White matter maturation of normal human fetal brain. An in vivo diffusion tensor tractography study

We demonstrate for the first time the ability to determine in vivo and in utero the transitions between the main stages of white matter (WM) maturation in normal human fetuses using magnetic resonance diffusion tensor imaging (DTI) tractography. Biophysical characteristics of water motion are used as an indirect probe to evaluate progression of the tissue matrix organization in cortico-spinal tracts (CSTs), optic radiations (OR), and corpus callosum (CC) in 17 normal human fetuses explored between 23 and 38 weeks of gestation (GW) and selected strictly on minimal motion artifacts. Nonlinear polynomial (third order) curve fittings of normalized longitudinal and radial water diffusivities (Z-scores) as a function of age identify three different phases of maturation with specific dynamics for each WM bundle type. These phases may correspond to distinct cellular events such as axonal organization, myelination gliosis, and myelination, previously reported by other groups on post-mortem fetuses using immunostaining methods. According to the DTI parameter dynamics, we suggest that myelination (phase 3) appears early in the CSTs, followed by the OR and by the CC, respectively. DTI tractography provides access to a better understanding of fetal WM maturation

Inflammatory Multiple-Sclerosis Plaques Generate Characteristic Metabolic Profiles in Cerebrospinal Fluid

International audienceBackgroundMultiple sclerosis (MS), an inflammatory disease of the central nervous system, manifests itself in numerous forms and stages. A number of brain metabolic alterations have been reported for MS patients vs. control subjects. However, metabolite profiles of cerebrospinal fluid (CSF) are not consistent among the published MS studies, most probably due to variations in the patient cohorts studied. We undertook the first investigation of highly homogeneous MS patient cohorts to determine characteristic effects of inflammatory MS plaques on the CSF metabolome, including only patients with clinically isolated syndrome (CIS) with or without inflammatory brain plaques, and controls.Methodology/Principal FindingsCSF obtained by lumbar puncture was analyzed by proton magnetic resonance spectroscopy. 27 metabolites were quantified. Differences between groups of control subjects (n = 10), CIS patients with (n = 21) and without (n = 12) inflammatory plaques were evaluated by univariate statistics and principal component analysis (PCA). Seven metabolites showed statistically significant inter-group differences (p<0.05). Interestingly, a significant increase in β-hydroxyisobutyrate (BHIB) was detected in CIS with vs. without active plaques, but not when comparing either CIS group with control subjects. Moreover, a significant correlation was found, for the first time, between CSF lactate concentration and the number of inflammatory MS brain plaques. In contrast, fructose concentrations were equally enhanced in CIS with or without active plaques. PCA based on all 27 metabolites yielded group-specific clusters.Conclusions/SignificanceCSF metabolic profiles suggest a close link between MS plaque activity in CIS patients on the one hand and organic-acid metabolism on the other. Our detection of increased BHIB levels points to a hitherto unsuspected role for this compound in MS with active plaques, and serves as a basis for further investigation. The metabolic effects described in our study are crucial elements in the explanation of biochemical mechanisms involved in specific MS manifestations

Metabolic counterparts of sodium accumulation in multiple sclerosis: A whole brain 23Na-MRI and fast 1H-MRSI study

Increase of brain total sodium concentrations (TSC) is present in multiple sclerosis (MS), but its pathological involvement has not been assessed yet. To determine in vivo the metabolic counterpart of brain sodium accumulation. Whole brain Na-MR imaging and 3D- H-EPSI data were collected in 21 relapsing-remitting multiple sclerosis (RRMS) patients and 20 volunteers. Metabolites and sodium levels were extracted from several regions of grey matter (GM), normal-appearing white matter (NAWM) and white matter (WM) T lesions. Metabolic and ionic levels expressed as Z-scores have been averaged over the different compartments and used to explain sodium accumulations through stepwise regression models. MS patients showed significant Na accumulations with lower choline and glutamate-glutamine (Glx) levels in GM; Na accumulations with lower N-acetyl aspartate (NAA), Glx levels and higher Myo-Inositol (m-Ins) in NAWM; and higher Na, m-Ins levels with lower NAA in WM T lesions. Regression models showed associations of TSC increase with reduced NAA in GM, NAWM and T lesions, as well as higher total-creatine, and smaller decrease of m-Ins in T lesions. GM Glx levels were associated with clinical scores. Increase of TSC in RRMS is mainly related to neuronal mitochondrial dysfunction while dysfunction of neuro-glial interactions within GM is linked to clinical scores

Prevalence of Grey Matter Pathology in Early Multiple Sclerosis Assessed by Magnetization Transfer Ratio Imaging

The aim of the study was to assess the prevalence, the distribution and the impact on disability of grey matter (GM) pathology in early multiple sclerosis. Eighty-eight patients with a clinically isolated syndrome with a high risk developing multiple sclerosis were included in the study. Forty-four healthy controls constituted the normative population. An optimized statistical mapping analysis was performed to compare each subject's GM Magnetization Transfer Ratio (MTR) imaging maps with those of the whole group of controls. The statistical threshold of significant GM MTR decrease was determined as the maximum p value (p<0.05 FDR) for which no significant cluster survived when comparing each control to the whole control population. Using this threshold, 51% of patients showed GM abnormalities compared to controls. Locally, 37% of patients presented abnormalities inside the limbic cortex, 34% in the temporal cortex, 32% in the deep grey matter, 30% in the cerebellum, 30% in the frontal cortex, 26% in the occipital cortex and 19% in the parietal cortex. Stepwise regression analysis evidenced significant association (p = 0.002) between EDSS and both GM pathology (p = 0.028) and T2 white matter lesions load (p = 0.019). In the present study, we evidenced that individual analysis of GM MTR map allowed demonstrating that GM pathology is highly heterogeneous across patients at the early stage of MS and partly underlies irreversible disability

Interictal Functional Connectivity of Human Epileptic Networks Assessed by Intracerebral EEG and BOLD Signal Fluctuations

In this study, we aimed to demonstrate whether spontaneous fluctuations in the blood oxygen level dependent (BOLD) signal derived from resting state functional magnetic resonance imaging (fMRI) reflect spontaneous neuronal activity in pathological brain regions as well as in regions spared by epileptiform discharges. This is a crucial issue as coherent fluctuations of fMRI signals between remote brain areas are now widely used to define functional connectivity in physiology and in pathophysiology. We quantified functional connectivity using non-linear measures of cross-correlation between signals obtained from intracerebral EEG (iEEG) and resting-state functional MRI (fMRI) in 5 patients suffering from intractable temporal lobe epilepsy (TLE). Functional connectivity was quantified with both modalities in areas exhibiting different electrophysiological states (epileptic and non affected regions) during the interictal period. Functional connectivity as measured from the iEEG signal was higher in regions affected by electrical epileptiform abnormalities relative to non-affected areas, whereas an opposite pattern was found for functional connectivity measured from the BOLD signal. Significant negative correlations were found between the functional connectivities of iEEG and BOLD signal when considering all pairs of signals (theta, alpha, beta and broadband) and when considering pairs of signals in regions spared by epileptiform discharges (in broadband signal). This suggests differential effects of epileptic phenomena on electrophysiological and hemodynamic signals and/or an alteration of the neurovascular coupling secondary to pathological plasticity in TLE even in regions spared by epileptiform discharges. In addition, indices of directionality calculated from both modalities were consistent showing that the epileptogenic regions exert a significant influence onto the non epileptic areas during the interictal period. This study shows that functional connectivity measured by iEEG and BOLD signals give complementary but sometimes inconsistent information in TLE

Functional connectivity changes differ in early and late-onset alzheimer's disease

International audienceAbstract At a similar stage, patients with early onset Alzheimer's disease (EOAD) have greater neocortical but less medial temporal lobe dysfunction and atrophy than the late‐onset form of the disease (LOAD). Whether the organization of neural networks also differs has never been investigated. This study aims at characterizing basal functional connectivity (FC) patterns of EOAD and LOAD in two groups of 14 patients matched for disease duration and severity, relative to age‐matched controls. All subjects underwent an extensive neuropsychological assessment. Magnetic resonance imaging was used to quantify atrophy and resting‐state FC focusing on : the default mode network (DMN), found impaired in earlier studies on AD, and the anterior temporal network (ATN) and dorso‐lateral prefrontal network (DLPFN), respectively involved in declarative memory and executive functions. Patterns of atrophy and cognitive impairment in EOAD and LOAD were in accordance with previous reports. FC within the DMN was similarly decreased in both EOAD and LOAD relative to controls. However, a double‐dissociated pattern of FC changes in ATN and DLPFN was found. EOAD exhibited decreased FC in the DLPFN and increased FC in the ATN relative to controls, while the reverse pattern was found in LOAD. In addition, ATN and DLPFN connectivity correlated respectively with memory and executive performances, suggesting that increased FC is here likely to reflect compensatory mechanisms. Thus, large‐scale neural network changes in EOAD and LOAD endorse both common features and differences, probably related to a distinct distribution of pathological changes. Hum Brain Mapp 35:2978–2994, 2014. © 2013 Wiley Periodicals, Inc

Phospholipid fingerprints of milk from different mammalians determined by 31P NMR: towards specific interest in human health: Milk phospholipid fingerprints by 31P NMR

International audienceOur objective was to identify and quantify phospholipids in milk from different species (human HM, cow CoM, camel CaM, mare MM) using an optimised 31P NMR spectroscopy procedure. The phospholipid fingerprints were species-specific with a broader variety of classes found in HM and MM; HM and CaM were richer in sphingomyelin (78.3 and 117.5 µg/ml) and plasmalogens (27.3 and 24 µg/ml), possibly important for infant development. Total phospholipid content was higher in CaM (0.503 mM) and lower in MM (0.101 mM) compared to HM (0.324 mM) or CoM (0.265 mM). Our optimised method showed good sensitivity, high resolution, and easy sample preparation with minimal loss of target molecules. It is suitable for determining the accurate composition of a large number of bioactive phospholipids with putative health benefits, including plasmalogens, and should aid in selecting appropriate ingredient sources for infant milk substitutes or fortifiers, and for functional foods dedicated to adults

Brain magnetic resonance study of Mecp2 deletion effects on anatomy and metabolism

Following our previous reports based on parametric MRI methods (T(2)-weighted MRI, statistical mapping analysis of magnetization transfer ratio images and functional MRI) applied to a population of 18 patients with clinically isolated syndrome suggestive of multiple sclerosis, we have reviewed the possible structural and functional surrogates of MS that could explain the subtle cognitive impairment related to attention and working memory deficits evaluated with paced auditory serial addition test (PASAT). We propose that the brain substrates underlying cognitive impairment observed at the very early stage of MS are multifactorial. Several components could influence PASAT performances in patients: i) the extent of diffuse white matter damage, ii) the location of visible and non visible lesions, iii) the connectivity efficiency between distant brain functional areas involved in working memory processes and iv) the cortical reorganization. Nevertheless, individually, each of these parameters may have few influences on PASAT performance in patients. Using a multiregression model built with independent MR parameters, a very good evaluation of PASAT scores has been obtained in this limited number of patients explaining 90% of the variance. In conclusion, the different aspects of tissue and functional pathological brain underpinnings must be accounted to monitor accurately new therapeutic strategies for the treatment of early cognitive deficits related to MS

Spectroscopie de la maturation cérébrale et de ses anomalies

National audienceL'imagerie par résonance magnétique (IRM) est la technique de choix pour l'exploration de la maturation cérébrale et de ses anomalies. La spectroscopie par résonance magnétique (SRM) est une technique de résonance magnétique nucléaire non invasive et spatialement localisée qui permet d'accéder au métabolisme intracérébral. Elle prend une place importante en neuroradiologie clinique au cours d'un examen par IRM standard. Cependant, les indications restent limitées à un petit groupe de pathologies, principalement les tumeurs, la souffrance cérébrale diffuse en particulier en période néonatale, et les maladies innées du métabolisme cérébral. Dans cet article sont revus les principaux noyaux étudiés en SRM, les méthodes d'acquisition et de post-traitement des données, les principaux métabolites détectables en SRM du proton et leurs variations au cours de la maturation cérébrale, et les principales applications cliniques dans la population pédiatrique