spatial normalization and regional assessment of cord atrophy voxel based analysis of cervical cord 3d t1 weighted images

BACKGROUND AND PURPOSE: VBM is widely applied to characterize regional differences in brain volume among groups of subjects. The aim of this study was to develop and validate a method for voxelwise statistical analysis of cord volume and to test, with this method, the correlation between cord tissue loss and aging. MATERIALS AND METHODS: 3D T1-weighted scans of the spinal cord were acquired from 90 healthy subjects spanning several decades of life. Using an AS method, we outlined the cord surface and created output images reformatted with image planes perpendicular to the estimated cord centerline. Unfolded cervical cord images were coregistered into a common standard space, and smoothed cord binary masks, produced by using the cord outlines estimated by the AS approach, were used as input images for spatial statistics. RESULTS: High spatial correlation between normalized images was observed. Averaging of the normalized scans allowed the creation of a cervical cord template and of a standardized region-of-interest atlas. VBM analysis showed some significant associations between a decreased probability of cord tissue and aging. Results were robust across different smoothing levels, but the use of an anisotropic Gaussian kernel gave the optimal trade-off between spatial resolution and the requirements of the Gaussian random field theory. CONCLUSIONS: VBM analysis of the cervical cord was feasible and holds great promise for accurate localization of regional cord atrophy in several neurologic conditions

Functional MRI correlates of cognitive performance in patients with a clinically isolated syndrome suggestive of MS at presentation: an activation and connectivity study

Background/Objective: To assess whether abnormalities on functional magnetic resonance imaging (fMRI) are related to cognitive function in patients at presentation with clinically isolated syndrome (CIS) suggestive of multiple sclerosis. Methods: Eighteen patients with CIS and 15 healthy controls (HCs) performed an adapted fMRI version of the Paced Auditory Serial Addition Test (PASAT). According to their PASAT performance, CIS patients were divided into two groups: 10 with a low PASAT performance (<1 SD from the mean value of HCs) were considered ‘cognitive impairment’ (CI); eight patients were defined as ‘cognitively preserved’ (CP). Between-group differences in the patterns of brain activations and effective connectivity were assessed. Results: During PASAT, compared to HCs, CIS patients showed increased activations of the bilateral inferior parietal lobe (IPL), bilateral precuneus, bilateral middle frontal gyrus (MFG), left anterior cingulate cortex (ACC), left claustrum, right thalamus and right caudate nucleus. When CIS patients were analyzed, the CI group had a more significant activation of the bilateral IPL than HCs and CP patients. Compared to CP patients, they also had more significant recruitment of the right superior parietal lobe, right cerebellum, left MFG and left ACC. The analysis of effective connectivity showed stronger connections between several regions of the right hemisphere involved in working memory function in CI patients versus CP and HC. Conclusions: During performance of the PASAT, CIS patients show abnormalities in the patterns of cortical recruitment and connectivity related to the level of their cognitive impairment.This research has been supported by the following grants: Alicia Koplowitz Foundation; CSD2007-00012 (Consolider-Ingenio 2010 Programme), SEJ2007-65929/PSIC and PSI2010-20168 from the Spanish Ministry of Science and Education; the Dávalos Foundation Grant and P1·1A2010-07 from Bancaixa

A three-year study of brain atrophy after autologous hematopoietic stem cell transplantation in rapidly evolving secondary progressive multiple sclerosis

BACKGROUND AND PURPOSE: In multiple sclerosis (MS), autologous hematopoietic stem cell transplantation (AHSCT) induces a profound suppression of clinical activity and MR imaging-detectable inflammation, but it may be associated with a rapid brain volume loss in the months subsequent to treatment. The aim of this study was to assess how AHSCT affects medium-term evolution of brain atrophy in MS. MATERIALS AND METHODS: MR imaging scans of the brain from 14 patients with rapidly evolving secondary-progressive MS obtained 3 months before and every year after AHSCT for 3 years were analyzed. Baseline normalized brain volumes and longitudinal percentage of brain volume changes (PBVCs) were assessed using the Structural Image Evaluation of Normalized Atrophy software. RESULTS: The median decrease of brain volume was 1.92% over the first year after AHSCT and then declined to 1.35% at the second year and to 0.69% at the third year. The number of enhancing lesions seen on the pretreatment scans was significantly correlated with the PBVCs between baseline and month 12 (r = -0.62; P = .02); no correlation was found with the PBVCs measured over the second and third years. CONCLUSIONS: After AHSCT, the rate of brain tissue loss in patients with MS declines dramatically after the first 2 years. The initial rapid development of brain atrophy may be a late consequence of the pretransplant disease activity and/or a transient result of the intense immunoablative conditioning procedure

Quantification of Cervical Cord Cross-Sectional Area: Which Acquisition, Vertebra Level, and Analysis Software? A Multicenter Repeatability Study on a Traveling Healthy Volunteer

Atrofia; Área transversal; Médula espinalAtròfia; Àrea transversal; Medul·la espinalAtrophy; Cross-sectional area; Spinal cordBackground: Considerable spinal cord (SC) atrophy occurs in multiple sclerosis (MS). While MRI-based techniques for SC cross-sectional area (CSA) quantification have improved over time, there is no common agreement on whether to measure at single vertebral levels or across larger regions and whether upper SC CSA can be reliably measured from brain images. Aim: To compare in a multicenter setting three CSA measurement methods in terms of repeatability at different anatomical levels. To analyze the agreement between measurements performed on the cervical cord and on brain MRI. Method: One healthy volunteer was scanned three times on the same day in six sites (three scanner vendors) using a 3T MRI protocol including sagittal 3D T1-weighted imaging of the brain (covering the upper cervical cord) and of the SC. Images were analyzed using two semiautomated methods [NeuroQLab (NQL) and the Active Surface Model (ASM)] and the fully automated Spinal Cord Toolbox (SCT) on different vertebral levels (C1–C2; C2/3) on SC and brain images and the entire cervical cord (C1–C7) on SC images only. Results: CSA estimates were significantly smaller using SCT compared to NQL and ASM (p < 0.001), regardless of the cord level. Inter-scanner repeatability was best in C1–C7: coefficients of variation for NQL, ASM, and SCT: 0.4, 0.6, and 1.0%, respectively. CSAs estimated in brain MRI were slightly lower than in SC MRI (all p ≤ 0.006 at the C1–C2 level). Despite protocol harmonization between the centers with regard to image resolution and use of high-contrast 3D T1-weighted sequences, the variability of CSA was partly scanner dependent probably due to differences in scanner geometry, coil design, and details of the MRI parameter settings. Conclusion: For CSA quantification, dedicated isotropic SC MRI should be acquired, which yielded best repeatability in the entire cervical cord. In the upper part of the cervical cord, use of brain MRI scans entailed only a minor loss of CSA repeatability compared to SC MRI. Due to systematic differences between scanners and the CSA quantification software, both should be kept constant within a study. The MRI dataset of this study is available publicly to test new analysis approaches.Parts of this work were funded by the German Federal Ministry for Education and Research, BMBF, German Competence Network Multiple Sclerosis KKNMS (Grant Nos. 01GI1601I and 01GI0914) and by grants from the UK MS Society. FP, CG, and MY were supported by the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Center. The funding institutions did not interfere with the study design, the collection, analysis and interpretation of data, the writing of the report, or the decision to submit the article for publication

The C-terminal domain of yeast Ero1p mediates membrane localization and is essential for function

AbstractIn eukaryotes, members of the Ero1 family control oxidative protein folding in the endoplasmic reticulum (ER). Yeast Ero1p is tightly associated with the ER membrane, despite cleavage of the leader peptide, the only hydrophobic sequence that could mediate lipid insertion. In contrast, human Ero1-Lα and a yeast mutant (Ero1pΔC) lacking the 127 C-terminal amino acids are soluble when expressed in yeast. Neither Ero1-Lα nor Ero1pΔC complements an ERO1 disrupted strain. Appending the yeast C-terminal tail to human Ero1-Lα restores membrane association and allows growth of ERO1 disrupted cells. Therefore, the tail of Ero1p mediates membrane association and is crucial for function

The polo-like kinase 1 (PLK1) inhibitor NMS-P937 is effective in a new model of disseminated primary CD56+ acute monoblastic leukaemia

CD56 is expressed in 15–20% of acute myeloid leukaemias (AML) and is associated with extramedullary diffusion, multidrug resistance and poor prognosis. We describe the establishment and characterisation of a novel disseminated model of AML (AML-NS8), generated by injection into mice of leukaemic blasts freshly isolated from a patient with an aggressive CD56+ monoblastic AML (M5a). The model reproduced typical manifestations of this leukaemia, including presence of extramedullary masses and central nervous system involvement, and the original phenotype, karyotype and genotype of leukaemic cells were retained in vivo. Recently Polo-Like Kinase 1 (PLK1) has emerged as a new candidate drug target in AML. We therefore tested our PLK1 inhibitor NMS-P937 in this model either in the engraftment or in the established disease settings. Both schedules showed good efficacy compared to standard therapies, with a significant increase in median survival time (MST) expecially in the established disease setting (MST = 28, 36, 62 days for vehicle, cytarabine and NMS-P937, respectively). Importantly, we could also demonstrate that NMS-P937 induced specific biomarker modulation in extramedullary tissues. This new in vivo model of CD56+ AML that recapitulates the human tumour lends support for the therapeutic use of PLK1 inhibitors in AML

Characterizing 1-year development of cervical cord atrophy across different MS phenotypes: A voxel-wise, multicentre analysis

Background: Spatio-temporal evolution of cord atrophy in multiple sclerosis (MS) has not been investigated yet. Objective: To evaluate voxel-wise distribution and 1-year changes of cervical cord atrophy in a multicentre MS cohort. Methods: Baseline and 1-year 3D T1-weighted cervical cord scans and clinical evaluations of 54 healthy controls (HC) and 113 MS patients (14 clinically isolated syndromes (CIS), 77 relapsing-remitting (RR), 22 progressive (P)) were used to investigate voxel-wise cord volume loss in patients versus HC, 1-year volume changes and clinical correlations (SPM12). Results: MS patients exhibited baseline cord atrophy versus HC at anterior and posterior/lateral C1/C2 and C4–C6 (p < 0.05, corrected). While CIS patients showed baseline volume increase at C4 versus HC (p < 0.001, uncorrected), RRMS exhibited posterior/lateral C1/C2 atrophy versus CIS, and PMS showed widespread cord atrophy versus RRMS (p < 0.05, corrected). At 1 year, 13 patients had clinically worsened. Cord atrophy progressed in MS, driven by RRMS, at posterior/lateral C2 and C3–C6 (p < 0.05, corrected). CIS patients showed no volume changes, while PMS showed circumscribed atrophy progression. Baseline cord atrophy at posterior/lateral C1/C2 and C3–C6 correlated with concomitant and 1-year disability (r = −0.40/–0.62, p < 0.05, corrected). Conclusions: Voxel-wise analysis characterized spinal cord neurodegeneration over 1 year across MS phenotypes and helped to explain baseline and 1-year disability

Quantification of Cervical Cord Cross-Sectional Area: Which Acquisition, Vertebra Level, and Analysis Software? A Multicenter Repeatability Study on a Traveling Healthy Volunteer

BACKGROUND: Considerable spinal cord (SC) atrophy occurs in multiple sclerosis (MS). While MRI-based techniques for SC cross-sectional area (CSA) quantification have improved over time, there is no common agreement on whether to measure at single vertebral levels or across larger regions and whether upper SC CSA can be reliably measured from brain images. AIM: To compare in a multicenter setting three CSA measurement methods in terms of repeatability at different anatomical levels. To analyze the agreement between measurements performed on the cervical cord and on brain MRI. METHOD: One healthy volunteer was scanned three times on the same day in six sites (three scanner vendors) using a 3T MRI protocol including sagittal 3D T1-weighted imaging of the brain (covering the upper cervical cord) and of the SC. Images were analyzed using two semiautomated methods [NeuroQLab (NQL) and the Active Surface Model (ASM)] and the fully automated Spinal Cord Toolbox (SCT) on different vertebral levels (C1–C2; C2/3) on SC and brain images and the entire cervical cord (C1–C7) on SC images only. RESULTS: CSA estimates were significantly smaller using SCT compared to NQL and ASM (p < 0.001), regardless of the cord level. Inter-scanner repeatability was best in C1–C7: coefficients of variation for NQL, ASM, and SCT: 0.4, 0.6, and 1.0%, respectively. CSAs estimated in brain MRI were slightly lower than in SC MRI (all p ≤ 0.006 at the C1–C2 level). Despite protocol harmonization between the centers with regard to image resolution and use of high-contrast 3D T1-weighted sequences, the variability of CSA was partly scanner dependent probably due to differences in scanner geometry, coil design, and details of the MRI parameter settings. CONCLUSION: For CSA quantification, dedicated isotropic SC MRI should be acquired, which yielded best repeatability in the entire cervical cord. In the upper part of the cervical cord, use of brain MRI scans entailed only a minor loss of CSA repeatability compared to SC MRI. Due to systematic differences between scanners and the CSA quantification software, both should be kept constant within a study. The MRI dataset of this study is available publicly to test new analysis approaches

MAGNIMS recommendations for harmonization of MRI data in MS multicenter studies

There is an increasing need of sharing harmonized data from large, cooperative studies as this is essential to develop new diagnostic and prognostic biomarkers. In the field of multiple sclerosis (MS), the issue has become of paramount importance due to the need to translate into the clinical setting some of the most recent MRI achievements. However, differences in MRI acquisition parameters, image analysis and data storage across sites, with their potential bias, represent a substantial constraint. This review focuses on the state of the art, recent technical advances, and desirable future developments of the harmonization of acquisition, analysis and storage of large-scale multicentre MRI data of MS cohorts. Huge efforts are currently being made to achieve all the requirements needed to provide harmonized MRI datasets in the MS field, as proper management of large imaging datasets is one of our greatest opportunities and challenges in the coming years. Recommendations based on these achievements will be provided here. Despite the advances that have been made, the complexity of these tasks requires further research by specialized academical centres, with dedicated technical and human resources. Such collective efforts involving different professional figures are of crucial importance to offer to MS patients a personalised management while minimizing consumption of resource

Association of Gray Matter Atrophy Patterns with Clinical Phenotype and Progression in Multiple Sclerosis

OBJECTIVES: Grey matter (GM) involvement is clinically relevant in multiple sclerosis (MS). Using source-based morphometry (SBM), we characterized GM atrophy and its 1-year evolution across different MS phenotypes. METHODS: Clinical and MRI data were obtained at 8 European sites from 170 healthy controls (HCs) and 398 MS patients (34 clinically isolated syndromes [CIS], 226 relapsing-remitting [RR], 95 secondary progressive [SP] and 43 primary progressive [PP] MS). Fifty-seven HC and 144 MS underwent 1-year follow-up. Baseline GM loss, atrophy progression and correlations with disability and 1-year clinical worsening were assessed. RESULTS: SBM identified 26 cerebellar, subcortical, sensory, motor and cognitive GM components. GM atrophy was found in MS vs HC in almost all components (p=range<0.001-0.04). Compared to HCs, CIS patients showed circumscribed subcortical, cerebellar, temporal and salience GM atrophy, while RRMS patients exhibited widespread GM atrophy. Cerebellar, subcortical, sensorimotor, salience and fronto-parietal GM atrophy was found in PPMS patients vs HCs, and SPMS vs RRMS. At 1-year, 21 (15%) patients had clinically worsened. GM atrophy progressed in MS in subcortical, cerebellar, sensorimotor, and fronto-temporo-parietal components. Baseline higher disability was associated (R2=0.65) with baseline lower normalized brain volume (beta=-0.13, p=0.001), greater sensorimotor GM atrophy (beta=-0.12, p=0.002) and longer disease duration (beta=0.09, p=0.04). Baseline normalized GM volume (odds ratio=0.98, p=0.008) and cerebellar GM atrophy (odds ratio=0.40, p=0.01) independently predicted clinical worsening (area-under-the-curve=0.83). CONCLUSION: GM atrophy differed across disease phenotypes and progressed at 1-year in MS. In addition to global atrophy measures, sensorimotor and cerebellar GM atrophy explained baseline disability and clinical worsening