Cervical spinal cord volume loss is related to clinical disability progression in multiple sclerosis.

OBJECTIVE: To examine the temporal evolution of spinal cord (SC) atrophy in multiple sclerosis (MS), and its association with clinical progression in a large MS cohort. METHODS: A total of 352 patients from two centres with MS (relapsing remitting MS (RRMS): 256, secondary progressive MS (SPMS): 73, primary progressive MS (PPMS): 23) were included. Clinical and MRI parameters were obtained at baseline, after 12 months and 24 months of follow-up. In addition to conventional brain and SC MRI parameters, the annualised percentage brain volume change and the annualised percentage upper cervical cord cross-sectional area change (aUCCA) were quantified. Main outcome measure was disease progression, defined by expanded disability status scale increase after 24 months. RESULTS: UCCA was lower in SPMS and PPMS compared with RRMS for all time points. aUCCA over 24 months was highest in patients with SPMS (-2.2% per year) and was significantly higher in patients with disease progression (-2.3% per year) than in stable patients (-1.2% per year; p=0.003), while annualised percentage brain volume change did not differ between subtypes (RRMS: -0.42% per year; SPMS -0.6% per year; PPMS: -0.46% per year) nor between progressive and stable patients (p=0.055). Baseline UCCA and aUCCA over 24 months were found to be relevant contributors of expanded disability status scale at month-24, while baseline UCCA as well as number of SC segments involved by lesions at baseline but not aUCCA were relevant contributors of disease progression. CONCLUSIONS: SC MRI parameters including baseline UCCA and SC lesions were significant MRI predictors of disease progression. Progressive 24-month upper SC atrophy occurred in all MS subtypes, and was faster in patients exhibiting disease progression at month-24.

Combined visual and motor evoked potentials predict multiple sclerosis disability after 20 years.

BACKGROUND: The development of predictors of multiple sclerosis (MS) disability is difficult due to the complex interplay of pathophysiological and adaptive processes. OBJECTIVE: The purpose of this study was to investigate whether combined evoked potential (EP)-measures allow prediction of MS disability after 20 years. METHODS: We examined 28 patients with clinically definite MS according to Poser's criteria with Expanded Disability Status Scale (EDSS) scores, combined visual and motor EPs at entry (T0), 6 (T1), 12 (T2) and 24 (T3) months, and a cranial magnetic resonance imaging (MRI) scan at T0 and T2. EDSS testing was repeated at year 14 (T4) and year 20 (T5). Spearman rank correlation was used. We performed a multivariable regression analysis to examine predictive relationships of the sum of z-transformed EP latencies (s-EPT0) and other baseline variables with EDSST5. RESULTS: We found that s-EPT0 correlated with EDSST5 (rho=0.72, p<0.0001) and ΔEDSST5-T0 (rho=0.50, p=0.006). Backward selection resulted in the prediction model: E (EDSST5)=3.91-2.22×therapy+0.079×age+0.057×s-EPT0 (Model 1, R (2)=0.58) with therapy as binary variable (1=any disease-modifying therapy between T3 and T5, 0=no therapy). Neither EDSST0 nor T2-lesion or gadolinium (Gd)-enhancing lesion quantities at T0 improved prediction of EDSST5. The area under the receiver operating characteristic (ROC) curve was 0.89 for model 1. CONCLUSIONS: These results further support a role for combined EP-measures as predictors of long-term disability in MS.

Head motion parameters in fMRI differ between patients with mild cognitive impairment and Alzheimer disease versus elderly control subjects.

Motion artifacts are a well-known and frequent limitation during neuroimaging workup of cognitive decline. While head motion typically deteriorates image quality, we test the hypothesis that head motion differs systematically between healthy controls (HC), amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD) and consequently might contain diagnostic information. This prospective study was approved by the local ethics committee and includes 28 HC (age 71.0 ± 6.9 years, 18 females), 15 aMCI (age 67.7 ± 10.9 years, 9 females) and 20 AD (age 73.4 ± 6.8 years, 10 females). Functional magnetic resonance imaging (fMRI) at 3T included a 9 min echo-planar imaging sequence with 180 repetitions. Cumulative average head rotation and translation was estimated based on standard fMRI preprocessing and compared between groups using receiver operating characteristic statistics. Global cumulative head rotation discriminated aMCI from controls [p < 0.01, area under curve (AUC) 0.74] and AD from controls (p < 0.01, AUC 0.73). The ratio of rotation z versus y discriminated AD from controls (p < 0.05, AUC 0.71) and AD from aMCI (p < 0.05, AUC of 0.75). Head motion systematically differs between aMCI/AD and controls. Since motion is not random but convoluted with diagnosis, the higher amount of motion in aMCI and AD as compared to controls might be a potential confounding factor for fMRI group comparisons. Additionally, head motion not only deteriorates image quality, yet also contains useful discriminatory information and is available for free as a "side product" of fMRI data preprocessing.

Relevance of spinal cord abnormalities to clinical disability in multiple sclerosis: MR imaging findings in a large cohort of patients.

PURPOSE: To determine whether spinal cord atrophy differs among disease subtypes in multiple sclerosis (MS) and whether it offers diagnostic and clinical correlative information beyond that provided by other magnetic resonance (MR) imaging markers. MATERIALS AND METHODS: The institutional review board approved the study; all subjects gave written informed consent. Upper cervical cord cross-sectional area (UCCA), brain and spinal cord lesion loads, and brain atrophy were measured in 440 patients with MS (311 with relapsing-remitting [RR] MS, 92 with secondary-progressive [SP] MS, and 37 with primary-progressive [PP] MS) studied in two centers. Disability was scored with the Expanded Disability Status Scale (EDSS), the timed 25-foot walk test (TWT), and the nine-hole peg test. UCCA was compared between groups with the Mann-Whitney U test. Correlations were assessed with the Spearman ρ test. Multivariate associations between UCCA and clinical and other MR imaging parameters, including number of hypointense brain lesions on T1-weighted MR images, presence of diffuse abnormalities, and number of involved segments in the spinal cord, were assessed by using multiple linear regression, adjusted for study center site. RESULTS: The UCCA in patients with SP MS (median, 79 mm(2); interquartile range, 72.4-84.9 mm(2)) and PP MS (median, 77.3 mm(2); interquartile range, 69-82.5 mm(2)) was significantly smaller (P < .001) than that in patients with RR MS (median, 84 mm(2); interquartile range, 78.7-89.3 mm(2)). UCCA was inversely correlated with EDSS score, TWT, and nine-hole peg test findings (ρ ≤ -0.29, P < .001 for all comparisons). UCCA, number of hypointense brain lesions on T1-weighted MR images, presence of diffuse abnormalities, and number of involved segments in the spinal cord were found to be significant explanatory factors for clinical disability (R(2) = 0.564). The UCCA and the number of hypointense brain lesions on T1-weighted images were the strongest MR imaging parameters for explaining physical disability, as measured with the EDSS. CONCLUSION: Spinal cord abnormalities have a strong effect on clinical disability in MS. MR imaging-derived UCCA was found to be the most significant spinal cord parameter for explaining EDSS score.

Grey matter volume in a large cohort of MS patients: relation to MRI parameters and disability.

BACKGROUND: Although grey matter damage in multiple sclerosis is currently recognized, determinants of grey matter volume and its relationship with disability are not yet clear. OBJECTIVES: The objectives of the study were to measure grey and white matter volumes across different disease phenotypes; identify MRI parameters associated with grey matter volume; and study grey and white matter volume as explanatory variables for clinical impairment. METHODS: This is a cross-sectional study in which MRI data of 95 clinically isolated syndrome, 657 relapsing-remitting, 125 secondary-progressive and 50 primary-progressive multiple sclerosis patients from three centres were acquired. Grey and white matter volumes were determined, together with T2 and T1 lesion volumes. Physical disability was assessed with the Expanded Disability Status Scale, cognitive impairment with the Paced Auditory Serial Addition Task. Data were analysed using multiple regression. RESULTS: Grey matter volume was lower in relapsing-remitting patients (mean [SD]: 0.80 [0.05] L) than in clinically isolated syndrome patients (0.82 [0.05] L), and even greater relative atrophy was found in secondary-progressive patients (0.77 [0.05] L). In contrast, white matter volume in secondary-progressive patients was comparable to that in relapsing-remitting patients. Grey matter volume was the strongest independent predictor of physical disability and cognitive impairment, and was associated with both T2 and T1 lesion volume. CONCLUSIONS: Our findings show that grey matter volume is lower in secondary-progressive than in relapsing-remitting disease. Grey matter volume explained physical and cognitive impairment better than white matter volume, and is itself associated with T2 and T1 lesion volume.

Oral fingolimod (FTY720) for relapsing multiple sclerosis.

BACKGROUND: Fingolimod (FTY720) is a new oral immunomodulating agent under evaluation for the treatment of relapsing multiple sclerosis. METHODS: We randomly assigned 281 patients to receive oral fingolimod, at a dose of 1.25 mg or 5.0 mg, or a placebo once daily, and we followed these patients for 6 months with magnetic resonance imaging (MRI) and clinical evaluations (core study, months 0 to 6). The primary end point was the total number of gadolinium-enhanced lesions recorded on T(1)-weighted MRI at monthly intervals for 6 months. In an extension study in which the investigators and patients remained unaware of the dose assignments (months 7 to 12), patients who received placebo underwent randomization again to one of the fingolimod doses. RESULTS: A total of 255 patients completed the core study. The median total number of gadolinium-enhanced lesions on MRI was lower with 1.25 mg of fingolimod (1 lesion, P<0.001) and 5.0 mg of fingolimod (3 lesions, P=0.006) than with placebo (5 lesions). The annualized relapse rate was 0.77 in the placebo group, as compared with 0.35 in the group given 1.25 mg of fingolimod (P=0.009) and 0.36 in the group given 5.0 mg of fingolimod (P=0.01). For the 227 patients who completed the extension study, the number of gadolinium-enhanced lesions and relapse rates remained low in the groups that received continuous fingolimod, and both measures decreased in patients who switched from placebo to fingolimod. Adverse events included nasopharyngitis, dyspnea, headache, diarrhea, and nausea. Clinically asymptomatic elevations of alanine aminotransferase levels were more frequent with fingolimod (10 to 12%, vs. 1% in the placebo group). One case of the posterior reversible encephalopathy syndrome occurred in the 5.0-mg group. Fingolimod was also associated with an initial reduction in the heart rate and a modest decrease in the forced expiratory volume in 1 second. CONCLUSIONS: In this proof-of-concept study, fingolimod reduced the number of lesions detected on MRI and clinical disease activity in patients with multiple sclerosis. Evaluation in larger, longer-term studies is warranted. (Clinicaltrials.gov numbers, NCT00333138 [core study] and NCT00235430 [ClinicalTrials.gov] [extension].).

Can cortical thickness asymmetry analysis contribute to detection of at-risk mental state and first-episode psychosis? A pilot study.

PURPOSE: To investigate whether cortical thickness analysis in individuals with an at-risk mental state (ARMS) might contribute to early detection of psychosis. MATERIALS AND METHODS: Ethics committee approval and written informed consent were obtained. Cortical thickness was analyzed because early disease-related morphometric changes were expected to be most pronounced in the cerebral cortex. With the assumption of progressive change in cortical thickness from control subjects, to those with an ARMS, and then to those who have had a first episode (FE) of psychosis, the brain regions that substantially differ between those with FE psychosis and control subjects were identified. Whether these regions help discriminate between the ARMS group and control subjects was tested. Because normal interindividual variation of cortical thickness, even for control subjects, may exceed that expected with early disease-related changes, intraindividual cortical thickness asymmetry was analyzed. Twenty age- and sex-matched individuals for each group (ARMS group, FE group, and control subjects) were recruited within a prospective early-detection study. High-spatial-resolution magnetization-prepared rapid gradient-echo magnetic resonance (MR) brain images were acquired with a 1.5-T MR imager. Cortical thickness asymmetry was analyzed in 41 anatomic regions corresponding to the Talairach standard brain atlas. RESULTS: Direct cortical thickness analysis did not help distinguish between groups. Cortical thickness asymmetry analysis helped distinguish between groups (P = .007); variability increased from control subjects, to the ARMS group, and then to the FE group in seven anatomic regions (P < .0001). Cortical thickness asymmetry in these regions helped distinguish the FE group from control subjects (P = .0006; sensitivity, 70.0%; specificity, 85.0%) and showed a trend toward helping to distinguish the ARMS group from control subjects (P = .06; sensitivity, 75.0%; specificity, 65.0%). CONCLUSION: Cortical thickness asymmetry analysis is more accurate than direct cortical thickness measurement in distinguishing the control from the FE group and might contribute to early detection of an ARMS.

MEsenchymal StEm cells for Multiple Sclerosis (MESEMS): a randomized, double blind, cross-over phase I/II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system with a degenerative component, leading to irreversible disability. Mesenchymal stem cells (MSC) have been shown to prevent inflammation and neurodegeneration in animal models of MS, but no large phase II clinical trials have yet assessed the exploratory efficacy of MSC for MS. METHODS/DESIGN: This is an academic, investigator-initiated, randomized, double-blind, placebo-compared phase I/II clinical trial with autologous, bone-marrow derived MSC in MS. Enrolled subjects will receive autologous MSC at either baseline or at week 24, through a cross-over design. Primary co-objectives are to test safety and efficacy of MSC treatment compared to placebo at 6 months. Secondary objectives will evaluate the efficacy of MSC at clinical and MRI levels. In order to overcome funding constraints, the MEsenchymal StEm cells for Multiple Sclerosis (MESEMS) study has been designed to merge partially independent clinical trials, following harmonized protocols and sharing some key centralized procedures, including data collection and analyses. DISCUSSION: Results will provide patients and the scientific community with data on the safety and efficacy of MSC for MS. The innovative approach utilized to obtain funds to support the MESEMS trial could represent a new model to circumvent limitation of funds encountered by academic trials. TRIAL REGISTRATION: Andalusia: NCT01745783 , registered on Dec 10, 2012. Badalona: NCT02035514 EudraCT, 2010-024081-21. Registered on 2012. Canada: ClinicalTrials.gov, NCT02239393 . Registered on September 12, 2014. Copenhagen: EudraCT, 2012-000518-13 . Registered on June 21, 2012. Italy: EudraCT, 2011-001295-19, and ClinicalTrials.gov, NCT01854957 . Retrospectively registered on May 16, 2013. London: Eudra CT 2012-002357-35, and ClinicalTrials.gov, NCT01606215 . Registered on May 25, 2012. Salzburg: EudraCT, 2015-000137-78 . Registered on September 15, 2015. Stockholm: ClinicalTrials.gov, NCT01730547 . Registered on November 21, 2012. Toulouse: ClinicalTrials.gov, NCT02403947 . Registered on March 31, 2015.

Neural activation associated with corrective saccades during tasks with fixation, pursuit and saccades.

Corrective saccades are small eye movements that redirect gaze whenever the actual eye position differs from the desired eye position. In contrast to various forms of saccades including pro-saccades, recentering-saccades or memory guided saccades, corrective saccades have been widely neglected so far. The fMRI correlates of corrective saccades were studied that spontaneously occurred during fixation, pursuit or saccadic tasks. Eyetracking was performed during the fMRI data acquisition with a fiber-optic device. Using a combined block and event-related design, we isolated the cortical activations associated with visually guided fixation, pursuit or saccadic tasks and compared these to the activation associated with the occurrence of corrective saccades. Neuronal activations in anterior inferior cingulate, bilateral middle and inferior frontal gyri, bilateral insula and cerebellum are most likely specifically associated with corrective saccades. Additionally, overlapping activations with the established pro-saccade and, to a lesser extent, pursuit network were present. The presented results imply that corrective saccades represent a potential systematic confound in eye-movement studies, in particular because the frequency of spontaneously occurring corrective saccades significantly differed between fixation, pursuit and pro-saccades.

Antimyelin antibodies in clinically isolated syndromes correlate with inflammation in MRI and CSF.

OBJECTIVE: We investigated the correlation of antimyelin oligodendrocyte glycoprotein-(anti-MOG) and anti-myelin basic protein antibodies (anti-MBP) in serum of CIS patients with inflammatory signs in MRI and in CSF and, as previously suggested,the incidence of more frequent and rapid progression to clinically definite MS (CDMS). METHODS: 133CIS patients were analysed for anti-MOG and anti-MBP (Western blot). Routine CSF and cranial MRI (quantitatively and qualitatively) measures were analyzed. 55 patients had a follow-up of at least 12 months or until conversion to CDMS. RESULTS: Patients with anti-MOG and anti-MBP had an increased intrathecal IgG production and CSF white blood cell count(p = 0.048 and p = 0.036). When anti-MBP alone, or both antibodies were present the cranial MRI showed significantly more T2 lesions (p = 0.007 and p = 0.01,respectively). There was a trend for more lesion dissemination in anti-MBP positive patients (p = 0.076).Conversely, anti-MOG- and/or anti-MBP failed to predict conversion to CDMS in our follow-up group (n = 55). Only in female patients with at least one MRI lesion (n = 34) did the presence of anti-MOG correlate with more frequent (p = 0.028) and more rapid (p = 0.0209) transition to CDMS. CONCLUSIONS: Presence of anti-MOG or anti-MBP or both was not significantly associated with conversion to CDMS in our CIS cohort. However, patients with anti-MOG and anti-MBP had higher lesion load and more disseminated lesions in cranial MRI as well as higher values for CSF leucocytes and intrathecal IgG production. Our data support a correlation of anti-MOG and anti-MBP to inflammatory signs in MRI and CSF. The prognostic value of these antibodies for CDMS, however, seems to be less pronounced than previously reported.