Long-term course and morphological MRI correlates of cognitive function in multiple sclerosis.

BACKGROUND: Cognitive impairment frequently occurs in patients with MS (pwMS). Magnetic resonance imaging (MRI) markers could help to identify patients at risk for decline. OBJECTIVE: To characterize the long-term course and morphological MRI correlates of cognitive function in pwMS. METHODS: We invited 116 pwMS who had undergone clinical, cognitive, and MRI evaluations between 2006 and 2012 (baseline, BL) to attend follow-up (FU) testing between 2016 and 2018. Disability (expanded disability status scale (EDSS)), cognition (brief repeatable battery of neuropsychological test (BRB-N)), global and regional T2-lesion load (T2-LL), brain volumes, and cortical thickness were assessed. RESULTS: Sixty-three pwMS were willing to attend the FU (54%; median EDSS = 2, interquartile range (IQR) = 2) and did not differ from non-participating pwMS regarding BL characteristics. At BL, half of the participants showed cognitive deficits in at least one domain. Across the entire group, we observed no relevant changes in physical disability and cognition over 10 years. BL thalamic volume best predicted cognitive function at FU, in addition to age and BL cognition, explaining 67% of variance. Cognitive decliners (23.8%) were older, had longer disease duration, and a tendency for lower thalamic volume at BL. CONCLUSION: Thalamic volume predicted FU cognitive function and distinguished declining from stable pwMS, underlining the potential of MRI to define risk groups.

Morphological MRI phenotypes of multiple sclerosis differ in resting-state brain function.

We aimed to assess differences in resting-state functional connectivity (FC) between distinct morphological MRI-phenotypes in multiple sclerosis (MS). Out of 180 MS patients, we identified those with high T2-hyperintense lesion load (T2-LL) and high normalized brain volume (NBV; a predominately white matter damage group, WMD; N = 37) and patients with low T2-LL and low NBV (N = 37; a predominately grey matter damage group; GMD). Independent component analysis of resting-state fMRI was used to test for differences in the sensorimotor network (SMN) between MS MRI-phenotypes and compared to 37 age-matched healthy controls (HC). The two MS groups did not differ regarding EDSS scores, disease duration and distribution of clinical phenotypes. WMD compared to GMD patients showed increased FC in all sub-units of the SMN (sex- and age-corrected). WMD patients had increased FC compared to HC and GMD patients in the central SMN (leg area). Only in the WMD group, higher EDSS scores and T2-LL correlated with decreased connectivity in SMN sub-units. MS patients with distinct morphological MRI-phenotypes also differ in brain function. The amount of focal white matter pathology but not global brain atrophy affects connectivity in the central SMN (leg area) of the SMN, consistent with the notion of a disconnection syndrome.

Self-regulation of brain activity and its effect on cognitive function in patients with multiple sclerosis - First insights from an interventional study using neurofeedback.

OBJECTIVE: To investigate the effects of EEG-based neurofeedback training, in which one can learn to self-regulate one's own brain activity, on cognitive function in patients with multiple sclerosis (pwMS). METHODS: Fourteen pwMS performed ten neurofeedback training sessions within 3-4 weeks at home using a tele-rehabilitation system. The aim of the neurofeedback training was to increase voluntarily the sensorimotor rhythm (SMR, 12-15 Hz) in the EEG over central brain areas by receiving visual real-time feedback thereof. Cognitive function was assessed before and after all neurofeedback training sessions using a comprehensive standardized neuropsychological test battery. RESULTS: Half of the pwMS (N = 7) showed cognitive improvements in long-term memory and executive functions after neurofeedback training. These patients successfully learned to self-regulate their own brain activity by means of neurofeedback training. The other half of pwMS (N = 7) did neither show any cognitive changes when comparing the pre- and post-assessment nor were they able to modulate their own brain activity in the desired direction during neurofeedback training. CONCLUSIONS: Data from this interventional study provide first preliminary evidence that successful self-regulation of one's own brain activity may be associated with cognitive improvements in pwMS. SIGNIFICANCE: These promising results should stimulate further studies. Neurofeedback might be a promising and alternative tool for future cognitive rehabilitation.

The impact of vascular risk factors on brain volume and lesion load in patients with early multiple sclerosis.

BACKGROUND: Vascular risk factors (VRF) in multiple sclerosis (MS) patients have been associated with lower brain volumes. It is currently unknown if this association already exists in early MS and how it develops over time. METHODS: We identified 82 patients with clinically isolated syndrome (CIS) ( n = 61) or with early relapsing-remitting MS ( n = 21) and assessed their VRF including arterial hypertension, hyperlipidaemia, diabetes mellitus and smoking. We analysed T2-lesion load, normalized brain volume (NBV), cortical grey (cGMV) and white matter volumes (WMV), thalamic and basal ganglia volumes at baseline and follow-up magnetic resonance imaging (MRI) and assessed the percentage of brain volume change (PBVC) using SIENA. RESULTS: Patient mean age was 32.4 (±8.7) years and 54 (65%) were women. Median follow-up period was 42 (29-54) months. In total, 26 patients (31.7%) had one or more VRF (VRF+). At baseline, VRF+ patients had a lower NBV (1530.9 cm3 vs 1591.2 cm3, p = 0.001), a lower cGMV (628.5 cm3 vs 668.6 cm3, p = 0.002) and WMV (752.2 cm3 vs 783.9 cm3, p = 0.009) than VRF-negative patients. Similar results were obtained at follow-up. PBVC was comparable between patients with and without VRF. CONCLUSION: VRF are associated with lower brain volume already in early MS but do not lead to increased brain volume loss during 3.5 years of follow-up.

Month-of-birth-effect in multiple sclerosis in Austria.

BACKGROUND: The month-of-birth-effect (MoBE) describes the finding that multiple sclerosis (MS) patients seem to have been born significantly more frequently in spring, with a rise in May, and significantly less often in autumn and winter with the fewest births in November. OBJECTIVES: To analyse if the MoBE can also be found in the Austrian MS population, and if so, whether the pattern is similar to the reported pattern in Canada, United Kingdom, and some Scandinavian countries. METHODS: The data of 7886 MS patients in Austria were compared to all live births in Austria from 1940 to 2010, that is, 7.256545 data entries of the Austrian birth registry and analysed in detail. RESULTS: Patterns observed in our MS cohort were not different from patterns in the general population, even when stratifying for gender. However, the noticeable and partly significant ups and downs over the examined years did not follow the distinct specific pattern with highest birth rates in spring and lowest birth rates in autumn that has been described previously for countries above the 49th latitude. CONCLUSION: After correcting for month-of-birth patterns in the general Austrian population, there is no evidence for the previously described MoBE in Austrian MS patients.

The effect of disease modifying therapies on CD62L expression in multiple sclerosis.

BACKGROUND: The increasing armamentarium of disease-modifying therapies in multiple sclerosis is accompanied by potentially severe adverse effects. The cell-adhesion molecule CD62L, which facilitates leukocyte extravasation, has been proposed as a predictive marker for treatment tolerability. However, pre-analytical procedures might impact test results, thereby limiting its clinical usability. Whether the immediate analysis of CD62L expression of peripheral blood mononuclear cells can aid treatment decision making is yet unclear. OBJECTIVE: To investigate the effect of various disease-modifying therapies in multiple sclerosis on CD62L expression of CD3+CD4+ peripheral blood mononuclear cells in freshly collected blood samples. METHODS: We collected peripheral blood samples from patients with clinically isolated syndrome and multiple sclerosis (baseline/follow up n = 234/n = 98) and healthy controls (n = 51). CD62L+CD3+CD4+ expression was analysed within 1 hour by fluorescence-activated cell sorting. RESULTS: CD62L+CD3+CD4+ expression was significantly decreased in patients treated with natalizumab (n = 26) and fingolimod (n = 20) and increased with dimethyl-fumarate (n = 15) compared to patients receiving interferon/glatiramer acetate (n = 90/30) or no disease-modifying therapies (n = 53) and controls (n = 51) (p<0.001). CD62L expression showed temporal stability during unchanged disease-modifying therapy usage, but increased after natalizumab withdrawal and decreased upon fingolimod introduction. CONCLUSION: CD62L+CD3+CD4+ expression is altered in patients treated with different disease-modifying therapies when measured in freshly collected samples. The clinical meaning of CD62L changes under disease-modifying therapies warrants further investigation.

Mucosal biopsy shows immunologic changes of the colon in patients with early MS.

OBJECTIVE: To investigate immune cells of the colonic mucosa and fecal short-chain fatty acids (SCFAs) in treatment-naive patients with a clinically isolated syndrome (CIS) or early relapsing MS. METHODS: In this cross-sectional proof-of-concept study, we obtained mucosal specimens during ileocolonoscopy from 15 untreated patients with CIS/MS and 10 controls. Mucosal immune cells were analyzed by FACS, and gas chromatography-mass spectrometry measurements of stool samples served to determine SCFA. RESULTS: The number of total dendritic cells (DCs), CD103+ tolerogenic DCs, and CD4+25+127-regulatory T cells (Tregs) was significantly reduced in the distal colon of patients with CIS/MS compared with controls, whereas we found no differences in the proximal colon. The patients' fecal samples also showed a substantially lower content of SCFA and especially lower levels of butyrate and acetate. CONCLUSIONS: Our findings indicate a disturbed homeostasis of colonic DCs and Tregs in patients with MS which could be associated with colonic SCFA depletion. Although not implying causality, these findings confirm parallel abnormalities of the gut in MS and warrant further research if modulation of the colonic SCFA profile or the colonic Treg pool can serve to modify the course of MS.

Prognostic value of free light chains lambda and kappa in early multiple sclerosis.

BACKGROUND: Cerebrospinal fluid (CSF) immunoglobulin free light chains (FLC) have been suggested as quantitative alternative to oligoclonal bands (OCB) in the diagnosis of multiple sclerosis (MS). However, little is known on their role in predicting clinical and paraclinical disease progression, particularly in early stages. OBJECTIVE: To assess the prognostic value of FLC in OCB-positive patients with clinically isolated syndrome (CIS) suggestive of MS and early MS. METHODS: We determined FLC kappa (KFLC) and lambda (LFLC) in CSF and serum by nephelometry in 61 patients (CIS ( n = 48), relapsing-remitting multiple sclerosis ( n = 13)) and 60 non-inflammatory neurological controls. Median clinical follow-up time in CIS was 4.8 years (interquartile range (IQR), 1.5-6.5 years). Patients underwent 3T magnetic resonance imaging (MRI) at baseline and follow-up (median time interval, 2.2 years; IQR, 1.0-3.7 years) to determine T2 lesion load (T2LL) and percent brain volume change (PBVC). RESULTS: CSF FLC were significantly increased in CIS/MS compared to controls (all p < 0.001). A lower KFLC/LFLC CSF ratio was associated with CIS-clinically definite multiple sclerosis (CDMS) conversion (hazard ratio (HR) = 2.89; 95% confidence interval (CI) = 1.17-7.14; p < 0.05). No correlations were found for FLC variables with T2LL or PBVC. CONCLUSION: Our study confirms increased intrathecal synthesis of FLC in CIS/MS which supports their diagnostic contribution. The KFLC/LFLC CSF ratio appears to have a prognostic value in CIS beyond OCB.

Reproducibility of Resting State Connectivity in Patients with Stable Multiple Sclerosis.

Given increasing efforts to use resting-state fMRI (rfMRI) as a biomarker of disease progression in multiple sclerosis (MS) we here explored the reproducibility of longitudinal rfMRI over three months in patients with clinically and radiologically stable MS. To pursue this aim, two approaches were applied in nine rfMRI networks: First, the intraclass correlation coefficient (ICC 3,1) was assessed for the mean functional connectivity maps across the entire network and a region of interest (ROI). Second, the ratio of overlap between Z-thresholded connectivity maps for each network was assessed. We quantified between-session functional reproducibility of rfMRI for 20 patients with stable MS and 14 healthy controls (HC). Nine rfMRI networks (RSNs) were examined at baseline and after 3 months of follow-up: three visual RSNs, the default-mode network, sensorimotor-, auditory-, executive control, and the left and right fronto-parietal RSN. ROI analyses were constrained to thresholded overlap masks for each individual (Z>0) at baseline and follow-up.In both stable MS and HC mean functional connectivity across the entire network did not reach acceptable ICCs for several networks (ICC<0.40) but we found a high reproducibility of ROI ICCs and of the ratio of overlap. ROI ICCs of all nine networks were between 0.98 and 0.99 for HC and ranged from 0.88 to 0.99 in patients with MS, respectively. The ratio of overlap for all networks was similar for both groups, ranging from 0.60 to 0.75.Our findings attest to a high reproducibility of rfMRI networks not only in HC but also in patients with stable MS when applying ROI analysis. This supports the utility of rfMRI to monitor functional changes related to disease progression or therapeutic interventions in MS.

Periventricular lesions correlate with cortical thinning in multiple sclerosis.

OBJECTIVE: It has been suggested recently that cortical pathology in multiple sclerosis (MS) may, at least partly, be caused by factors in cerebrospinal fluid (CSF). We thus hypothesized that MS-related tissue changes in compartments close to the CSF, such as periventricular lesions, might correlate with cortical pathology. METHODS: We investigated a cohort of 160 patients, comprising 91 with a clinically isolated syndrome (CIS) and 69 with relapsing-remitting MS (RRMS; mean age: CIS: 31.4 ± 9.0; RRMS: 33.0 ± 8.7 years; mean disease duration: CIS: 7.2 ± 15 months; RRMS: 8.0 ± 6.5 years, Expanded Disability Status Scale (median, min-max): CIS: 1, 0-3.5; RRMS: 1.25, 0-4) with 3.0T magnetic resonance imaging. MS lesions were segmented semiautomatically on fluid-attenuated inversion recovery images. To quantify periventricular lesion load (PV-LL), we generated ventricle masks and dilated them by a voxel factor of 3. Lesions within the dilated ventricle margin were classified as periventricular. Cortical thinning was assessed by cortical mean thickness (CMT) and compared to data from 58 healthy controls (HCs; mean age: 29.1 ± 7.4 years). RESULTS: Compared to HC, CIS and (even more so) RRMS patients demonstrated significantly reduced CMT. Even after controlling for ventricular volume and total lesion load, increased periventricular lesion occupancy (percentage of PV-LL) significantly correlated with decreased CMT in RRMS (r = -0.295; p = 0.015), but not in CIS (r = 0.032; p = 0.768) patients. INTERPRETATION: The correlation between increased periventricular lesion burden and decreased CMT indicative of subpial cortical pathology supports the concept that common CSF-mediated factors might play a role in the accumulation of damage to gray and white matter in MS.

Dynamics of brain iron levels in multiple sclerosis: A longitudinal 3T MRI study.

OBJECTIVE: We investigated longitudinal changes in iron concentration in the subcortical gray matter (caudate nucleus, globus pallidus, putamen, thalamus) of patients with clinically isolated syndrome (CIS) and definite multiple sclerosis (MS) and their relation to clinical and other morphologic variables. METHODS: We followed 144 patients (76 CIS; median Expanded Disability Status Scale [EDSS] 1.0 [interquartile range (IQR) 0.0-2.0]; 68 MS; median EDSS 2.0 [IQR 1.0-3.3]) clinically and with 3T MRI over a median period of 2.9 (IQR 1.3-4.0) years. Iron concentration was determined by R2* relaxometry at baseline and last follow-up. RESULTS: At baseline, subcortical gray matter iron deposition was higher in MS compared to CIS. In CIS, R2* rates increased in the globus pallidus (p < 0.001), putamen (p < 0.001), and caudate nucleus (p < 0.001), whereas R2* rates in the thalamus decreased (p < 0.05). In MS, R2* rates increased in the putamen (p < 0.05), remained stable in the globus pallidus and caudate nucleus, and decreased in the thalamus (p < 0.01). Changes in R2* relaxation rates were unrelated to changes in the volume of respective structures, of T2 lesion load, and of disability. CONCLUSIONS: Iron accumulation in the basal ganglia is more pronounced in the early than later phases of the disease and occurs independent from other morphologic brain changes. Short-term changes in iron concentration are not associated with disease activity or changes in disability.

Predictive value of different conventional and non-conventional MRI-parameters for specific domains of cognitive function in multiple sclerosis.

OBJECTIVE: While many studies correlated cognitive function with changes in brain morphology in multiple sclerosis (MS), few of them used a multi-parametric approach in a single dataset so far. We thus here assessed the predictive value of different conventional and quantitative MRI-parameters both for overall and domain-specific cognitive performance in MS patients from a single center. METHODS: 69 patients (17 clinically isolated syndrome, 47 relapsing-remitting MS, 5 secondary-progressive MS) underwent the "Brief Repeatable Battery of Neuropsychological Tests" assessing overall cognition, cognitive efficiency and memory function as well as MRI at 3 Tesla to obtain T2-lesion load (T2-LL), normalized brain volume (global brain volume loss), normalized cortical volume (NCV), normalized thalamic volume (NTV), normalized hippocampal volume (NHV), normalized caudate nuclei volume (NCNV), basal ganglia R2* values (iron deposition) and magnetization transfer ratios (MTRs) for cortex and normal appearing brain tissue (NABT). RESULTS: Regression models including clinical, demographic variables and MRI-parameters explained 22-27% of variance of overall cognition, 17-26% of cognitive efficiency and 22-23% of memory. NCV, T2-LL and MTR of NABT were the strongest predictors of overall cognitive function. Cognitive efficiency was best predicted by NCV, T2-LL and iron deposition in the basal ganglia. NTV was the strongest predictor for memory function and NHV was particularly related to memory function. CONCLUSIONS: The predictive value of distinct MRI-parameters differs for specific domains of cognitive function, with a greater impact of cortical volume, focal and diffuse white matter abnormalities on overall cognitive function, an additional role of basal ganglia iron deposition on cognitive efficiency, and thalamic and hippocampal volume on memory function. This suggests the usefulness of using multiparametric MRI to assess (micro)structural correlates of different cognitive constructs.

Improvement in Fatigue during Natalizumab Treatment is Linked to Improvement in Depression and Day-Time Sleepiness.

BACKGROUND: Fatigue is a frequent symptom in multiple sclerosis (MS) and often interrelated with depression and sleep disorders making symptomatic treatment decisions difficult. In the single-arm, observational phase IV TYNERGY study, relapsing-remitting MS patients showed a clinically meaningful decrease in fatigue over 1 year of treatment with natalizumab. OBJECTIVE: To evaluate whether fatigue improvement might be directly linked to improved depression and day-time sleepiness. METHODS: Patients were assessed regarding fatigue, depression, and day-time sleepiness. The relation between changes of the two latter symptoms and changes in fatigue was analyzed. RESULTS: After 1 year of natalizumab treatment, the majority of patients (>92%) remained stable or improved in total, motor, and cognitive fatigue. Proportion of patients without depression increased by 17% while proportions of mildly depressed patients or patients with potential major depression decreased by 5 and 12%, respectively. Proportion of patients classified as not being sleepy increased by 13% while proportions of sleepy and very sleepy patients decreased by 11 and 2%, respectively. Most importantly, improved depression and sleepiness were significantly related to improved fatigue. CONCLUSION: Our findings highlight the importance of patient-reported outcomes in identifying potential benefits of drug treatment beyond its well-established effects on disease activity and disability progression.

Brain activity changes in cognitive networks in relapsing-remitting multiple sclerosis - insights from a longitudinal FMRI study.

BACKGROUND: Extrapolations from previous cross-sectional fMRI studies suggest cerebral functional changes with progression of Multiple Sclerosis (MS), but longitudinal studies are scarce. We assessed brain activation changes over time in MS patients using a cognitive fMRI paradigm and examined correlations with clinical and cognitive status and brain morphology. METHODS: 13 MS patients and 15 healthy controls (HC) underwent MRI including fMRI (go/no-go task), neurological and neuropsychological exams at baseline (BL) and follow-up (FU; minimum 12, median 20 months). We assessed estimates of and changes in fMRI activation, total brain and subcortical grey matter volumes, cortical thickness, and T2-lesion load. Bland-Altman (BA) plots served to assess fMRI signal variability. RESULTS: Cognitive and disability levels remained largely stable in the patients. With the fMRI task, both at BL and FU, patients compared to HC showed increased activation in the insular cortex, precuneus, cerebellum, posterior cingulate cortex, and occipital cortex. At BL, patients vs. HC also had lower caudate nucleus, thalamus and putamen volumes. Over time, patients (but not HC) demonstrated fMRI activity increments in the left inferior parietal lobule. These correlated with worse single-digit-modality test (SDMT) performance. BA-plots attested to reproducibility of the fMRI task. In the patients, the right caudate nucleus decreased in volume which again correlated with worsening SDMT performance. CONCLUSIONS: Given preserved cognitive performance, the increased activation at BL in the patients may be viewed as largely adaptive. In contrast, the negative correlation with SDMT performance suggests increasing parietal activation over time to be maladaptive. Several areas with purported relevance for cognition showed decreased volumes at BL and right caudate nucleus volume decline correlated with decreasing SDMT performance. This highlights the dynamics of functional changes and the strategic importance of specific brain areas for cognitive processes in MS.

Higher education moderates the effect of T2 lesion load and third ventricle width on cognition in multiple sclerosis.

BACKGROUND: Previous work suggested greater intellectual enrichment might moderate the negative impact of brain atrophy on cognition. This awaits confirmation in independent cohorts including investigation of the role of T2-lesion load (T2-LL), which is another important determinant of cognition in MS. We here thus aimed to test this cognitive reserve hypothesis by investigating whether educational attainment (EA) moderates the negative effects of both brain atrophy and T2-LL on cognitive function in a large sample of MS patients. METHODS: 137 patients participated in the study. Cognition was assessed by the "Brief Repeatable Battery of Neuropsychological Tests." T2-LL, normalized brain volume (global volume loss) and third ventricle width (regional volume loss) served as MRI markers. RESULTS: Both T2-LL and atrophy predicted worse cognition, with a stronger effect of T2-LL. Higher EA (as assessed by years of education) also predicted better cognition. Interactions showed that the negative effects of T2-LL and regional brain atrophy were moderated by EA. CONCLUSIONS: In a cohort with different stages of MS, higher EA attenuated the negative effects of white matter lesion burden and third ventricle width (suggestive of thalamic atrophy) on cognitive performance. Actively enhancing cognitive reserve might thus be a means to reduce or prevent cognitive problems in MS in parallel to disease modifying drugs.

Neuromyelitis optica in Austria in 2011: to bridge the gap between neuroepidemiological research and practice in a study population of 8.4 million people.

BACKGROUND: In 2008 the Austrian Task Force for Neuromyelitis Optica (NMO) started a nation-wide network for information exchange and multi-centre collaboration. Their aim was to detect all patients with NMO or NMO spectrum disorders (NMO-SD) in Austria and to analyse their disease courses and response to treatment. METHODS: (1) As of March 2008, 1957 serum samples (of 1557 patients) have been tested with an established cell based immunofluorescence aquaporin-4 antibody (AQP4-ab) assay with a high sensitivity and specificity (both >95%). All tests were performed in a single reference laboratory (Clinical Dept. of Neurology of the Innsbruck Medical University). (2) A nation-wide survey with several calls for participation (via email newsletters, articles in the official journal of the Austrian Society of Neurology, and workshops) was initiated in 2008. All collected data will be presented in a way that allows that every individual patient can be traced back in order to ensure transparency and to avoid any data distortion in future meta-analyses. The careful and detailed presentation allows the visualization and comparison of the different disease courses in real time span. Failure and response to treatment are made visible at one glance. Database closure was 31 December 2011. All co-operators were offered co-authorship. RESULTS: All 71 NMO- or NMO-SD patients with AQP4-ab positivity (age range 12.3 to 79.6 years) were analysed in detail. Sex ratio (m:f = 1:7) and the proportion of patients without oligoclonal bands in cerebrospinal fluid (86.6%) were in line with previously published results. All identified patients were Caucasians. CONCLUSIONS: A nationwide collaboration amongst Austrian neurologists with good network communications made it possible to establish a database of 71 AQP4-ab positive patients with NMO/NMO-SD. This database is presented in detail and provides the basis for further studies and international cooperation in order to investigate this rare disease.

Recommendations for the use of prolonged-release fampridine in patients with multiple sclerosis (MS).

Prolonged-release fampridine (fampridine PR) is a potassium channel blocker that improves conductivity of signal on demyelinated axons in central nervous system. Fampridine PR has been approved to improve speed of walking in patients with multiple sclerosis. This statement provides a brief summary of data on fampridine PR and recommendations on practical use of the medication in clinical practice, prediction, and evaluation of response to treatment and patient management.

Natalizumab treatment reduces fatigue in multiple sclerosis. Results from the TYNERGY trial; a study in the real life setting.

UNLABELLED: Fatigue is a significant symptom in multiple sclerosis (MS) patients. First-generation disease modifying therapies (DMTs) are at best moderately effective to improve fatigue. Observations from small cohorts have indicated that natalizumab, an antibody targeting VLA-4, may reduce MS-related fatigue. The TYNERGY study aimed to further evaluate the effects of natalizumab treatment on MS-related fatigue. In this one-armed clinical trial including 195 MS patients, natalizumab was prescribed in a real-life setting, and a validated questionnaire, the Fatigue Scale for Motor and Cognitive functions (FSMC), was used both before and after 12 months of treatment to evaluate a possible change in the fatigue experienced by the patients. In the treated cohort all measured variables, that is, fatigue score, quality of life, sleepiness, depression, cognition, and disability progression were improved from baseline (all p values<0.0001). Walking speed as measured by the six-minute walk-test also increased at month 12 (p = 0.0016). All patients were aware of the nature of the treatment agent, and of the study outcomes. CONCLUSION: Natalizumab, as used in a real-life setting, might improve MS-related fatigue based on the results from this one-armed un-controlled stud. Also other parameters related to patients' quality of life seemed to improve with natalizumab treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT00884481.

An exploratory study on the spatial relationship between regional cortical volume changes and white matter integrity in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory central nervous system disorder with a neurodegenerative component. While in the past, MS has been predominantly viewed as a white matter (WM) disease, gray matter (GM) pathology receives increasing attention in MS research. In this study, we tested hypothesis-free for a possible spatial relationship between cortical volume changes and disturbed integrity of projecting WM tracts. We used voxel-based morphometry (VBM), lesion probability maps (LPM), and probabilistic tractography to compare brain magnetic resonance imaging (MRI) scans obtained at 3 Tesla of 15 low disabled MS patients with 15 matched healthy controls (HCs). Areas of decreased cortical volume in the patients identified by VBM were used as seeds for tractography. Volume in two cortical areas in the left inferior frontal gyrus (IFG) and the left lateral occipital cortex (LOC) was reduced in patients compared to HCs. Starting from the IFG-region, tractography suggested impaired connections between left and right portions of the frontal lobe in the patients. Using the LOC as a seed, in patients, the left inferior longitudinal and fronto-occipital pathways appeared disintegrated compared to HCs. Swapping the seeds to homologous contralateral areas showed similar results for frontal, but different results for occipital brain areas. This at least partly could be explained by differential interference with WM lesions. These findings suggest a regional dependence between cortical GM and WM tract alterations in MS patients. While confirmation in larger and more heterogenic samples is needed, this study indicates that combining several MRI methods (VBM, LPM, and Probabilistic Tractography) may provide important insights into interacting processes related to the fiber tract and GM changes in MS.

Quantitative susceptibility mapping in multiple sclerosis.

PURPOSE: To apply quantitative susceptibility mapping (QSM) in the basal ganglia of patients with multiple sclerosis (MS) and relate the findings to R2* mapping with regard to the sensitivity for clinical and morphologic measures of disease severity. MATERIALS AND METHODS: The local ethics committee approved this study, and all subjects gave written informed consent. Sixty-eight patients (26 with clinically isolated syndrome, 42 with relapsing-remitting MS) and 23 control subjects underwent 3-T magnetic resonance (MR) imaging. Susceptibility and R2* maps were reconstructed from the same three-dimensional multiecho spoiled gradient-echo sequence. Mean susceptibilities and R2* rates were measured in the basal ganglia and were compared between different phenotypes of the disease (clinically isolated syndrome, MS) and the control subjects by using analysis of variance, and regressing analysis was used to identify independent predictors. RESULTS: Compared with control subjects, patients with MS and clinically isolated syndrome had increased (more paramagnetic) magnetic susceptibilities in the basal ganglia. R2* mapping proved less sensitive than QSM regarding group differences. The strongest predictor of magnetic susceptibility was age. Susceptibilities were higher with increasing neurologic deficits (r = 0.34, P < .01) and lower with normalized volumes of gray matter (r = -0.35, P < .005) and the cortex (r = -0.35, P < .005). CONCLUSION: QSM provides superior sensitivity over R2* mapping in the detection of MS-related tissue changes in the basal ganglia. With QSM but not with R2* mapping, changes were already observed in patients with clinically isolated syndrome, which suggests that QSM can serve as a sensitive measure at the earliest stage of the disease.