Quantitative magnetic resonance imaging towards clinical application in multiple sclerosis

Quantitative MRI provides biophysical measures of the microstructural integrity of the CNS, which can be compared across CNS regions, patients, and centres. In patients with multiple sclerosis, quantitative MRI techniques such as relaxometry, myelin imaging, magnetization transfer, diffusion MRI, quantitative susceptibility mapping, and perfusion MRI, complement conventional MRI techniques by providing insight into disease mechanisms. These include: (i) presence and extent of diffuse damage in CNS tissue outside lesions (normal-appearing tissue); (ii) heterogeneity of damage and repair in focal lesions; and (iii) specific damage to CNS tissue components. This review summarizes recent technical advances in quantitative MRI, existing pathological validation of quantitative MRI techniques, and emerging applications of quantitative MRI to patients with multiple sclerosis in both research and clinical settings. The current level of clinical maturity of each quantitative MRI technique, especially regarding its integration into clinical routine, is discussed. We aim to provide a better understanding of how quantitative MRI may help clinical practice by improving stratification of patients with multiple sclerosis, and assessment of disease progression, and evaluation of treatment response

Traumatic and nontraumatic spinal cord injury: pathological insights from neuroimaging

Pathophysiological changes in the spinal cord white and grey matter resulting from injury can be observed with MRI techniques. These techniques provide sensitive markers of macrostructural and microstructural tissue integrity, which correlate with histological findings. Spinal cord MRI findings in traumatic spinal cord injury (tSCI) and nontraumatic spinal cord injury — the most common form of which is degenerative cervical myelopathy (DCM) — have provided important insights into the pathophysiological processes taking place not just at the focal injury site but also rostral and caudal to the spinal injury. Although tSCI and DCM have different aetiologies, they show similar degrees of spinal cord pathology remote from the injury site, suggesting the involvement of similar secondary degenerative mechanisms. Advanced quantitative MRI protocols that are sensitive to spinal cord pathology have the potential to improve diagnosis and, more importantly, predict outcomes in patients with tSCI or nontraumatic spinal cord injury. This Review describes the insights into tSCI and DCM that have been revealed by neuroimaging and outlines current activities and future directions for the field

Investigation of pathophysiological mechanisms in clinically isolated syndrome using advanced imaging techniques

This thesis concerns an observational study of patients recruited after their first episode of neurological symptoms suggestive of demyelination in the central nervous system and diagnosed either with clinically isolated syndrome or relapsing-remitting multiple sclerosis. In multiple sclerosis, brain tissues can exhibit extensive neuroaxonal microstructural and metabolic abnormalities, but little is known about their presence and significance at the time of the first demyelinating episode. I used a novel multi-parametric quantitative MRI approach, combining neurite orientation dispersion and density imaging (NODDI), which gives information about tissue microstructure, and 23Na MRI, which estimates total sodium concentration, a marker of metabolic dysfunction, in the brains of clinically isolated syndrome patients. I found microstructural and sodium homeostasis alterations in cortical areas of patients that showed clinical relevance. Within the diffuse axonal dispersion found in the normal-appearing white matter, the corpus callosum shared with lesions, signs of axonal damage and metabolic dysfunction, thus emerging as a possible target for early neuroprotective interventions. Structural cortical networks (SCNs) represent patterns of coordinated morphological modifications in cortical areas and they have shown pathophysiological changes in many brain disorders, including multiple sclerosis. I investigated alterations of SCNs at the individual level in this early cohort. Patients showed altered small-world topology, an efficient network organization combining dense local clustering with relatively few long-distance connections. These disruptions were worse for patients with higher lesion load and worse cognitive processing speed indicating that pathophysiological changes in the cortical morphology can influence clinical outcomes. Finally, I hypothesised that the patients in the cohort presenting with optic neuritis may have disturbances in neuropsychological functions related to visual processes. I found that cognitive visuospatial processing is affected after unilateral optic neuritis and improves over time with visual recovery, independently of the structural damage in the visual and central nervous system

MRI quantification of multiple sclerosis pathology

Background: Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease and a common cause of neurologic disability. MS pathology is characterized by demyelination, neuroaxonal loss and atrophy. Magnetic Resonance Imaging (MRI) is an essential tool in diagnosing and monitoring MS, but its clinical value could be even further expanded by more advanced and quantitative MRI methods, which may also provide additional pathophysiological insights. Purpose: The overall aim of this thesis was to quantify MS pathology using volumetric brain MRI, ultra-high field brain and cervical spinal cord MRI as well as a newly developed rapid myelin imaging technique in relation to cognitive and physical MS disability. Study I, a prospective 17-year longitudinal study of 37 MS participants with 23 age/sex- matched healthy controls for comparison at the last follow-up. Longitudinal volumetric brain 1.5 Tesla MRI during the second half of the study showed that lesion accumulation and corpus callosum atrophy were the most strongly associated neuroanatomical correlates of cognitive disability, with the lesion fraction being an independent predictor of cognitive performance 8.5 years later. Study II, a prospective cross-sectional study of 35 MS participants and 11 age-matched healthy controls using 3 and 7 Tesla MRI. The study demonstrated involvement of both grey and white matter in MS, not only the brain but also the cervical spinal cord, associated with MS disability. Lesions appeared in proximity to the cerebrospinal fluid (CSF), with special predilection to the periventricular and grey matter surrounding the central canal in secondary progressive MS. Study III, a prospective in vivo (71 MS participants and 21 age/sex-matched healthy controls) and ex vivo (brain tissue from 3 MS donors) study at 3 Tesla, showed that a new clinically approved and feasible rapid myelin imaging technique correlates well with myelin stainings and produces robust in vivo myelin quantification that is related to both current and future cognitive and physical disability in MS. Study IV, an in-depth topographical analysis based on Study III, mapped the distribution of demyelination, both in vivo and ex vivo, in the periventricular and perilesional regions of the brain. A gradient of demyelination with predominance near the CSF spaces was seen. Measures of clinical disability were consistently and more strongly associated with the myelin content in normal-appearing tissue compared to the intralesional myelin content. Conclusions: Lesions and atrophy contribute to cognitive and physical disability in MS but to a varying degree, likely dependent on the relative involvement of white vs. grey matter. Both focal lesions/demyelination as well as diffuse demyelination in normal-appearing white matter shows an apparent gradient from the CSF, which differ between relapsing-remitting and progressive MS subtypes/phases. The growing utility and clinical availability of advanced and quantitative MRI techniques holds promise for improved monitoring of MS pathology and likely represents a vital tool for assessing the efficacy of potential remyelinating/reparative therapies in MS

Quantitative magnetic resonance imaging towards clinical application in multiple sclerosis

Imaging; Multiple sclerosis; Quantitative MRIImatges; Esclerosi múltiple; Ressonància magnètica quantitativaImágenes; Esclerosis múltiple; Resonancia magnética cuantitativaQuantitative MRI provides biophysical measures of the microstructural integrity of the CNS, which can be compared across CNS regions, patients, and centres. In patients with multiple sclerosis, quantitative MRI techniques such as relaxometry, myelin imaging, magnetization transfer, diffusion MRI, quantitative susceptibility mapping, and perfusion MRI, complement conventional MRI techniques by providing insight into disease mechanisms. These include: (i) presence and extent of diffuse damage in CNS tissue outside lesions (normal-appearing tissue); (ii) heterogeneity of damage and repair in focal lesions; and (iii) specific damage to CNS tissue components. This review summarizes recent technical advances in quantitative MRI, existing pathological validation of quantitative MRI techniques, and emerging applications of quantitative MRI to patients with multiple sclerosis in both research and clinical settings. The current level of clinical maturity of each quantitative MRI technique, especially regarding its integration into clinical routine, is discussed. We aim to provide a better understanding of how quantitative MRI may help clinical practice by improving stratification of patients with multiple sclerosis, and assessment of disease progression, and evaluation of treatment response.C.G. is supported by the Swiss National Science Foundation (SNSF) grant PP00P3_176984, the Stiftung zur Förderung der gastroenterologischen und allgemeinen klinischen Forschung and the EUROSTAR E! 113682 HORIZON2020. F.B. is supported by the National Institute for Health Research biomedical research center at University College London Hospitals. J.W. is supported by the EU Horizon2020 research and innovation grant (FORCE, 668039). D.S.R. is supported by the Intramural Research Program of National Institute of Neurological Disorders and Stroke, National Institutes of Health. A.T.T. is supported by an Medical Research Council grant (MR/S026088/1). S.R. is supported by the Austrian Science Foundation (FWF) grant I-3001. P.S. is supported by the Intramural Research Program of National Institute of Neurological Disorders and Stroke, National Institutes of Health. H.V. is supported by the Dutch multiple sclerosis Research Foundation, ZonMW and HealthHolland

HARDI-ZOOMit protocol improves specificity to microstructural changes in presymptomatic myelopathy

ABSTRACT: Diffusion magnetic resonance imaging (dMRI) proved promising in patients with non-myelopathic degenerative cervical cord compression (NMDCCC), i.e., without clinically manifested myelopathy. Aim of the study is to present a fast multi-shell HARDI-ZOOMit dMRI protocol and validate its usability to detect microstructural myelopathy in NMDCCC patients. In 7 young healthy volunteers, 13 age-comparable healthy controls, 18 patients with mild NMDCCC and 15 patients with severe NMDCCC, the protocol provided higher signal-to-noise ratio, enhanced visualization of white/gray matter structures in microstructural maps, improved dMRI metric reproducibility, preserved sensitivity (SE = 87.88%) and increased specificity (SP = 92.31%) of control-patient group differences when compared to DTI-RESOLVE protocol (SE = 87.88%, SP = 76.92%). Of the 56 tested microstructural parameters, HARDI-ZOOMit yielded significant patient-control differences in 19 parameters, whereas in DTI-RESOLVE data, differences were observed in 10 parameters, with mostly lower robustness. Novel marker the white-gray matter diffusivity gradient demonstrated the highest separation. HARDI-ZOOMit protocol detected larger number of crossing fibers (5–15% of voxels) with physiologically plausible orientations than DTI-RESOLVE protocol (0–8% of voxels). Crossings were detected in areas of dorsal horns and anterior white commissure. HARDI-ZOOMit protocol proved to be a sensitive and practical tool for clinical quantitative spinal cord imaging

Quantification de la microstructure de la moelle épinière humaine par IRM et application chez des patients avec sclérose en plaques

Les pathologies degeneratives de la moelle epiniere sont encore aujourd'hui mal diagnostiquees et laissent les patients dans un etat de souffrance et de doute. L'imagerie par resonance magnetique (IRM) permet d'obtenir des informations quantitatives sur la microstructure de la matiere blanche. Nous avons demontre la faisabilité d'estimer la densite et le diametre des axones dans la moelle epiniere humaine en utilisant une IRM unique au monde installee a Boston, le "scanner Connectom", capable d'atteindre des gradients de champ magnetique de r@@mT/m. Cependant cette methode ne donne qu'une information partielle de la microstructure de la matiere blanche et ne tient pas compte de la gaine de myeline entourant les axones. Cette gaine de myeline permet d'assurer une bonne conductivite des axones et peut degenerer dans certaines pathologies comme la sclerose en plaques. Nos collaborateurs de l'université McGill ont proposé de combiner cette technique avec l'IRM quantitative de la myeline afin de mesurer son g-ratio, ou ratio du diametre interne sur externe de la myeline. Durant cette these, j’ai mis en place les techniques d’IRM de la microstructure, j’ai valide ces methodes en utilisant l’histologie a large champ de vue, puis je les ai appliquees chez des patients avec sclerose en plaques pour une application clinique.----------ABSTRACT Degenerative pathologies of the spinal cord are still difficult to diagnose today, leaving patients in a state of constant suffering and constant doubt about their future. Magnetic Resonance Imaging (MRI) can gather quantitative information about the white matter microstructure by playing on the phase and relaxation of the spins. Using a unique MRI system capable of magnetic gradients of r@@mT/m, the “Connectom scanner”, we showed that neuronal fibers (axons) density and diameter can be measured in the human spinal cord in vivo using diffusion MRI. Although very informative, this method only provides a partial description of the tissue and no direct information about the myelin sheath that surrounds the axons is extracted. The myelin sheath improves the speed and frequency of action potentials that are transmitted through the axons, and an alteration of myelin integrity leads to paralysis in diseases such as multiple sclerosis. Our collaborators at McGill University proposed to combine the diffusion technique with quantitative myelin imaging technique in order to measure the thickness of the myelin sheath. In this thesis, I developed quantitative MRI techniques in the spinal cord, I validated these methods using large-scale histology, and I applied them on patients with multiple sclerosis

Recommendations and guidelines from the ISMRM Diffusion Study Group for preclinical diffusion MRI: Part 1 -- In vivo small-animal imaging

The value of in vivo preclinical diffusion MRI (dMRI) is substantial. Small-animal dMRI has been used for methodological development and validation, characterizing the biological basis of diffusion phenomena, and comparative anatomy. Many of the influential works in this field were first performed in small animals or ex vivo samples. The steps from animal setup and monitoring, to acquisition, analysis, and interpretation are complex, with many decisions that may ultimately affect what questions can be answered using the data. This work aims to serve as a reference, presenting selected recommendations and guidelines from the diffusion community, on best practices for preclinical dMRI of in vivo animals. In each section, we also highlight areas for which no guidelines exist (and why), and where future work should focus. We first describe the value that small animal imaging adds to the field of dMRI, followed by general considerations and foundational knowledge that must be considered when designing experiments. We briefly describe differences in animal species and disease models and discuss how they are appropriate for different studies. We then give guidelines for in vivo acquisition protocols, including decisions on hardware, animal preparation, imaging sequences and data processing, including pre-processing, model-fitting, and tractography. Finally, we provide an online resource which lists publicly available preclinical dMRI datasets and software packages, to promote responsible and reproducible research. An overarching goal herein is to enhance the rigor and reproducibility of small animal dMRI acquisitions and analyses, and thereby advance biomedical knowledge.Comment: 69 pages, 6 figures, 1 tabl

Quantitative MRI for measuring myelin content in human spinal cord

The aim of this thesis is to progress the state-of-the art of quantitative Magnetic Resonance Imaging (MRI) in the human spinal cord, with particular focus on methods sensitive to myelin content. Myelin is a fundamental structure of the central nervous system, ensuring the correct transmission of action potentials along neuronal axons, affected in a number of neurological disorders, first and foremost Multiple Sclerosis (MS). MRI methods to assess myelin in the spinal cord have found limited development, despite the primary involvement of the spinal cord in demyelinating diseases, such as MS where the characterization of spinal cord pathology is key for a better diagnosis, understanding of pathological processes, and evaluation of neuroprotective and reparative treatments. In this thesis, we develop novel methods for the spinal cord to measure parameters that are known to correlate with myelin content, namely the longitudinal relaxation time (T₁) and quantitative Magnetization Transfer (qMT) parameters, and we compare them with a large set of myelin sensitive MRI indices in the post mortem MS spinal cord. The thesis is structured as follows: chapter 1 states the problem this thesis attempts to address and provides background information regarding the involvement of the spinal cord in MS; chapter 2 reviews the basic principles of MRI and introduces the theory behind the measurement of surrogate indices of myelin content with MRI; chapter 3 reviews an existing imaging sequence for the spinal cord, extends its use for measuring myelin sensitive parameters and discusses potential improvements for in vivo applications; chapter 4 and chapter 5 propose novel efficient methods to measure T₁ and qMT parameters in vivo in the spinal cord; and chapter 6 evaluates the performance of the methods developed in the previous chapter, together with other prospective myelin mapping methods, in the healthy and MS post mortem human spinal cord

Developing new imaging biomarkers in multiple sclerosis

To date, there have been significant advances in the use of magnetic resonance imaging (MRI) in the initial diagnostic work-up of patients suspected of having MS and also in the monitoring of disease activity during active treatment. However, there is often a discrepancy between the clinical and conventional MRI findings which arises due to the complex heterogeneous features of MS pathology. The development of imaging biomarkers, which are directly linked to the pathological processes underlying progressive and relapsing forms of MS, are vital to developing a better understanding of the pathological mechanisms driving the disease. In order to address this, I performed clinical studies in both progressive and relapsing forms of MS with both innovative imaging techniques and with other more established imaging measures. After the introduction (where I review the main characteristics of MS (Chapter I) and of conventional and advanced MRI techniques employed in the studies presented in this thesis (Chapter II)), I present the following studies: (A)Pilot studies with innovative imaging techniques – this included a gammaaminobutyric acid (GABA) magnetic resonance spectroscopy study in patients with secondary progressive multiple sclerosis (SPMS) (Chapter III) and a novel diffusion study (neurite orientation dispersion and density imaging, NODDI) in the brain of patients with relapsing remitting multiple sclerosis (RRMS) (Chapter IV). The main results of these investigations are that GABA may be a marker of neurodegeneration and NODDI may better characterise microstructural changes in the brain than standard diffusion tensor imaging. (B) Clinical studies with more established imaging measures including an MRI follow-up spinal cord study in primary progressive multiple sclerosis (PPMS) (Chapter V) using 1H-Magnetic resonance spectroscopy (1HMRS), Q-space imaging (QSI) and spinal cord area. Another study looked at the development of spinal cord atrophy in a progressive MS cohort of patients over 1 year to determine the sample sizes required to demonstrate a reduction in spinal cord cross-sectional area as a primary outcome measure in clinical trials (Chapter VI). Both of these studies demonstrated spinal cord atrophy occurred over 1 year and it may be a useful outcome measure in phase II neuroprotective trials in early PPMS. In the final chapter (Chapter VII), I will summarise the results of the studies presented in the thesis and propose future directions for the research