and MS presenting predominantly with spinal cord and optic nerve attacks (MS-SCON).Design: Cross-sectional study.Setting: MS Outpatient Clinic.Participants: Fourteen MS-SCON patients, 20 CMS patients without myelitis and optic neuritis attacks and 21 healthy individuals.Outcome measures: IL-8, IL-10, IFN-γ, IL-17 and TNF-α levels were measured by multiplex assay and CXCL2 and CXCL5 levels were measured by ELISA. A panel of neuropsychological tests, Beck depression inventory, 9-hole peg and timed 25-foot walk tests were employed.Results: CMS and MS-SCON patients showed similar clinical features. Both CMS and MS-SCON patients displayed reduced IL-8 and CXCL2 and increased TNF-α levels, while IL-10 and CXCL5 levels were identical among all groups.Conclusion: Neuropsychological and motor function test performances of CMS and MS-SCON patients were highly comparable. CMS and MS-SCON present with similar clinical, neuropsychological and immunological features. Therefore, optic nerve and spinal cord-dominant form of MS does not necessarily establish a distinct entity in our region. Cognitive networks of the central nervous system may be damaged during the disease course of MS, despite the absence of cerebral or cerebellar clinical attacks.

Sleep disturbance and cognitive decline in multiple sclerosis patients with isolated optic neuritis as the first demyelinating event.

PURPOSE: Multiple sclerosis (MS) patients whose first demyelinating event is optic neuritis have been claimed to display a milder disease course and reduced physical disability. Our aim was to investigate the impact of the clinical features of the first clinical episode on cognitive disability and sleep dysfunction in MS. METHODS: A total of 26 (10 with optic neuritis as the first clinical event) MS patients were recruited. A comprehensive sleep study was performed, and a panel of tests were administered to examine cognitive and motor performance. Serum levels of sleep-related mediators orexin-A and melatonin were measured by enzyme-linked immunosorbent assay. Subjective sleep quality was evaluated by Pittsburgh sleep quality test, and daytime excessive sleepiness was tested by Epworth sleepiness scale. RESULTS: MS patients with the first clinical episode of optic neuritis and patients with at least one optic neuritis attack exhibited increased daytime sleepiness, higher sleep efficiency and NREM duration and lower total wake time. Patients with a history of optic neuritis obtained more favorable scores in neuropsychological tests measuring executive functions and complex attention as compared to those who had never experienced optic neuritis. Melatonin and orexin-A levels were lower in patients with optic neuritis onset. The higher no. of optic neuritis attacks was associated with reduced wake time and higher symbol digit modalities test scores. CONCLUSIONS: Having a history of optic neuritis is associated with improved sleep quality and executive functions but increased daytime sleepiness. Reduction of orexin-A and melatonin levels might be one of the underlying mechanisms.

Serum orexin-A levels are associated with disease progression and motor impairment in multiple sclerosis.

OBJECTIVE: Diencephalon is frequently affected in multiple sclerosis (MS), and lesions of this region are associated with increased disability. Orexin-A and melatonin, two foremost mediators of diencephalon, modulate cognitive and motor functions through several pathways including the brain-derived neurotrophic factor (BDNF)-cAMP response element-binding protein (CREB) signaling pathway. In this pilot study, our aim was to investigate the prognostic value of these factors in progression of cognitive and physical disability. METHODS: Levels of BDNF, melatonin, CREB, and orexin-A were determined by ELISA in sera of 25 relapsing remitting MS (RRMS) patients, 15 secondary progressive MS (SPMS) patients, and 20 healthy controls. Cognitive and motor functions were assessed by a neuropsychological test battery, timed 25-ft walk (T25-FW) and 9-hole peg (9-HP) tests. RESULTS: MS patients had significantly lower serum levels of orexin-A and BDNF than healthy controls, and SPMS patients had significantly lower levels of melatonin and orexin-A than RRMS patients. Serum orexin-A levels were negatively correlated with 9-HP, T25-FW test scores, and progression index in RRMS patients. BDNF, CREB, and melatonin levels did not show any significant correlation with clinical features including EDSS and cognitive/motor performance of the patients. CONCLUSION: Our results suggest that orexin-A levels are decreased in parallel to disease progression and motor system deterioration in the earlier stages of the disease. Thus, orexin-A might be used as a potential biomarker of physical disability.

Effects of computer-assisted cognitive rehabilitation in benign multiple sclerosis

Background/aim: Benign multiple sclerosis (BMS) patients display preserved somatic neurological functions but nevertheless may develop cognitive dysfunction. Our aim was to explore the impact of computer-assisted cognitive rehabilitation (CCR) on cognitive functions of BMS patients. Materials and methods: Age- and sex-matched BMS patients (n = 21), non-BMS patients (n = 22), and healthy individuals (n = 38) were recruited for evaluation of cognitive functions. CCR was administered to 10 BMS patients and a panel of neuropsychological tests were employed at baseline and 6 months. CCR was based on mental exercise software containing attention, memory, reasoning, visual, and verbal task modules. Results: BMS and non-BMS patients showed impaired selective reminding, spatial recall, symbol digit modalities (SDMTs), controlled oral word association (COWAT), paced auditory serial addition-3 (PASAT-3), and Stroop tests. Timed 25-foot walk and 9-hole peg test results of BMS patients were comparable to those of healthy controls. BMS patients with CCR showed significantly improved SDMTs, COWAT, and Stroop test results compared to those without CCR. Conclusion: Several cognitive domains including memory and executive functions are impaired in BMS patients. CCR has an ameliorating impact particularly on sustained attention, information processing speed, verbal fluency, categorical reasoning, and executive functions of BMS patients.