Céline Louapre

Brain networks disconnection in early multiple sclerosis cognitive deficits: an anatomofunctional study.

Severe cognitive impairment involving multiple cognitive domains can occur early during the course of multiple sclerosis (MS). We investigated resting state functional connectivity changes in large‐scale brain networks and related structural damage underlying cognitive dysfunction in patients with early MS. Patients with relapsing MS (3–5 years disease duration) were prospectively assigned to two groups based on a standardized neuropsychological evaluation: (1) cognitively impaired group (CI group, n = 15), with abnormal performances in at least 3 tests; (2) cognitively preserved group (CP group, n = 20) with normal performances in all tests. Patients and age‐matched healthy controls underwent a multimodal 3T magnetic resonance imaging (MRI) including anatomical T1 and T2 images, diffusion imaging and resting state functional MRI. Structural MRI analysis revealed that CI patients had a higher white matter lesion load compared to CP and a more severe atrophy in gray matter regions highly connected to networks involved in cognition. Functional connectivity measured by integration was increased in CP patients versus controls in attentional networks (ATT), while integration was decreased in CI patients compared to CP both in the default mode network (DMN) and ATT. An anatomofunctional study within the DMN revealed that functional connectivity was mostly altered between the medial prefrontal cortex (MPFC) and the posterior cingulate cortex (PCC) in CI patients compared to CP and controls. In a multilinear regression model, functional correlation between MPFC and PCC was best predicted by PCC atrophy. Disconnection in the DMN and ATT networks may deprive the brain of compensatory mechanisms required to face widespread structural damage. Hum Brain Mapp 35:4706–4717, 2014.

The neuroinflammatory component of gray matter pathology in multiple sclerosis

In multiple sclerosis (MS), using simultaneous magnetic resonance–positron emission tomography (MR‐PET) imaging with 11C‐PBR28, we quantified expression of the 18kDa translocator protein (TSPO), a marker of activated microglia/macrophages, in cortex, cortical lesions, deep gray matter (GM), white matter (WM) lesions, and normal‐appearing WM (NAWM) to investigate the in vivo pathological and clinical relevance of neuroinflammation.

Immunological Hallmarks of JC Virus Replication in Multiple Sclerosis Patients on Long-Term Natalizumab Therapy

ABSTRACT Progressive multifocal leukoencephalopathy (PML) is the main adverse effect of natalizumab. Detectable JC virus-specific effector memory T-cell (TEM) responses may indicate ongoing JCV replication. We detected JCV-specific TEM responses in blood of patients with multiple sclerosis (MS) treated with natalizumab, including 2 patients with PML. The frequency of detection of these responses increased with the time on natalizumab. Thus, a subset of MS patients exhibit immunological hallmarks of JCV replication during prolonged natalizumab therapy.

Beyond focal cortical lesions in MS: An in vivo quantitative and spatial imaging study at 7T

Objectives: Using quantitative T2* 7-tesla (7T) MRI as a marker of demyelination and iron loss, we investigated, in patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), spatial and tissue intrinsic characteristics of cortical lesion(s) (CL) types, and structural integrity of perilesional normal-appearing cortical gray matter (NACGM) as a function of distance from lesions. Methods: Patients with MS (18 RRMS, 11 SPMS), showing at least 2 CL, underwent 7T T2* imaging to obtain (1) magnitude images for segmenting focal intracortical lesion(s) (ICL) and leukocortical lesion(s) (LCL), and (2) cortical T2* maps. Anatomical scans were collected at 3T for cortical surface reconstruction using FreeSurfer. Seventeen age-matched healthy participants served as controls. Results: ICL were predominantly located in sulci of frontal, parietal, and cingulate cortex; LCL distribution was more random. In MS, T2* was higher in both ICL and LCL, indicating myelin and iron loss, than in NACGM (p < 0.00003) irrespective of CL subtype and MS phenotype. T2* was increased in perilesional cortex, tapering away from CL toward NACGM, the wider changes being for LCL in SPMS. NACGM T2* was higher in SPMS relative to RRMS (p = 0.006) and healthy cortex (p = 0.02). Conclusions: CL had the same degree of demyelination and iron loss regardless of lesion subtype and disease stage. Cortical damage expanded beyond visible CL, close to lesions in RRMS, and more diffusely in SPMS. Evaluation of NACGM integrity, beyond focal CL, could represent a surrogate marker of MS progression.

Reproducibility of T2* mapping in the human cerebral cortex in vivo at 7 tesla MRI

To assess the test–retest reproducibility of cortical mapping of T2* relaxation rates at 7 Tesla (T) MRI. T2* maps have been used for studying cortical myelo‐architecture patterns in vivo and for characterizing conditions associated with changes in iron and/or myelin concentration.

Neurodegeneration in multiple sclerosis is a process separate from inflammation: Yes.

Multiple sclerosis (MS) is historically described as an immune-mediated inflammatory disease of the central nervous system (CNS) characterized by focal areas of demyelination in the white matter (WM). However, advances from neuropathological and imaging studies have highlighted early and sustained neurodegenerative mechanisms, including neuronal and neuritic (axon and dendrites) injury, correlating best with long-term clinical disability. It is still debated whether these two components, inflammation and neurodegeneration, are primary or secondary processes and how they interplay over the disease course. Despite evidence that loss of myelin in acute inflammatory WM lesions can locally induce axonal degeneration, several reports emphasize that neuronal and axonal loss also occurs outside areas of inflammation, suggesting, at least partly, independent processes.

In vivo characterization of cortical and white matter neuroaxonal pathology in early multiple sclerosis.

Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T1/T2-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ≤5 years) and 24 age-matched healthy controls underwent 7 T T2*-weighted imaging for cortical lesion segmentation and 3 T T1/T2-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions.

The association between intra- and juxta-cortical pathology and cognitive impairment in multiple sclerosis by quantitative T2* mapping at 7 T MRI

Using quantitative T2* at 7 Tesla (T) magnetic resonance imaging, we investigated whether impairment in selective cognitive functions in multiple sclerosis (MS) can be explained by pathology in specific areas and/or layers of the cortex. Thirty-one MS patients underwent neuropsychological evaluation, acquisition of 7 T multi-echo T2* gradient-echo sequences, and 3 T anatomical images for cortical surfaces reconstruction. Seventeen age-matched healthy subjects served as controls. Cortical T2* maps were sampled at various depths throughout the cortex and juxtacortex. Relation between T2*, neuropsychological scores and a cognitive index (CI), calculated from a principal component analysis on the whole battery, was tested by a general linear model. Cognitive impairment correlated with T2* increase, independently from white matter lesions and cortical thickness, in cortical areas highly relevant for cognition belonging to the default-mode network (p < 0.05 corrected). Dysfunction in different cognitive functions correlated with longer T2* in selective cortical regions, most of which showed longer T2* relative to controls. For most tests, this association was strongest in deeper cortical layers. Executive dysfunction, however, was mainly related with pathology in juxtameningeal cortex. T2* explained up to 20% of the variance of the CI, independently of conventional imaging metrics (adjusted-R2: 52–67%, p < 5.10− 4). Location of pathology across the cortical width and mantle showed selective correlation with impairment in differing cognitive domains. These findings may guide studies at lower field strength designed to develop surrogate markers of cognitive impairment in MS.

Is the Relationship between Cortical and White Matter Pathologic Changes in Multiple Sclerosis Spatially Specific? A Multimodal 7-T and 3-T MR Imaging Study with Surface and Tract-based Analysis

PURPOSE To investigate in vivo the spatial specificity of the interdependence between intracortical and white matter (WM) pathologic changes as function of cortical depth and distance from the cortex in multiple sclerosis (MS), and their independent contribution to physical and cognitive disability. MATERIALS AND METHODS This study was institutional review board-approved and participants gave written informed consent. In 34 MS patients and 17 age-matched control participants, 7-T quantitative T2* maps, 3-T T1-weighted anatomic images for cortical surface reconstruction, and 3-T diffusion tensor images (DTI) were obtained. Cortical quantitative T2* maps were sampled at 25%, 50%, 75% depth from pial surface. Tracts of interest were reconstructed by using probabilistic tractography. The relationship between DTI metrics voxelwise of the tracts and cortical integrity in the projection cortex was tested by using multilinear regression models. RESULTS In MS, DTI abnormal findings along tracts correlated with quantitative T2* changes (suggestive of iron and myelin loss) at each depth of the cortical projection area (P < .01, corrected). This association, however, was not spatially specific because abnormal findings in WM tracts also related to cortical pathologic changes outside of the projection cortex of the tract (P < .001). Expanded Disability Status Scale pyramidal score was predicted by axial diffusivity along the corticospinal tract (β = 4.6 × 10(3); P < .001), Symbol Digit Modalities Test score by radial diffusivity along the cingulum (β = -4.3 × 10(4); P < .01), and T2* in the cingulum cortical projection at 25% depth (β = -1.7; P < .05). CONCLUSION Intracortical and WM injury are concomitant pathologic processes in MS, which are not uniquely distributed according to a tract-cortex-specific pattern; their association may reflect a common stage-dependent mechanism.

Advanced imaging tools to investigate multiple sclerosis pathology.

Conventional MR imaging techniques still lack specificity for the underlying central nervous system tissue damage in multiple sclerosis (MS), impeding a comprehensive investigation of the key mechanisms responsible for neurological disability such as myelin damage and repair, neurodegeneration and neuroinflammation. A range of novel and advanced imaging tools, using quantitative magnetic resonance (MR) or positron emission tomography (PET) technologies are now emerging and open the perspective to obtain unique insights into the disease mechanisms. Both can be employed either in experimental models or in patients with MS, and they have already allowed to obtain imaging metrics that significantly correlate with clinical scores. In this review, we summarize the main evidence supporting the use of quantitative MR and PET as essential investigation tools to explore myelin changes, neuronal damage and compartmentalized inflammation in MS. The clinical translation of these imaging techniques has the potential to improve the design of future clinical trials and to allow the measurement of the effects of new drugs aimed at enhancing myelin repair and reducing neurodegeneration and neuroinflammation.