Imaging Neurodegeneration and Repair in Multiple Sclerosis

Agenda

* Presentation times are subject to change.

Abstracts

Day 1: Friday, June 15, 2012

Session I: Imaging the Brain before Lesion Development

Monitoring Normal White Matter Development
Sean CL Deoni, PhD, Brown University, School of Engineering, Providence, Rhode Island

A growing number of neurological and psychiatric disorders are believed to have their genesis in early development. The first five years are a dynamic period of structural brain maturation and associated behavioral development. A primary structural change during this period is myelination, facilitating rapid and coordinated information transfer throughout the brain. This process is of particular interest given the hypothesized spatial and temporal associations with behavioral development. Abnormalities in, or disorders that affect, myelination (such as childhood MS), will likely result in profound functional and behavioral consequences. Unfortunately, direct investigation of myelination in-vivo has been challenging and, to-date, the normal myelination trajectory remains unknown.
 
In this talk, we will outline our recent efforts to model this developmental trajectory using data acquired of over 200 healthy children across the age spectrum from 3 months through 5 years of age. We will show normative developmental trajectories and relationships between myelination and cognitive development. We will also highlight the use of this dataset to understanding abnormal development, including hearing-impaired children and infants born premature.

Microstructural Imaging of the Brain
Jeff Duyn, PhD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Monitoring Immune Cell Infiltration
Erik M Shapiro, PhD, Yale University School of Medicine, New Haven, Connecticut

In stroke, significant brain damage is caused by immune cell infiltration. In multiple sclerosis, peripheral lymphocytes infiltrate the brain and destroy the myelin sheaths surrounding nerve fibers. For other diseases, such as Alzheimer's disease, ALS and Huntington's disease, the involvement of immune cells in disease progression is less understood. Imaging technologies which can monitor immune cell infiltration into the brain will make tremendous impact in both preclinical research and clinical utility. MRI-based cell tracking involves labeling specific cell types with magnetic particles, enabling sensitive and specific detection of the labeled cells. Critical requirements for translating these technologies to patients include the fabrication of an FDA approvable magnetic particle, efficient cell labeling schemes and robust quantification tools. Our work in these areas will be discussed.

Session II: The Multiple Sclerosis Lesion

What Can Imaging Animal Models Tell Us about the Pathogenesis of Multiple Sclerosis?
Istvan Pirko, MD, Mayo Clinic, Rochester, Minnesota

Animal models of MS have been utilized for decades to understand key features of MS pathogenesis, and as tools for preclinical development of new therapeutics. More recently, MS models have also been studied with high resolution in vivo and ex vivo MRI. The aim of these studies is either to decipher the pathogenesis of empirically known and clinically utilized MRI findings; or to characterize MRI detectable features of pathogenesis, or as outcome measures in preclinical trials; some are also performed to develop new MRI methodologies. Using 7 and 16.4 Tesla MRI studies, our team has demonstrated several known MRI features of MS in the Theiler's Murine Encephalitis Virus (TMEV) induced MS model, including brain, brainstem and spinal cord lesion formation; models with strong and other models with weak MRI lesion load – disability correlation; models demonstrating four temporal patterns of lesion formation; brain and spinal cord atrophy; deep gray matter T2 hypointensity; and models of severe hemorrhagic demyelination among others. We also utilize MRI and MRS in preclinical studies of upcoming remyelination and axonal preservation promoting treatment approaches. While the above models provide a unique opportunity to study certain features of MS, one must never forget that a model is never the human disease itself, and MS is also a very heterogeneous condition, therefore no single model (or even model family) will be able to capture the full spectrum of MS. Carefully conducted human disease-animal model correlational studies encompassing MRI and histopathology are the most likely to resolve the above paradox.

Imaging the Development of New Lesions
Daniel S. Reich, MD, PhD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Charcot, and several generations later Dawson, recognized very clearly that MS lesions in the white matter are intimately associated with small blood vessels, most commonly the deep and superficial medullary veins in white matter. Autopsy studies have demonstrated that blood vessels near the center of MS lesions are surrounded by inflammatory infiltrates, which form the so-called "perivascular cuff." Interestingly, inflamed vessels with perivascular cuffs have been described not only within lesions, but also in otherwise normal white matter – and even gray matter – near and distant from those lesions. In this talk, I will describe the imaging techniques we are using to visualize and describe small brain veins at 3 and 7 tesla; the characteristics of those veins, to the extent that we can observe them using MRI; and the spatiotemporal dynamics of contrast enhancement in and around new MS lesions. These observations lead to a new model of perivascular lesion formation and to specific predictions about the mechanisms of focal tissue damage in MS.

High-field MRI of Lesions in Multiple Sclerosis: Correlation with Pathology
Klaus Schmierer, PhD, FRCP, Blizard Institute, Barts and The London School of Medicine & Dentistry, London, United Kingdom

Although focal demyelination is the most obvious feature of multiple sclerosis (MS) pathology, the aetiology, pathogenesis, and clinical significance of such focal lesions for the course of the disease is not fully understood. A number of factors contribute to the difficulties in understanding this human disease, including (i) the histological heterogeneity of what appears as a ‘lesion' on standard T2 weighted (T2w) MRI, (ii) the re-discovery that MS lesions may affect any part of the central nervous system (CNS), not only the brain white matter, (iii) pathological changes in areas of the CNS that do not appear to be directly affected by demyelinating lesions, (iv) variably effective mechanisms of repair, and (v) the lack of a model that integrates these factors into a coherent framework of disease pathogenesis. High-field MRI (HF-MRI; 3 Tesla and beyond) is an important tool to better understand and monitor MS. This presentation will focus on the detection and quantitative assessment of lesions using HF-MRI, with an emphasis on results obtained using tissue of people who have died with MS. Lesions affecting the cortical and sub-cortical grey matter and the spinal cord will be discussed, as well as specific features of lesions and mechanisms underlying their evolution.

Session III: Imaging Multiple Sclerosis After and Around the Lesion

Imaging the Optic Nerve after Optic Neuritis
Robert T. Naismith, MD, Washington University, St. Louis, Missouri

The optic nerve has many advantages for the study of neuroprotection and neurodegeneration in multiple sclerosis (MS). Optic neuritis is common in this MS, and results in substantial disability. A clinical episode of optic neuritis has a clear and well-defined onset, occurs in a discreet tract, and impacts visual function in a well-studied manner. Paraclinical tests of visual-evoked potentials and optical coherence tomography provide additional information about axons and myelin. While quantitative imaging of the visual pathways can be challenging, clinical trials are now reporting results using several promising techniques. In addition, the optic nerve can be used to validate imaging methodologies that could then be applied to the brain and spinal cord. Finally, the visual pathways can provide information about trans-synaptic neurodegeneration and neural plasticity. This presentation will review imaging of the visual pathways by optic nerve T2-weighted sequences and gadolinium enhancement, atrophy, diffusion tensor imaging, magnetization transfer imaging, and functional MRI.

Imaging the Spinal Cord in Multiple Sclerosis and the Structural and Functional Correlates
Govind Nair, PhD, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Focal or diffuse lesions and atrophy of the spinal cord are observed in a majority of clinically definite MS patients, with an estimated 20% of patients presenting lesions in the cord alone. Furthermore, spinal cord abnormalities are thought to manifest in more significant clinical symptoms, highlighting the importance of its imaging for a more complete picture of the degree of CNS involvement in MS. However, comparatively small lesions with low signal- and contrast-to-noise ratios, and imaging artifacts associated with MRI of the spinal cord render detection of all cord lesions challenging.
 
Atrophy of the cord, measured as a decrease in cross sectional area, correlates with clinical measures of disability in MS. However, such correlations have not been observed with volume of focal lesions, possibly due to the failure to detect small lesions in routine scans. Recent advances in MRI technology such as higher field strengths and spine-array coils have helped in the development of more sensitive imaging techniques such as magnetization-transfer preparation, phase-sensitive reconstruction, magnetization-prepared rapid gradient echo (MPRAGE), and fluid attenuated inversion recovery (FLAIR) sequences that promise a more accurate quantification of lesion burden in the cord. Various diffusion tensor imaging studies have shown decrease in fractional anisotropy and increase in mean diffusivity of normal appearing cord in MS patients indicating axonal degeneration. Spectroscopic studies of the cord have shown reduced N-acetyl aspartate concentrations, which correlated with increased disability in MS. Functional MRI studies describe altered response to stimulus and abnormal connectivity in the cervical cord of MS. Other techniques such as arterial spin labeling has been developed for spinal cord, which may prove useful for better characterization of grey matter in the cord of MS patients.

Investigating the Downstream Effects of Lesions
Daniel Pelletier, MD, Yale University School of Medicine, New Haven, Connecticut

Previous studies suggest that thalamic degeneration is prominent in multiple sclerosis (MS) and even in pre-MS patients presenting with a clinically isolated syndrome (CIS). However, the relationships between white matter lesions and deep grey matter loss are not well understood. We analyzed the association between white matter lesions and the thalami in CIS patients to determine if connectivity is an important determinant. We studied CIS patients and normal controls with anatomical and diffusion tensor (DTI) MRI images. DTI fiber tracking was used to create probabilistic templates of the thalamocortical white matter and to define white matter connecting lesions and thalami. DTI metrics in the lesions and normal-appearing white matter (NAWM) regions were compared between CIS and controls, and correlated with thalamic volume changes estimated by voxel-based morphometry. There was 10 times higher density of lesions in thalamocortical compared to other brain white matter. Increased diffusivities and decreased fractional anisotropies were measured in the thalamocortical NAWM of CIS patients compared to controls. A step-wise regression analysis demonstrated that thalamocortical lesion volume and the mean diffusivity in track regions connecting lesion and thalami were significantly correlated with thalamic volumes in patients (Rsq=0.66, p<0.001), a finding not observed in regions outside the thalamocortical white matter. These results provide compelling evidence for a direct relationship between white matter lesions and thalamic atrophy in early MS.

Using Imaging to Understand the Relationship between Brain Atrophy, Pathology, and Disease Progression
Elizabeth Fisher, PhD, Cleveland Clinic Lerner Research Institute, Cleveland, Ohio

Brain atrophy is commonly measured in MS clinical trials and research studies to assess overall disease burden and progression. Atrophy begins early in the course of MS, correlates moderately with concurrent level of disability, and has some predictive value for future disability. As a marker of irreversible tissue loss, atrophy provides information on disease severity that is complementary to lesion measures. However, atrophy is pathologically non-specific, and changes in volumes reflect not only axonal loss and neurodegeneration, but also inflammation, demyelination, gliosis, and changes in hydration status. We and others are investigating the pathologic processes that contribute to brain atrophy through correlative studies with other MRI markers. T2 lesions consistently correlate with brain atrophy, but typically account for less than 30% of the variance. Interestingly, white matter lesions tend to be more strongly correlated to gray matter than to white matter atrophy. Correlations between T2 lesion volume and gray matter fraction support the hypothesis that gray matter atrophy is partly due to retrograde neurodegeneration secondary to focal tissue damage in the white matter, but the proportion of cortical tissue loss that stems from pathology in white matter versus that which arises from focal pathology in gray matter is unknown. Regional analyses performed to address this question have demonstrated associations between regional cortical atrophy and T2 lesions in the nearby white matter in some studies, but not all. Ongoing longitudinal studies and improved detection of cortical lesions should help to clarify the pathologic mechanisms underlying brain atrophy in MS.

Novel Metabolic Imaging Techniques for Investigating Changes in Brain Tissue in Multiple Sclerosis Patients
Matilde Inglese, MD, PhD, Mount Sinai School of Medicine, New York, New York

The advent of high and ultra-high field MRI has prompted the development of novel metabolic imaging techniques such as MR spectroscopy of brain metabolites with low concentrations, sodium and iron imaging. A significant reduction of Glutathione has been shown in the cortical gray matter and white matter lesions of patients with multiple sclerosis suggesting an impairment of the oxidative status. Recent studies have suggested that intra-axonal sodium accumulation contributes to axonal degeneration by reversing the action of the sodium/calcium exchanger and thus inducing a lethal rise in intra-axonal calcium. Sodium 23 yields the second strongest nuclear magnetic resonance signal among biologically relevant active nuclei. A preliminary study of patients with multiple sclerosis using a novel triple quantum filtered sodium MRI sequence at 7.0 Tesla has shown an increase of whole brain intracellular sodium concentration in patients when compared to healthy controls. Magnetic susceptibility-shifted compounds such as iron increase the local magnetic field shift gradients. This provides a contrast mechanism which is more pronounced at ultra-high field. Recent MRI development enabled high-resolution quantitative imaging of local magnetic field shifts in patients with multiple sclerosis. The phase images showed an increased local field in the basal ganglia of patients relative to control subjects and showed contrast in most white matter lesions, with distinct peripheral rings in the lesions of bigger size. This is consistent with the results of postmortem histological studies showing iron accumulation in both the deep gray matter and white matter plaques.

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