High-resolution quantitative MRI of multiple sclerosis spinal cord lesions

PURPOSE: Validation of quantitative MR measures for myelin imaging in the postmortem multiple sclerosis spinal cord. METHODS: Four fixed spinal cord samples were imaged first with a 3T clinical MR scanner to identify areas of interest for scanning, and then with a 7T small bore scanner using a multicomponent‐driven equilibrium single‐pulse observation of T(1) and T(2) protocol to produce apparent proton density, T(1), T(2), myelin water, intracellular water, and free‐water fraction maps. After imaging, the cords were sectioned and stained with histological markers (hematoxylin and eosin, myelin basic protein, and neurofilament protein), which were quantitatively compared with the MR maps. RESULTS: Excellent correspondence was found between high‐resolution MR parameter maps and histology, particularly for apparent proton density MRI and myelin basic protein staining. CONCLUSION: High‐resolution quantitative MRI of the spinal cord provides biologically meaningful measures, and could be beneficial to diagnose and track multiple sclerosis lesions in the spinal cord

On the track of the brain's microstructure : myelin water imaging using quantitative MRI

Conventional quantitative magnetic resonance imaging (MRI), for example monoexponential determination of the relaxation times T1 and T2, is sensitive to the various pathologies of myelinated tissue in the brain. However, it gives relatively unspecific information about the underlying nature of the disease. A parameter that directly correlates with the integrity of the myelin sheath is the so-called myelin water fraction (MWF). Based on multi-component analysis of non-invasive quantitative MRI measurements, mapping of the MWF becomes feasible and proved to be useful for studying demyelination and remyelination processes in the course of multiple sclerosis (MS) and other myelin related pathologies. Common myelin water imaging techniques often suffer from a lack of volume coverage due to their 2D acquisition schemes. This thesis focuses on the development of new myelin water mapping procedures, especially on fast 3D MRI measurements that provide whole brain coverage. In chapter 2, an MWF mapping technique based on balanced steady-state free precession (bSSFP) sequences is introduced. An extended bSSFP signal equation, which is based on a two-pool water model describing brain tissue, is derived to determine typical multi-compartment parameters, including the MWF, of healthy subjects. Possible influences of magnetization transfer effects, infinite radiofrequency pulses and B0/B1 inhomogeneities are discussed extensively. Chapter 3 introduces a 3D acquisition scheme based on multi-gradient-echo (mGRE) pulse sequences that is applied for sampling multi-component T2* decays in the human brain of healthy volunteers and MS patients. Quantitative myelin water maps are generated based on analysis of T2* spectra. Chapter 4 discusses possible adaptations and modifications of the proposed procedure from chapter 3 when moving to higher main magnetic field strengths. The effects of B0 inhomogeneities on the data sets and possible correction methods are additionally covered in this part of the thesis. Finally, the crucial role of accurate B1 and B0 imaging and the influences on myelin water imaging are revisited in chapter 5. A solution to simultaneous mapping of B1 and B0 is presented that might help to overcome systematic error sources in MWF mapping in the future

High-resolution quantitative MRI of multiple sclerosis spinal cord lesions

Purpose: Validation of quantitative MR measuresfor myelin imaging in the postmortem multiple sclerosis spinal cord. Methods: Four fixed spinal cord samples were imaged first with a 3T clinical MR scannerto identify areas of interest forscanning, and then with a 7T small bore scanner using a multicomponent-driven equilibrium single-pulse observation of T1 and T2 protocol to produce apparent proton density, T1, T2, myelin water, intracellular water, and free-water fraction maps. After imaging, the cords were sectioned and stained with histological markers (hematoxylin and eosin, myelin basic protein, and neurofilament protein), which were quantitatively compared with the MR maps. Results: Excellent correspondence was found between high-resolution MR parameter maps and histology, particularly for apparent proton density MRI and myelin basic protein staining. Conclusion: High-resolution quantitative MRI of the spinal cord provides biologically meaningful measures, and could be beneficial to diagnose and track multiple sclerosis lesions in the spinal cord

Advances in noninvasive myelin imaging

Myelin is important for the normal development and healthy function of the nervous system. Recent developments in MRI acquisition and tissue modeling aim to provide a better characterization and more specific markers for myelin. This allows for specific monitoring of myelination longitudinally and noninvasively in the healthy brain as well as assessment of treatment and intervention efficacy. Here, we offer a nontechnical review of MRI techniques developed to specifically monitor myelin such as magnetization transfer (MT) and myelin water imaging (MWI). We further summarize recent studies that employ these methods to measure myelin in relation to development and aging, learning and experience, and neuropathology and psychiatric disorders

Comparing MRI metrics to quantify white matter microstructural damage in multiple sclerosis

Quantifying white matter damage in vivo is becoming increasingly important for investigating the effects of neuroprotective and repair strategies in multiple sclerosis (MS). While various approaches are available, the relationship between MRI-based metrics of white matter microstructure in the disease, that is, to what extent the metrics provide complementary versus redundant information, remains largely unexplored. We obtained four microstructural metrics from 123 MS patients: fractional anisotropy (FA), radial diffusivity (RD), myelin water fraction (MWF), and magnetisation transfer ratio (MTR). Coregistration of maps of these four indices allowed quantification of microstructural damage through voxel-wise damage scores relative to healthy tissue, as assessed in a group of 27 controls. We considered three white matter tissue-states, which were expected to vary in microstructural damage: normal appearing white matter (NAWM), T2-weighted hyperintense lesional tissue without T1-weighted hypointensity (T2L), and T1-weighted hypointense lesional tissue with corresponding T2-weighted hyperintensity (T1L). All MRI indices suggested significant damage in all three tissue-states, the greatest damage being in T1L. The correlations between indices ranged from r = 0.18 to r = 0.87. MWF was most sensitive when differentiating T2L from NAWM, while MTR was most sensitive when differentiating T1L from NAWM and from T2L. Combining the four metrics into one, through a principal component analysis, did not yield a measure more sensitive to damage than any single measure. Our findings suggest that the metrics are (at least partially) correlated with each other, but sensitive to the different aspects of pathology. Leveraging these differences could be beneficial in clinical trials testing the effects of therapeutic interventions

Magnetic resonance imaging of brain tissue abnormalities: transverse relaxation time in autism and Tourette syndrome and development of a novel whole-brain myelin mapping technique

The transverse relaxation time (T2) is a fundamental parameter of magnetic resonance imaging sensitive to tissue microstructure and water content, thus offering a non-invasive approach to evaluate abnormalities of brain tissue in-vivo. Prevailing hypotheses of two childhood psychiatric disorders were tested using quantitative T2 imaging and automated region of interest (ROI) analyses. In autism, the under-connectivity theory, which proposes aberrant connectivity within white matter (WM) was assessed, finding T2 to be eleveted in the frontal and parietal lobes, while dividing whole brain data into neurodevelopmentally relevant WM ROIs found increased T2 in bridging and radiate WM. In Tourette syndrome, tissue abnormalities of deep gray matter structures implicated in the symptomology of this disorder were evaluated and increased T2 of the caudate was found. Despite the sensitivity of quantitative T2 measurements to underlying pathophysiology, interpretation remain difficult. However, in WM, the compartmentalization of distinct water environments may lead to the detection of multi-exponential T2 decay. The metric of interest is principally the myelin water fraction (MWF), which is the proportion of the MRI signal arising from water trapped within layers of the myelin sheath. As a proof of concept study, the ability to measure the MWF based on T2* decay was evaluated and compared to a MWF measurements obtained from T2 decay. Data were analysed using both non-negative least squares and a two-pool model. Signal losses near sources of magnetic field inhomogeneity, such as the sinuses, rendered T2* components inseparable, invalidating this approach for whole brain MWF measurements. However, this study demonstrated the suitability of a two-pool model to calculate the MWF in WM. A novel approach, based on the multi-component gradient echo sampling of spin echoes (mcGESSE) and a two-pool model of WM, is proposed and its feasibility demonstrated using simulations. The in-vivo implementation of mcGESSE followed, with reproducibility of MWF measurements being assessed and the potential of an accelerated protocol using parallel imaging being investigated. While further work is needed to assess data quality, this approach shows great potential to obtain whole brain MWF data within a clinically relevant scan time

Myelination of the right parahippocampal cingulum is associated with physical activity in young healthy adults

Recent evidence suggests that individual differences in physical activity (PA) may be associated with individual differences in white matter microstructure and with grey matter volume of the hippocampus. Therefore, this study investigated the association between PA and white matter microstructure of pathways connecting to the hippocampus. A total of 33 young, healthy adults underwent magnetic resonance imaging (MRI). High angular resolution diffusion-weighted imaging and multi-component relaxometry MRI scans (multi-component driven equilibrium pulse observation of T1 and T2) were acquired for each participant. Activity levels (AL) of participants were calculated from 72-h actigraphy recordings. Tractography using the damped Richardson Lucy algorithm was used to reconstruct the fornix and bilateral parahippocampal cinguli (PHC). The mean fractional anisotropy (FA) and the myelin water fraction (MWF), a putative marker of myelination, were determined for each pathway. A positive correlation between both AL and FA and between AL and MWF were hypothesized for the three pathways. There was a selective positive correlation between AL and MWF in the right PHC (r = 0.482, p = 0.007). Thus, our results provide initial in vivo evidence for an association between myelination of the right PHC and PA in young healthy adults. Our results suggest that MWF may not only be more specific, but also more sensitive than FA to detect white matter microstructural alterations. If PA was to induce structural plasticity of the right PHC this may contribute to reverse structural alterations of the right PHC in neuropsychiatric disorder with hippocampal pathologies

Backward Walking: A Novel Marker Of Fall Risk, Cognitive Dysfunction, And Myelin Damage In Persons With Multiple Sclerosis

Multiple sclerosis (MS) is a progressive, neurologic disease of the central nervous system that causes debilitating motor, sensory and cognitive impairments. As a result, persons with MS are at an increased risk for falls and falls represent a serious public health concern for the MS population. The current clinical measures used to assess fall risk in MS patients lack sensitivity and predictive validity for falls and are limited in their ability to capture to multiple functional domains (i.e., motor, sensory, cognitive and pathological domains) that are impaired by MS. Backward walking sensitively detects falls in the elderly and other neurologic diseases. However, backward walking and falls has never been explored in the MS population and the underlying reasons as to why backward walking sensitively detects falls remains unknown. Identification of a quick, simply and clinically feasible fall risk measures related to multiple functions impacted by MS and related to fall risk, which can detect falls before they occur is critical for fall prevention and timely and targeted intervention. Therefore, this dissertation examines backward walking as a novel marker of fall risk and its cognitive and pathological underpinnings to support its clinical utility. Our results indicate that backward walking is a sensitive marker of fall risk in the MS population, regardless of co-morbid cognitive deficits, and that examining underlying brain regions likely to contribute to backward walking performance including the corticospinal tract, corpus callosum and cerebellum, with neuroimaging tools sensitive to myelin (i.e., Myelin Water Imaging) demonstrate potential to identify underlying mechanisms of backward walking performance in the MS population. This work is the critical first step in establishing backward walking as a sensitive marker of fall risk for the MS population and leads the way to more personalized fall prevention therapies and interventions to improve clinical outcomes and decrease fall rates in the MS population

Comparing MRI metrics to quantify white matter microstructural damage in multiple sclerosis

Quantifying white matter damage in vivo is becoming increasingly important for investigating the effects of neuroprotective and repair strategies in multiple sclerosis (MS). While various approaches are available, the relationship between MRI‐based metrics of white matter microstructure in the disease, that is, to what extent the metrics provide complementary versus redundant information, remains largely unexplored. We obtained four microstructural metrics from 123 MS patients: fractional anisotropy (FA), radial diffusivity (RD), myelin water fraction (MWF), and magnetisation transfer ratio (MTR). Coregistration of maps of these four indices allowed quantification of microstructural damage through voxel‐wise damage scores relative to healthy tissue, as assessed in a group of 27 controls. We considered three white matter tissue‐states, which were expected to vary in microstructural damage: normal appearing white matter (NAWM), T2‐weighted hyperintense lesional tissue without T1‐weighted hypointensity (T2L), and T1‐weighted hypointense lesional tissue with corresponding T2‐weighted hyperintensity (T1L). All MRI indices suggested significant damage in all three tissue‐states, the greatest damage being in T1L. The correlations between indices ranged from r = 0.18 to r = 0.87. MWF was most sensitive when differentiating T2L from NAWM, while MTR was most sensitive when differentiating T1L from NAWM and from T2L. Combining the four metrics into one, through a principal component analysis, did not yield a measure more sensitive to damage than any single measure. Our findings suggest that the metrics are (at least partially) correlated with each other, but sensitive to the different aspects of pathology. Leveraging these differences could be beneficial in clinical trials testing the effects of therapeutic interventions

IMAGING T1, T2 AND MYELIN WATER FRACTION IN THE POST-MORTEM MULTIPLE SCLEROSIS CENTRAL NERVOUS SYSTEM

PhDThe subject of this thesis is the use of Magnetic Resonance (MR) Imaging to quantify biometric MR indices in the Multiple Sclerosis (MS) fixed post-mortem central nervous system (CNS) tissue. Evaluating these indices in fixed tissue allows for the use of histology to verify the findings of MRI. However, it must first be discovered if the indices can be evaluated in fixed post-mortem spinal cord tissue. There is very little literature in this specific area, though some in the fixed brain, the results of which have been assumed to be equivalent in the spinal cord without proof. Therefore, the methodology must first be verified before the consideration of any index as useful and translatable to in-vivo spinal cord. This thesis concentrates on the evaluation of MR relaxometry methods using the indices T1 and T2 by themselves and to evaluate the myelin content of fixed post-mortem CNS tissue. The Carr-Purcell-Meiboom-Gill (CPMG) and Multicomponent Driven Equilibrium Single Pulse Observation of T1 & T2 (mcDESPOT) sequences are used to calculate T1, T2 and the Myelin Water Fraction (MWF) which is believed to be proportional to myelin content in the CNS. This is performed at 3T in a clinical scanner and at 7T in a small animal and wholebody scanner. The methods are first evaluated for use in fixed post-mortem CNS tissue. The two myelin measurement methods are then compared to histological staining if appropriate and where available to verify that the results obtained are proportional to myelin content. The T1 and T2 values in fixed tissue were found to be shortened in fixed tissue, T2 values were so short as to be at the limits of measurement by a clinical scanner, and values converged in white and grey matter, and therefore contrast was found to be limited between these tissues. Proton density images provided the most contrast between tissues. However, even with shortened T2 values, the CPMG sequence was able to identify the myelin water component in fixed tissue. The mcDESPOT algorithm struggled to separate the myelin water component due to clinical scanner limitations and the shortened, converging T1 and T2 values. However, the mcDESPOT algorithm was successful in discerning the myelin water component in the high signal situation of a small bore 7T peclinical scanner. An evaluation was then made of the usefulness of these indices for translation into clinical imaging. The CPMG sequence was found to be proportional to myelin content under all conditions, and therefore useful for disease monitoring in demyelinating diseases. The mcDESPOT sequence, was found to be proportional to myelin in some conditions, and is likely to be useful for monitoring myelination, though the sequence could not be fully validated in this thesis.Barts and the London Charit