B Cells in the CNS at Postmortem Are Associated With Worse Outcome and Cell Types in Multiple Sclerosis.

Background And Objectives: To define the clinical and pathologic correlations of compartmentalized perivascular B cells in postmortem progressive multiple sclerosis (MS) brains.

Methods: Brain slices were acquired from 11 people with secondary progressive (SP) MS, 5 people with primary progressive (PP) MS, and 4 controls. Brain slices were immunostained for B lymphocytes (CD20), T lymphocytes (CD3), cytotoxic T lymphocytes (CD8), neuronal neurofilaments (NF200), myelin (SMI94), macrophages/microglia (CD68 and IBA1), astrocytes (glial fibrillary acidic protein [GFAP]), and mitochondria (voltage-dependent anion channel and cytochrome c oxidase subunit 4).

Magnetisation transfer ratio combined with magnetic resonance neurography is feasible in the proximal lumbar plexus using healthy volunteers at 3T.

Magnetic resonance neurography (MRN) has been used extensively to study pathological conditions affecting the peripheral nervous system (PNS). However, tissue damage is assessed qualitatively with little information regarding the underlying pathophysiological processes involved. Magnetisation transfer ratio (MTR) is a quantitative magnetic resonance imaging method which is sensitive to tissue macromolecular content and may therefore have an important role in the study of pathologies affecting the PNS.

Bi-exponential Na T * component analysis in the human brain.

The purpose of this study was to measure the sodium transverse relaxation time T * in the healthy human brain. Five healthy subjects were scanned with 18 echo times (TEs) as short as 0.17 ms.

Is multiple sclerosis a length-dependent central axonopathy? The case for therapeutic lag and the asynchronous progressive MS hypotheses.

Trials of anti-inflammatory therapies in non-relapsing progressive multiple sclerosis (MS) have been stubbornly negative except recently for an anti-CD20 therapy in primary progressive MS and a S1P modulator siponimod in secondary progressive MS. We argue that this might be because trials have been too short and have focused on assessing neuronal pathways, with insufficient reserve capacity, as the core component of the primary outcome. Delayed neuroaxonal degeneration primed by prior inflammation is not expected to respond to disease-modifying therapies targeting MS-specific mechanisms.

Longitudinal multiple sclerosis lesion segmentation: Resource and challenge.

In conjunction with the ISBI 2015 conference, we organized a longitudinal lesion segmentation challenge providing training and test data to registered participants. The training data consisted of five subjects with a mean of 4.4 time-points, and test data of fourteen subjects with a mean of 4.

HLA-DRB*1501 associations with magnetic resonance imaging measures of grey matter pathology in multiple sclerosis.

Background: The HLA-DRB*1501 haplotype influences the risk of developing multiple sclerosis (MS), but it is not known how it affects grey matter pathology.

Aim: To assess HLA-DRB(*)1501 effects on magnetic resonance imaging (MRI) cortical grey matter pathology.

Methods: Whole and lesional cortical grey matter volumes, lesional and normal-appearing grey matter magnetization transfer ratio were measured in 85 people with MS and 36 healthy control subjects.

Motor network efficiency and disability in multiple sclerosis.

Objective: To develop a composite MRI-based measure of motor network integrity, and determine if it explains disability better than conventional MRI measures in patients with multiple sclerosis (MS).

Methods: Tract density imaging and constrained spherical deconvolution tractography were used to identify motor network connections in 22 controls. Fractional anisotropy (FA), magnetization transfer ratio (MTR), and normalized volume were computed in each tract in 71 people with relapse onset MS.

Reduced gamma-aminobutyric acid concentration is associated with physical disability in progressive multiple sclerosis.

Neurodegeneration is thought to be the major cause of ongoing, irreversible disability in progressive stages of multiple sclerosis. Gamma-aminobutyric acid is the principle inhibitory neurotransmitter in the brain. The aims of this study were to investigate if gamma-aminobutyric acid levels (i) are abnormal in patients with secondary progressive multiple sclerosis compared with healthy controls; and (ii) correlate with physical and cognitive performance in this patient population.

Grey and White Matter Magnetisation Transfer Ratio Measurements in the Lumbosacral Enlargement: A Pilot In Vivo Study at 3T.

Magnetisation transfer (MT) imaging of the central nervous system has provided further insight into the pathophysiology of neurological disease. However, the use of this method to study the lower spinal cord has been technically challenging, despite the important role of this region, not only for motor control of the lower limbs, but also for the neural control of lower urinary tract, sexual and bowel functions. In this study, the feasibility of obtaining reliable grey matter (GM) and white matter (WM) magnetisation transfer ratio (MTR) measurements within the lumbosacral enlargement (LSE) was investigated in ten healthy volunteers using a clinical 3T MRI system.

White matter compartment models for in vivo diffusion MRI at 300mT/m.

This paper compares a range of compartment models for diffusion MRI data on in vivo human acquisitions from a standard 60mT/m system (Philips 3T Achieva) and a unique 300mT/m system (Siemens Connectom). The key aim is to determine whether both systems support broadly the same models or whether the Connectom higher gradient system supports significantly more complex models. A single volunteer underwent 8h of acquisition on each system to provide uniquely wide and dense sampling of the available space of pulsed-gradient spin-echo (PGSE) measurements.

DIR-visible grey matter lesions and atrophy in multiple sclerosis: partners in crime?

Background: The extent and clinical relevance of grey matter (GM) pathology in multiple sclerosis (MS) are increasingly recognised. GM pathology may present as focal lesions, which can be visualised using double inversion recovery (DIR) MRI, or as diffuse pathology, which can manifest as atrophy. It is, however, unclear whether the diffuse atrophy centres on focal lesions.

Complex motor task associated with non-linear BOLD responses in cerebro-cortical areas and cerebellum.

Unlabelled: Previous studies have used fMRI to address the relationship between grip force (GF) applied to an object and BOLD response. However, whilst the majority of these studies showed a linear relationship between GF and neural activity in the contralateral M1 and ipsilateral cerebellum, animal studies have suggested the presence of non-linear components in the GF-neural activity relationship. Here, we present a methodology for assessing non-linearities in the BOLD response to different GF levels, within primary motor as well as sensory and cognitive areas and the cerebellum.

Evidence for early neurodegeneration in the cervical cord of patients with primary progressive multiple sclerosis.

Spinal neurodegeneration is an important determinant of disability progression in patients with primary progressive multiple sclerosis. Advanced imaging techniques, such as single-voxel (1)H-magnetic resonance spectroscopy and q-space imaging, have increased pathological specificity for neurodegeneration, but are challenging to implement in the spinal cord and have yet to be applied in early primary progressive multiple sclerosis. By combining these imaging techniques with new clinical measures, which reflect spinal cord pathology more closely than conventional clinical tests, we explored the potential for spinal magnetic resonance spectroscopy and q-space imaging to detect early spinal neurodegeneration that may be responsible for clinical disability.

Magnetization transfer ratio measures in normal-appearing white matter show periventricular gradient abnormalities in multiple sclerosis.

In multiple sclerosis, there is increasing evidence that demyelination, and neuronal damage occurs preferentially in cortical grey matter next to the outer surface of the brain. It has been suggested that this may be due to the effects of pathology outside the brain parenchyma, in particular meningeal inflammation or through cerebrospinal fluid mediated factors. White matter lesions are often located adjacent to the ventricles of the brain, suggesting the possibility of a similar outside-in pathogenesis, but an investigation of the relationship of periventricular normal-appearing white matter abnormalities with distance from the ventricles has not previously been undertaken.

Effects of delayed-release dimethyl fumarate on MRI measures in the phase 3 CONFIRM study.

Objective: To evaluate the effects of oral delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) on MRI lesion activity and load, atrophy, and magnetization transfer ratio (MTR) measures from the Comparator and an Oral Fumarate in Relapsing-Remitting Multiple Sclerosis (CONFIRM) study.

Methods: CONFIRM was a 2-year, placebo-controlled study of the efficacy and safety of DMF 240 mg twice (BID) or 3 times daily (TID) in 1,417 patients with relapsing-remitting multiple sclerosis (RRMS); subcutaneous glatiramer acetate 20 mg once daily was included as an active reference comparator. The number and volume of T2-hyperintense, T1-hypointense, and gadolinium-enhancing (Gd+) lesions, as well as whole brain volume and MTR, were assessed in 681 patients (MRI cohort).

Neurite orientation dispersion and density imaging of the healthy cervical spinal cord in vivo.

Here we present the application of neurite orientation dispersion and density imaging (NODDI) to the healthy spinal cord in vivo. NODDI provides maps such as the intra-neurite tissue volume fraction (vin), the orientation dispersion index (ODI) and the isotropic volume fraction (viso), and here we investigate their potential for spinal cord imaging. We scanned five healthy volunteers, four of whom twice, on a 3T MRI system with a ZOOM-EPI sequence.

Cervical cord lesion load is associated with disability independently from atrophy in MS.

Objective: To investigate whether spinal cord (SC) lesion load, when quantified on axial images with high in-plane resolution, is associated with disability in multiple sclerosis (MS).

Methods: Twenty-eight healthy controls and 92 people with MS had cervical SC 3T MRI with axial phase sensitive inversion recovery, T2, and magnetization transfer (MT) sequences. We outlined all visible focal lesions from C2 to C4 to obtain lesion load and also measured upper cervical cord area.

A modality-agnostic patch-based technique for lesion filling in multiple sclerosis.

Multiple Sclerosis lesions influence the process of image analysis, leading to tissue segmentation problems and biased morphometric estimates. With the aim of reducing this bias, existing techniques fill segmented lesions as normal appearing white matter. However, due to lesion segmentation errors or the presence of neighbouring structures, such as the ventricles and deep grey matter structures, filling all lesions as white matter like intensities is prone to introduce errors and artefacts.

Machine learning based compartment models with permeability for white matter microstructure imaging.

The residence time Ti of water inside axons is an important biomarker for white matter pathologies of the human central nervous system, as myelin damage is hypothesised to increase axonal permeability, and thus reduce Ti. Diffusion-weighted (DW) MRI is potentially able to measure Ti as it is sensitive to the average displacement of water molecules in tissue. However, previous work addressing this has been hampered by a lack of both sensitive data and accurate mathematical models.

In vivo estimation of dispersion anisotropy of neurites using diffusion MRI.

We present a technique for mapping dispersion anisotropy of neurites in the human brain in vivo. Neurites are the structural substrate of the brain that support its function. Measures of their morphology from histology provide the gold standard for diagnosing various brain disorders.

Age related changes in metabolite concentrations in the normal spinal cord.

Magnetic resonance spectroscopy (MRS) studies have previously described metabolite changes associated with aging of the healthy brain and provided insights into normal brain aging that can assist us in differentiating age-related changes from those associated with neurological disease. The present study investigates whether age-related changes in metabolite concentrations occur in the healthy cervical spinal cord. 25 healthy volunteers, aged 23-65 years, underwent conventional imaging and single-voxel MRS of the upper cervical cord using an optimised point resolved spectroscopy sequence on a 3T Achieva system.

Measuring brain atrophy with a generalized formulation of the boundary shift integral.

Brain atrophy measured using structural magnetic resonance imaging (MRI) has been widely used as an imaging biomarker for disease diagnosis and tracking of pathologic progression in neurodegenerative diseases. In this work, we present a generalized and extended formulation of the boundary shift integral (gBSI) using probabilistic segmentations to estimate anatomic changes between 2 time points. This method adaptively estimates a non-binary exclusive OR region of interest from probabilistic brain segmentations of the baseline and repeat scans to better localize and capture the brain atrophy.

Voxel-based cervical spinal cord mapping of diffusion abnormalities in MS-related myelitis.

Objective: To apply a novel postprocessing voxel-based analysis for diffusion tensor imaging of the cervical spinal cord in multiple sclerosis (MS) in a prospective cross-sectional study.

Methods: Fourteen patients with MS who were within 4 weeks of the onset of cervical myelitis (lesion C1-3) and 11 healthy controls underwent cervical spinal cord diffusion tensor imaging. Cervical spinal cord maps of fractional anisotropy (FA), mean diffusivity, radial diffusivity (RD), and axial diffusivity were registered and compared between patients and controls.

The use of the lumbosacral enlargement as an intrinsic imaging biomarker: feasibility of grey matter and white matter cross-sectional area measurements using MRI at 3T.

Histopathological studies have demonstrated the involvement of spinal cord grey matter (GM) and white matter (WM) in several diseases and recent research has suggested the use of magnetic resonance imaging (MRI) as a promising tool for in vivo assessment of the upper spinal cord. However, many neurological conditions would benefit from quantitative assessment of tissue integrity at different levels and relatively little work has been done, mainly due to technical challenges associated with imaging the lower spinal cord. In this study, the value of the lumbosacral enlargement (LSE) as an intrinsic imaging biomarker was determined by exploring the feasibility of obtaining within it reliable GM and WM cross-sectional area (CSA) measurements by means of a commercially available MRI system at 3 tesla (T).