SPMS Patients Research Articles

Determinants of disability in multiple sclerosis: an immunological and MRI study.

Multiple sclerosis (MS) is characterized by a wide interpatient clinical variability and available biomarkers of disease severity still have suboptimal reliability. We aimed to assess immunological and MRI-derived measures of brain tissue damage in patients with different motor impairment degrees, for in vivo investigating the pathogenesis of MS-related disability. Twenty-two benign (B), 26 secondary progressive (SP), and 11 early, nondisabled relapsing-remitting (RR) MS patients and 37 healthy controls (HC) underwent conventional and diffusion tensor brain MRI and, as regards MS patients, immunophenotypic and functional analysis of stimulated peripheral blood mononuclear cells (PBMC). Corticospinal tract (CST) fractional anisotropy and grey matter volume were lower and CST diffusivity was higher in SPMS compared to RRMS and BMS patients. CD14+IL6+ and CD4+IL25+ cell percentages were higher in BMS than in SPMS patients. A multivariable model having EDSS as the dependent variable retained the following independent predictors: grey matter volume, CD14+IL6+ and CD4+IL25+ cell percentages. In patients without motor impairment after long-lasting MS, the grey matter and CST damage degree seem to remain as low as in the earlier disease stages and an immunological pattern suggestive of balanced pro- and anti-inflammatory activity is observed. MRI-derived and immunological measures might be used as complementary biomarkers of MS severity.

Oxidative modification of blood serum proteins in multiple sclerosis after interferon or mitoxantrone treatment

This study was aimed at (i) comparison of the usefulness of serum protein oxidation parameters for assessment of oxidative stress (OS) in multiple sclerosis (MS), and (ii) comparison of OS in MS patients subject to various therapies. Elevated glycophore level was noted in relapsing–remitting (RRMS) patients without treatment and patients treated with interferons β1a and β1b (10.33±3.27, 8.02±2.22 and 8.56±2.45 vs control 5.27±0.73 fluorescence units (FU)/mg protein). Advanced oxidation protein products (295±135 vs 83±65nmol/mg protein), carbonyl groups (3.68±1.44nmol/mg protein vs 2.03±0.23nmol/mg protein), kynurenine (7.71±0.1.67 vs 5.5±0.63 FU/mg protein) and N′-formylkynurenine (7.69±0.7 vs 4.97±0.59 FU/mg protein) levels were increased, while thioredoxin level was decreased in RRMS patients without treatment (5.03±2.18 vs 10.83±2.75ng/ml) with respect to control. The level of OS was higher in untreated RRMS patients and in SPMS patients treated with mitoxantrone than in patients treated with interferon.

Long-term effects of whole body cryostimulation on uric acid concentration in plasma of secondary progressive multiple sclerosis patients

Background. Uric acid (UA) has been suggested to be a marker of multiple sclerosis (MS) activity. Whole body cryostimulation (WBCT) is a new form of additional treatment and becoming popular in medicine. Objectives. The aims of this study were to determine the long-term effects of WBCT on the level of plasma UA in selected group of MS patients only with secondary progressive (SPMS) clinical form and verify results with functional state of patients assessed by expanded disability status scale (EDSS). Materials and methods. SPMS patients (n = 22) and healthy controls (n = 22) participated in 10 3-min-long exposures of WBCT (one exposure per day). Results were collected before the WBCT treatment and after completion the WBCT series as well as one and three months later. Results. WBCT increased UA concentration in plasma of SPMS patients not only directly after 10 exposures (p < 0.0001) but also one (p < 0.0001) and three (p < 0.005) months later. Furthermore, WBCT causes positive changes in EDSS scale both directly after WBCT (7% lower) and maintain this level 1month later as well as 3 month later (5% lower). Conclusions. WBCT may be used as adjuvant therapy via increase UA blood level; it improves functional status of SPMS patients.

Circulating CD56dim NK cells expressing perforin are increased in progressive multiple sclerosis

In this study we evaluated the percentages of CD3−CD56bright, CD3−CD56dim, CD3−CD56brightperforin+ and CD3−CD56dimperforin+ Natural Killer (NK) cells in peripheral blood from untreated secondary progressive (SP) and primary progressive (PP) multiple sclerosis (MS) patients and age and sex matched healthy subjects.Both PPMS patients and SPMS patients showed increased percentages of circulating CD3−CD56dimperforin+ NK cells than healthy subjects. The increased percentage of CD3−CD56dim NK cells expressing perforin in patients affected by the progressive forms of MS suggests a possible role of this NK cell subpopulation in the pathogenesis of the disease.

Gene expression analysis of relapsing–remitting, primary progressive and secondary progressive multiple sclerosis

Background: Previous studies of multiple sclerosis (MS) have indicated differences in the pathogenesis in relapsing–remitting (RRMS), secondary progressive (SPMS) and primary progressive (PPMS) disease. Objective: We hypothesized that different MS subtypes would show differences in gene expression that could be traced to specific subsets of peripheral blood mononuclear cells (PBMCs). Methods: Gene expression in RRMS, SPMS, PPMS and healthy control (HC) PBMCs was analyzed on Affymetrix arrays. In addition, we studied gene expression in pools of purified PBMC subsets. Results: We found 380 genes that were differentially expressed in RRMS, PPMS, SPMS and HCs (false discovery rate < 5%). There were no major differences between the subtypes of MS. The genes showing most prominent expression changes in RRMS were associated with adaptive immune pathways, while genes in PPMS were associated with innate immune system pathways. SPMS patients shared pathways with RRMS and PPMS patients. Gene expression changes were most prominent in B cells, CD8+ T cells and monocytes. Conclusion: Differences in gene expression, which could be traced to B cells, CD8+ T cells and monocytes, were found between MS patients and HCs but only minor differences were observed between MS subgroups.

Cytometric profiling in various clinical forms of multiple sclerosis with respect to CD21+, CD32+, and CD35+ B and T cells

BackgroundWe aimed to evaluate the frequency of various types of B and T cells expressing CD21, CD32, and CD35 in multiple sclerosis (MS) clinical courses.MethodsPeripheral blood mononuclear cell from 30 MS patients (17 relapsing remitting [RRMS], six secondary progressive [SPMS], and seven primary progressive MS [PPMS]) and 18 healthy subjects were analyzed. All patients were in acute attack. Healthy controls were matched for age and gender ratio. The frequencies of various subsets of B and T cells were determined using flow cytometry.ResultsThe frequency of CD4+T cells was lower in MS patients compared to control subjects (41.14 ± 9.45% vs. 46.88 ± 6.98%, respectively, P < 0.05). The CD32+ fraction of CD4+T cells and the CD21+ fraction of CD8+T cells were higher in MS patients (2.85 ± 3.72% vs. 1.06 ± 0.62% for CD32+CD4+T cells, 2.71 ± 1.86% vs. 1.16 ± 0.99% for CD21+CD8+T cells in MS patients and control subjects, respectively, P < 0.05). After dividing subjects by type of MS course, higher values of these two T cell subsets were found in SPMS patients compared to control subjects (P < 0.05). Further, RRMS patients had lower levels of CD32+CD4+T cells than SPMS patients and also they had lower levels of CD32+CD8+T cells than PPMS patients (P < 0.05). However, neither the expression of CD35 on T cells nor the various B cell subsets were statistically different between the compared groups.ConclusionsOur findings demonstrate that T cell subsets expressing CD21 and CD32 may differ with respect to the presence or clinical forms of MS disease. By contrast, CD35+T cells and different subsets of B cells are not altered in various MS clinical courses.

Association of serum vitamin D levels in Japanese patients with multiple sclerosis

Objective Vitamin D levels are one of the most likely environmental factors related to the development of multiple sclerosis (MS). As vitamin D levels differ between ethnicities, the associated risk of MS also differs. We aimed to determine the associations of serum vitamin D levels in Japanese patients with MS. Methods Serum levels of 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH]2D), and vitamin D-binding protein (DBP) were measured in 29 patients with relapsing-remitting (RR) and secondary-progressive (SP) MS, and in 34 healthy controls. Results The serum levels of 25(OH)D in SPMS patients were significantly decreased compared with those of controls and RRMS patients at remitting phase (7.9 ± 7.2 nM vs 24.2 ± 14.2 nM vs 22.5 ± 13.2 nM, respectively; P < 0.05, P < 0.01, respectively). DBP levels in RRMS and SPMS patients were also decreased compared with controls (419.4 ± 76.2 μg/mL vs 416.7 ± 65.9 μg/mL vs 527.6 ± 149.4 μg/mL, respectively; P < 0.01, P < 0.05, respectively). Furthermore, serum 25(OH)D was found to correlate negatively with disease severity in patients with RRMS in the remitting phase and SPMS using the Expanded Disability Status Scale and the Multiple Sclerosis Severity Score. Conclusions Our results suggest that low 25(OH)D levels are associated with an increased risk of developing SPMS, and a likelihood of developing more severe MS with a worse prognosis in Japanese patients. [Correction added on 2 August 2013, after first online publication: ‘serum 25 (OH)D was found to correlate negatively with 1,25(OH)2D levels in patients’ has been corrected to ‘serum 25(OH)D was found to correlate negatively with disease severity in patients’ in the Results section of the abstract.]

Melatonin reduces oxidative stress in the erythrocytes of multiple sclerosis patients with secondary progressive clinical course

Oxidative stress plays a major role in multiple sclerosis (MS). Melatonin is a potent neuroprotectant. The aims of this study were to determine the actions of melatonin in the reduction of oxidative stress in MS. Therefore, we estimated lipid peroxidation and activities of main antioxidative enzymes in the red blood cells (RBCs) from selective group of MS patients only with secondary progressive (SPMS) clinical form and verified results with functional state. The sixteen (n=16) SPMS patients were supplemented with melatonin (10mg daily/30days). Age matched healthy subjects were used as a control (n=13). We determined the level of lipid peroxidation by malondialdehyde (MDA) and activities of main antioxidative enzymes: superoxide dismutase (SOD), catalase (CAT) and glutathione peroxide (GPx) in RBCs of SPMS patients. Melatonin caused statistically significant increase of SOD, GPx (p<0.0001 and p=0.004065, respectively) and decrease of MDA in erythrocytes of SPMS patients (p=0.00019). Correlation analysis of Spearman showed positive correlation between SOD and (expanded disability status scale) EDSS scale both before (r=0.64, p=0.00756) and after (r=0.634, p=0.00834) melatonin treatment. These results demonstrate that supplementation with melatonin SPMS patients should be taken into account, especially in progressive form of MS.

Correction: Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17- and Activated B-Cells and Correlates with Progression.

[This corrects the article DOI: 10.1371/journal.pone.0057820.].

Systemic Inflammation in Progressive Multiple Sclerosis Involves Follicular T-Helper, Th17- and Activated B-Cells and Correlates with Progression

Pathology studies of progressive multiple sclerosis (MS) indicate a major role of inflammation including Th17-cells and meningeal inflammation with ectopic lymphoid follicles, B-cells and plasma cells, the latter indicating a possible role of the newly identified subset of follicular T-helper (TFH) cells. Although previous studies reported increased systemic inflammation in progressive MS it remains unclear whether systemic inflammation contributes to disease progression and intrathecal inflammation. This study aimed to investigate systemic inflammation in progressive MS and its relationship with disease progression, using flow cytometry and gene expression analysis of CD4+ and CD8+T-cells, B-cells, monocytes and dendritic cells. Furthermore, gene expression of cerebrospinal fluid cells was studied. Flow cytometry studies revealed increased frequencies of ICOS+TFH-cells in peripheral blood from relapsing-remitting (RRMS) and secondary progressive (SPMS) MS patients. All MS subtypes had decreased frequencies of Th1 TFH-cells, while primary progressive (PPMS) MS patients had increased frequency of Th17 TFH-cells. The Th17-subset, interleukin-23-receptor+CD4+T-cells, was significantly increased in PPMS and SPMS. In the analysis of B-cells, we found a significant increase of plasmablasts and DC-SIGN+ and CD83+B-cells in SPMS. ICOS+TFH-cells and DC-SIGN+B-cells correlated with disease progression in SPMS patients. Gene expression analysis of peripheral blood cell subsets substantiated the flow cytometry findings by demonstrating increased expression of IL21, IL21R and ICOS in CD4+T-cells in progressive MS. Cerebrospinal fluid cells from RRMS and progressive MS (pooled SPMS and PPMS patients) had increased expression of TFH-cell and plasmablast markers. In conclusion, this study is the first to demonstrate the potential involvement of activated TFH-cells in MS. The increased frequencies of Th17-cells, activated TFH- and B-cells parallel findings from pathology studies which, along with the correlation between activated TFH- and B-cells and disease progression, suggest a pathogenic role of systemic inflammation in progressive MS. These observations may have implications for the treatment of progressive MS.

Monitoring of Active Human Herpes Virus 6 Infection in Iranian Patients with Different Subtypes of Multiple Sclerosis

Background. Recently, it has been suggested that human herpes virus 6 (HHV6) may play a role in the pathogenesis of multiple sclerosis (MS). Our purpose is to determine the incidence of reactivated HHV6 in MS patients. Methods. Viral sequence analyzed by qPCR in the peripheral blood mononuclear cells (PBMCs), serum, and saliva samples of different subtypes of MS patients (n = 78) and healthy controls (n = 123). HHV6 IgG and IgM antibody levels measured by ELISA technique in the plasma samples of both groups. Likewise, cerebrospinal fluid (CSF) samples of some MS patients (n = 38) were analyzed for viral sequence. Results. Results demonstrate increased levels of anti-HHV6-IgG (78.2% versus 76.4% in controls; P = NS), and IgM (34.6% versus 6.5% in controls; P < 0.05) in MS patients. Furthermore, RRMS and SPMS patients showed relatively higher anti-HHV6 IgG and IgM compared to PPMS (P < 0.001). Moreover, load of cell-free viral DNA was higher in RRMS and SPMS patients and detected in 60.2% (47/78) of MS patients, compared with 14.6% (18/123) of healthy controls (P < 0.001). Moreover, load of cell-free viral DNA was higher in RRMS and SPMS patients and detected in 60.2% (47/78) of MS patients, compared with 14.6% (18/123) of healthy controls (P < 0.001). Conclusions. The results extend the observation of an increased frequency of systemic reactivated HHV6 infection in MS patients with developed stages of disease.

CSF inflammation and axonal damage are increased and correlate in progressive multiple sclerosis

Background: The mechanism underlying disease progression in progressive multiple sclerosis (MS) is uncertain. Pathological studies found widespread inflammation in progressive MS brains correlating with disease progression and axonal damage. Objectives: To study cerebrospinal fluid (CSF) biomarkers and clarify whether inflammation and axonal damage are associated in progressive MS. Methods: Using enzyme-linked immunosorbent assay (ELISA), we analysed CSF from 40 secondary progressive (SPMS), 21 primary progressive (PPMS), and 36 relapsing–remitting (RRMS) and 20 non-inflammatory neurological disease (NIND) patients. Twenty-two of the SPMS patients participated in an MBP8298 peptide clinical trial and had CSF follow-up after one year. Results: Compared to NIND patients, inflammatory biomarkers osteopontin and matrix metalloproteinase-9 (MMP9) were increased in all MS patients while CXCL13 was increased in RRMS and SPMS patients. Biomarkers of axonal damage (NFL) and demyelination (MBP) were increased in all MS patients. In progressive MS patients CSF levels of osteopontin and CXCL13 correlated with NFL while osteopontin and MMP9 correlated with MBP. MBP8298 treatment did not affect the levels of the biomarkers after one year of treatment. All biomarkers were continuously increased after one year of follow-up except MBP, which decreased. Conclusion: CSF biomarkers of inflammation, axonal damage and demyelination are continuously increased in progressive MS patients and correlate. These findings parallel pathology studies, emphasise a relationship between inflammation, axonal damage and demyelination and support the use of CSF biomarkers in progressive MS clinical trials.

Cerebrospinal fluid biomarkers of β-amyloid metabolism in multiple sclerosis

Background: Amyloid precursor protein (APP) and amyloid β (Aβ) peptides are intensely studied in neuroscience and their cerebrospinal fluid (CSF) measurements may be used to track the metabolic pathways of APP in vivo. Reduced CSF levels of Aβ and soluble APP (sAPP) fragments are reported in inflammatory diseases, including multiple sclerosis (MS); but in MS, the precise pathway of APP metabolism and whether it can be affected by disease-modifying treatments remains unclear. Objective: To characterize the CSF biomarkers of APP degradation in MS, including the effects of disease-modifying therapy. Methods: CSF samples from 87 MS patients (54 relapsing–remitting (RR) MS; 33 secondary progressive (SP) MS and 28 controls were analyzed for sAPP and Aβ peptides by immunoassays, plus a subset of samples was analyzed by immunoprecipitation and mass spectrometry (IP-MS). Patients treated with natalizumab or mitoxantrone were examined at baseline, and after 1–2 years of treatment. Results: CSF sAPP and Aβ peptide levels were reduced in MS patients; but they increased again towards normal, after natalizumab treatment. A multivariate model of IP-MS-measured Aβ species separated the SPMS patients from controls, with RRMS patients having intermediate levels. Conclusions: We confirmed and extended our previous observations of altered CSF sAPP and Aβ peptide levels in MS patients. We found that natalizumab therapy may be able to counteract the altered APP metabolism in MS. The CSF Aβ isoform distribution was found to be distinct in SPMS patients, as compared to the controls.

Microstructural magnetic resonance imaging of cortical lesions in multiple sclerosis

Background: Pathologic and magnetic resonance imaging (MRI) studies have shown that cortical lesions (CLs) are a frequent finding in multiple sclerosis (MS). Objective: To quantify microstructural damage in CLs and normal appearing (NA) cortex in relapse-onset MS patients at different stages of the disease. Methods: Brain double inversion recovery (DIR), diffusion tensor (DT) MRI and 3D T 1-weighted scans were acquired from 35 relapsing–remitting (RR) patients, 23 secondary progressive (SP) patients, 12 benign (B) MS patients and 41 healthy controls (HC). Diffusivity values in CLs, cortex, white matter (WM) lesions and normal-appearing white matter (NAWM) were assessed. Results: Compared to HC, MS patients had a significantly lower fractional anisotropy (FA) and higher mean diffusivity (MD) in the cortex and NAWM. CLs had higher FA vs HC cortex and vs patients’ cortex. Compared to RRMS patients, SPMS patients had higher WM lesion volume, higher MD in the cortex, and more severe damage to the NAWM and WM lesions. Compared to SPMS patients, BMS patients had lower MD and FA of CLs. Damage in other compartments was similar between SPMS and BMS patients. Damage in CLs had a high power to discriminate BMS from SPMS (area under the curve: 79–91%), with high specificity (85%), sensitivity (100%) and accuracy (90%). Conclusions: Microstructural imaging features of CLs differ from those of WM lesions and are likely to reflect neuronal damage and microglial activation. The nature and extent of CL damage can be used to help distinguish the different MS clinical phenotypes.

Microstructural MR Imaging of Cortical Lesions in Multiple Sclerosis Phenotypes (S21.001)

Objective: We used double inversion recovery (DIR) and diffusion tensor (DT) MRI to quantify tissue damage in cortical lesions (CLs) and the apparently normal cortical gray matter (GM) in patients with MS at different stages of the disease. Background DIR sequences allow the in vivo visualization of a proportion of CLs in MS and their application has demonstrated that CLs occur in all the major disease clinical phenotypes. Design/Methods: Brain DIR, DT MRI and 3D T 1 -weighted scans were acquired from 35 relapsing remitting (RR), 23 secondary progressive (SP), 12 benign (B) MS patients and 41 healthy controls (HC). Diffusivity values in CLs, skeletonised cortical GM, white matter (WM) lesions and normal-appearing (NA) WM were assessed. Results: Compared to HC, MS patients had a significantly lower fractional anisotropy (FA) and higher axial (AD), radial (RD) and mean diffusivity (MD) in the skeletonized cortical GM and NAWM. CLs had higher FA (p=0.02), AD (p=0.01) and MD (p=0.05) vs . HC skeletonized cortical GM, as well as higher FA (p=0.00002) and lower RD (p=0.01) vs . patients9 skeletonized cortical GM. Compared to RRMS, SPMS patients had higher WM lesion volume and more severe damage to the skeletonized cortical GM, NAWM and WM lesions. Damage in the other compartments was similar between SPMS and BMS patients. Compared to SPMS, BMS patients had lower MD, AD and FA of CLs. Damage in the CLs had a high power to discriminate BMS from SPMS (area under the curve: 77-80%), with high specificity (93%), sensitivity (89%) and accuracy (87%). Conclusions: Microstructural diffusivity features of CLs differ from those of WM lesions and are likely to reflect neuronal damage and microglial activation. Their quantification may help in the early identification of RRMS patients at risk of developing a progressive form of disease. Supported by: Partially supported by a grant from FISM/2008/R/13. Disclosure: Dr. Pagani has nothing to disclose. Ms. Rocca has received personal compensation for activities with Bayer Schering Pharma and Biogen Idec as a consultant. Dr. Preziosa has nothing to disclose. Dr. Copetti has nothing to disclose. Dr. Mesaros has received personal compensation for activities with Merck-Serono and Bayer Schering Pharma. Dr. Colombo has nothing to disclose. Dr. Horsfield has received compensation for serving as a Director of Xinapse Systems Ltd.Dr. Horsfield holds stock and/or stock options in Xinapsse Systems Ltd. Dr. Falini has nothing to disclose. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Lassmann has nothing to disclose. Dr. Filippi has received personal compensation for activities with ECTRIMS, MSIF, MS Ireland, US NMSS, Bayer-Schering, Biogen-Dompe AG, Genmab, Merck Serono, Pepgen Corporation, Teva, and Sanofi-Aventis. Dr. Filippi has received research support from Teva, Bayer-Schering and Genmab.

Macrophage Recruitment in Secondary Progressive Multiple Sclerosis (S40.002)

Objective: To identify the operating biological pathways which associated with progression from relapsing remitting (RR) to secondary progressive (SP) phase of multiple sclerosis (MS). Background Clinically, 85% of MS patients have a RR course characterized by inflammatory attacks associated with neurological deficits and variable periods of remissions. After a period of 10 years, 50% of RRMS patients progress to the SPMS disease course, which is characterized by progressive neurological deterioration with or without coincidental relapses. The molecular events leading to the evolution from RRMS to SPMS are not clearly understood. Design/Methods: Peripheral blood samples obtained from 38 patients that met the diagnostic criteria for SPMS (EDSS>6.0, at least 1.0 point progression by the expanded disability status scale (EDSS) during the preceding two-year period) and 44 patients with RRMS were applied for gene expression microarray analysis using HG-U133A-2 array (Affymetrix). Data were analyzed by Partek (www.partek.com) and pathway reconstruction was performed by Ingenuity (www.ingenuity.com) for the most informative genes (MIGs) with p Results: A total of 429 MIGs (30 genes passed FDR) differentiated between SPMS patients (25 females, age 51.9±2.2 years, disease duration 16.9±2.5 years, EDSS 6.8±0.3) and RRMS patients (27 females, age 44.5±2.0 years, disease duration 3.4±0.6 years, EDSS 2.2±0.4). The SPMS gene expression signature was characterized by significant enrichment of over-expressed genes associated with inflammatory response related to IL1b, IL6, and IL8 mediated monocytes recruitment. The most significantly enriched pathways were infiltration by neutrophils (p=8.3*10-12, CXCL1,2 and3), transmigration of phagocytes (p=6.2*10-7, CCL3,4 and 20) and activation of chemokines production (p=7.8*10-8, TNFa, IL1b, IL8, IL6) followed by down regulation of cell apoptotic machinery (p=1.9*10-6 to 1.1*10-17, BAX, FADD, CASP8, CFLAR). Conclusions: The inflammatory process in SPMS is characterized by IL1b-IL6-IL8 mediated activation of macrophage recruitment. Disclosure: Dr. Hanael has nothing to disclose. Dr. Rothmann has nothing to disclose. Dr. Zilkha-Falb has nothing to disclose. Dr. Gurevich has nothing to disclose. Dr. Achiron has received personal compensation from Biogen Idec, Teva Pharmaceutical Industries Ltd. and Novartis for serving on scientific advisory board and as a consultant. Dr. Achiron received research support from Bayer-Schering Pharma, Biogen Idec, Teva Pharmaceutical Industries Ltd., Merck Serono, and Novartis.

Functional Connectivity Abnormalities and Cognitive Impairment in Relapse-Onset MS Patients: A Whole-Brain Functional Network Connectivity Analysis (P03.072)

Objective: To explore abnormalities of functional connectivity (FC) and of functional interaction among cognitive resting state networks (RSNs) in patients with relapsing remitting (RR) and secondary progressive (SP) MS, and their correlation with cognitive impairment and damage to selected white matter (WM) tracts. Background Previous studies showed abnormal RS FC of the default mode network (DMN) in progressive MS patients. Design/Methods: RS fMRI and diffusion tensor (DT) MRI were acquired from 30 RRMS, 30 SPMS patients and 30 matched controls. Maps of the corpus callosum (CC) and cingulum were produced using DT tractography. Independent component analysis (ICA) and a template-matching procedure identified the DMN, the executive control network (ECN) and the salience network (SN). Within-group and between-group RS FC comparisons were performed with SPM8. The Functional network connectivity (FNC) toolbox was used to assess changes of interactions among RSNs. In MS patients, correlations between network abnormalities, cognitive impairment and structural damage were also assessed. Results: Significant RS FC abnormalities, which were more pronounced in SPMS vs. RRMS, were detected in the three RSNs, and were characterized by a decreased FC in the frontal, temporal, parahippocampal gyri, and the cerebellum, as well as an increased FC in the anterior cingulate cortex. FC abnormalities were more severe in cognitively impaired vs. cognitively preserved patients, and were correlated moderately with DT MRI indexes of damage to the CC and cingulum. FNC analysis detected a decreased connection between the DMN and ECN, and an increased connection between the SN and ECN in both RRMS and SPMS patients. SPMS also showed an increased FC between the SN and DMN. Altered connectivity among RSNs was correlated moderately with cognitive and structural MRI variables. Conclusions: Intra-network and inter-network dysfunction at rest is associated to more severe cognitive deficits in MS patients. Supported by: The study was partially supported by a grant from FISM/2008/R/13. Disclosure: Ms. Rocca has received personal compensation for activities with Bayer Schering Pharma and Biogen Idec as a consultant. Dr. Valsasina has nothing to disclose. Dr. Preziosa has nothing to disclose. Dr. Riccitelli has nothing to disclose. Dr. Martinelli has received personal compensation for activities with Biogen Dompe, Merck Serono, Bayer Schering, Teva, and Sanofi Aventis as a speaker. Dr. Falini has nothing to disclose. Dr. Comi has received personal compensation for activities with Novartis, Teva Neuroscience, Sanofi-Aventis Pharmaceuticals, Inc., Merck Serono, Bayer Schering, and Biogen Dompe. Dr. Filippi has received personal compensation for activities with ECTRIMS, MSIF, MS Ireland, US NMSS, Bayer-Schering, Biogen-Dompe AG, Genmab, Merck Serono, Pepgen Corporation, Teva, and Sanofi-Aventis. Dr. Filippi has received research support from Teva, Bayer-Schering and Genmab.

Clinical use of H1 MR spectroscopy in assessment of relapsing remitting and secondary progressive multiple sclerosis

BackgroundConventional MRI has a limited ability to provide specific information about axonal pathology in MS, recently, MRI spectroscopy used for assessment of the axonal loss even in normal appearing white matter. ObjectiveTo assess the axonal degeneration in plaques and normal appearing white matter in patients with relapsing remitting MS and secondary progressive MS, and correlate their clinical disability using expanded disability status scale (EDSS) score with H1 MRS abnormalities. Patients and methodsThirty-two MS patients (20 RRMS, 12 SPMS) and 20 controls were subjected to thorough history taking, clinical examination with special attention to: age at first symptoms, disease duration and the EDSS score. MRS was performed in order to map N-acetylaspartate (NAA), choline (Cho) and creatine (Cr). ResultsIn SPMS, the NAA/Cr ratio and absolute concentrations for NAA in MS plaques and NAWM were significantly reduced compared to RRMS and to controls, also, significant relation with this metabolite values and clinical disability using EDSS score. ConclusionIn SPMS patients group there were significant reduction in the levels of NAA in both plaques and NAWM compared to RRMS and control groups, moreover significant correlation of NAA reduction in the plaques of both groups related to clinical disability and disease progression.

Human Herpesvirus 6 and 7 Reactivation and Disease Activity in Multiple Sclerosis

Recent studies have focused on the associations between human herpesvirus 6 (HHV-6) and human herpesvirus 7 (HHV-7), and multiple sclerosis (MS). The aim of this study was to investigate the associations between HHV-6 and HHV-7 reactivation and MS disease activity, and interleukin 12 (IL-12) and tumor necrosis factor α (TNF-α) production. The frequency of plasma viremia by nested polymerase chain reaction and transcription of viral mRNA in peripheral blood mononuclear cells by reverse transcriptase-polymerase chain reaction (RT-PCR) of 14 relapsing/remitting (RR) and 14 secondary progressive (SP) MS patients were studied in comparison with clinical manifestation of the disease. Serum concentrations of cytokines IL-12 and TNF-α were analyzed by enzyme-linked immunosorbent assay. Plasma samples from 25 of the 28 MS patients with estimated latent/persistent HHV-6 and/or HHV-7 infection were examined during relapse and remission/relative remission. HHV-6 reactivation was found in 4 of the 7 RRMS and 4 of the 7 SPMS patients, and HHV-7 reactivation was identified in 3 of the 7 RRMS and 1 of the 7 SPMS patients (all in relapse). In 2 of the 3 RRMS patients without viremia in relapse, HHV-6 mRNA transcription was detected. In RRMS and SPMS patients with active HHV-6 and HHV-7 infection in relapse, the serum concentrations of IL-12 and TNF-α were significantly higher than in those with latent virus infection. HHV-6 and HHV-7 reactivation could be implicated in the exacerbation of MS via activation of Th1 lymphocyte subsets.

Oxidative modification of patient's plasma proteins and its role in pathogenesis of multiple sclerosis

BackgroundOxidative stress plays an important role in multiple sclerosis (MS). Objective and methodsThe present study was designed to evaluate the modifications of plasma proteins by estimation markers of oxidative/nitrosative stress: carbonyl groups and 3-nitrotyrosines (3-NT) levels in relapsing-remitting (RR) (n=10) and secondary progressive (SP) (n=10) clinical course of multiple sclerosis. Moreover, we estimated the level of uric acid (UA) in plasma of MS patients. ResultsCompared to controls (n=10), the levels of carbonyl groups in plasma proteins were elevated (P<0.0001) as well in RRMS as in SPMS. The highest concentration of 3-NT was observed in plasma proteins obtained from SPMS patients (P<0.0005). The level of uric acid in plasma was significantly lower in RRMS (P<0.0001) than SPMS. ConclusionThis is the first report which presented differences between SPMS and RRMS patients in 3-NT and protein carbonyl groups in plasma proteins.