Periventricular magnetisation transfer abnormalities in early multiple sclerosis

OBJECTIVE: Recent studies suggested that CSF-mediated factors contribute to periventricular (PV) T2-hyperintense lesion formation in multiple sclerosis (MS) and this in turn correlates with cortical damage. We thus investigated if such PV-changes are observable microstructurally in early-MS and if they correlate with cortical damage. METHODS: We assessed the magnetisation transfer ratio (MTR) in PV normal-appearing white matter (NAWM) and in MS lesions in 44 patients with a clinically isolated syndrome (CIS) suggestive of MS and 73 relapsing-remitting MS (RRMS) patients. Band-wise MTR values were related to cortical mean thickness (CMT) and compared with 49 healthy controls (HCs). For each band, MTR changes were assessed relative to the average MTR values of all HCs. RESULTS: Relative to HCs, PV-MTR was significantly reduced up to 2.63% in CIS and 5.37% in RRMS (p<0.0001). The MTR decreased towards the lateral ventricles with 0.18%/mm in CIS and 0.31%/mm in RRMS patients, relative to HCs. In RRMS, MTR-values adjacent to the ventricle and in PV-lesions correlated positively with CMT and negatively with EDSS. CONCLUSION: PV-MTR gradients are present from the earliest stage of MS, consistent with more pronounced microstructural WM-damage closer to the ventricles. The positive association between reduced CMT and lower MTR in PV-NAWM suggests a common pathophysiologic mechanism. Together, these findings indicate the potential use of multimodal MRI as refined marker for MS-related tissue changes

Quantitative magnetisation transfer imaging in relapsing-remitting multiple sclerosis: a systematic review and meta-analysis

Myelin-sensitive MRI such as magnetization transfer imaging has been widely used in multiple sclerosis. The influence of methodology and differences in disease subtype on imaging findings is, however, not well established. Here, we systematically review magnetization transfer brain imaging findings in relapsing-remitting multiple sclerosis. We examine how methodological differences, disease effects and their interaction influence magnetization transfer imaging measures. Articles published before 06/01/2021 were retrieved from online databases (PubMed, EMBASE and Web of Science) with search terms including ‘magnetization transfer’ and ‘brain’ for systematic review, according to a pre-defined protocol. Only studies that used human in vivo quantitative magnetization transfer imaging in adults with relapsing-remitting multiple sclerosis (with or without healthy controls) were included. Additional data from relapsing-remitting multiple sclerosis subjects acquired in other studies comprising mixed disease subtypes were included in meta-analyses. Data including sample size, MRI acquisition protocol parameters, treatments and clinical findings were extracted and qualitatively synthesized. Where possible, effect sizes were calculated for meta-analyses to determine magnetization transfer (i) differences between patients and healthy controls; (ii) longitudinal change and (iii) relationships with clinical disability in relapsing-remitting multiple sclerosis. Eighty-six studies met inclusion criteria. MRI acquisition parameters varied widely, and were also underreported. The majority of studies examined the magnetization transfer ratio in white matter, but magnetization transfer metrics, brain regions examined and results were heterogeneous. The analysis demonstrated a risk of bias due to selective reporting and small sample sizes. The pooled random-effects meta-analysis across all brain compartments revealed magnetization transfer ratio was 1.17 per cent units (95% CI −1.42 to −0.91) lower in relapsing-remitting multiple sclerosis than healthy controls (z-value: −8.99, P < 0.001, 46 studies). Linear mixed-model analysis did not show a significant longitudinal change in magnetization transfer ratio across all brain regions [β = 0.12 (−0.56 to 0.80), t-value = 0.35, P = 0.724, 14 studies] or normal-appearing white matter alone [β = 0.037 (−0.14 to 0.22), t-value = 0.41, P = 0.68, eight studies]. There was a significant negative association between the magnetization transfer ratio and clinical disability, as assessed by the Expanded Disability Status Scale [r = −0.32 (95% CI −0.46 to −0.17); z-value = −4.33, P < 0.001, 13 studies]. Evidence suggests that magnetization transfer imaging metrics are sensitive to pathological brain changes in relapsing-remitting multiple sclerosis, although effect sizes were small in comparison to inter-study variability. Recommendations include: better harmonized magnetization transfer acquisition protocols with detailed methodological reporting standards; larger, well-phenotyped cohorts, including healthy controls; and, further exploration of techniques such as magnetization transfer saturation or inhomogeneous magnetization transfer ratio

Continuous reorganization of cortical information flow in multiple sclerosis : a longitudinal fMRI effective connectivity study

Effective connectivity (EC) is able to explore causal effects between brain areas and can depict mechanisms that underlie repair and adaptation in chronic brain diseases. Thus, the application of EC techniques in multiple sclerosis (MS) has the potential to determine directionality of neuronal interactions and may provide an imaging biomarker for disease progression. Here, serial longitudinal structural and resting-state fMRI was performed at 12-week intervals over one year in twelve MS patients. Twelve healthy subjects served as controls (HC). Two approaches for EC quantification were used: Causal Bayesian Network (CBN) and Time-resolved Partial Directed Coherence (TPDC). The EC strength was correlated with the Expanded Disability Status Scale (EDSS) and Fatigue Scale for Motor and Cognitive functions (FSMC). Our findings demonstrated a longitudinal increase in EC between specific brain regions, detected in both the CBN and TPDC analysis in MS patients. In particular, EC from the deep grey matter, frontal, prefrontal and temporal regions showed a continuous increase over the study period. No longitudinal changes in EC were attested in HC during the study. Furthermore, we observed an association between clinical performance and EC strength. In particular, the EC increase in fronto-cerebellar connections showed an inverse correlation with the EDSS and FSMC. Our data depict continuous functional reorganization between specific brain regions indicated by increasing EC over time in MS, which is not detectable in HC. In particular, fronto-cerebellar connections, which were closely related to clinical performance, may provide a marker of brain plasticity and functional reserve in MS

From micro‐ to macro‐structures in multiple sclerosis: what is the added value of diffusion imaging

Diffusion imaging has been instrumental in understanding damage to the central nervous system as a result of its sensitivity to microstructural changes. Clinical applications of diffusion imaging have grown exponentially over the past couple of decades in many neurological and neurodegenerative diseases, such as multiple sclerosis (MS). For several reasons, MS has been extensively researched using advanced neuroimaging techniques, which makes it an ‘example disease’ to illustrate the potential of diffusion imaging for clinical applications. In addition, MS pathology is characterized by several key processes competing with each other, such as inflammation, demyelination, remyelination, gliosis and axonal loss, enabling the specificity of diffusion to be challenged. In this review, we describe how diffusion imaging can be exploited to investigate micro‐, meso‐ and macro‐scale properties of the brain structure and discuss how they are affected by different pathological substrates. Conclusions from the literature are that larger studies are needed to confirm the exciting results from initial investigations before current trends in diffusion imaging can be translated to the neurology clinic. Also, for a comprehensive understanding of pathological processes, it is essential to take a multiple‐level approach, in which information at the micro‐, meso‐ and macroscopic scales is fully integrated

Grey matter pathology in multiple sclerosis: in vivo and post mortem magnetic resonance imaging studies

The extent and clinical relevance of grey matter (GM) pathology in multiple sclerosis (MS) is increasingly recognised. Previous work has shown that GM pathology is more closely associated with some aspects of clinical disability than white matter (WM) injury, which has been suggested to arise independently. Magnetic resonance imaging (MRI) allows the study of GM lesions, atrophy, and non-lesional injury with techniques including double inversion recovery (DIR), volumetric scans, and magnetisation transfer ratio (MTR), respectively. This thesis includes three independent in vivo and post mortem MRI studies specifically addressing (1) the clinical impact and spatial distribution of DIR-detected GM lesions and atrophy, (2) the longitudinal development of MTR changes in thalamo-cortical systems, and (3) the histopathological substrates underlying MTR in the MS brain. This work shows that (1) DIR-detected GM lesions are mainly found throughout the cerebellar and cerebral cortex, whereas particularly subcortical GM structures show atrophy. Both GM lesions and atrophy contribute to disability, suggesting that the substrates of disability in MS are both pathologically and spatially heterogeneous. (2) WM injury to thalamo-cortical systems is most likely to precede (both thalamic and cortical) GM damage. In addition, lower regional cortical MTR is found not to be consistently associated with lower cortical volume, suggesting that significant cortical microstructural damage can occur in the absence of atrophy. Furthermore, observed hemispheric asymmetries and WM tract inhomogeneities emphasise the need for more refined statistical models to detect disease-specific changes. (3) MTR is associated with histologically quantified myelin (and to a lesser extent neuronal content) in normal appearing grey matter and normal appearing white matter, but not in cortical lesions and chronic inactive WM lesions. Finally, the cytological make-up differs significantly between normal appearing and lesional WM and GM, and provides extra evidence for microglia-mediated mitochondria damage in normal appearing MS tissue

Imaging Iron Content In Patients With Multiple Sclerosis Using Magnetic Resonance Imaging

The importance of iron in maintaining normal physiological processes in the human body has been well emphasized in the literature. However, when iron behaves badly , its abnormal presence might lead to a spectrum of pathologies depending on what function has been altered. In the brain, for instance, abnormal iron content is thought to be associated with neurodegenerative diseases. In this dissertation, we study iron involvement in one of the most debilitating neurological diseases, multiple sclerosis (MS), using in vivo magnetic resonance imaging. We first test the sensitivity and specificity of the MR method used, known as susceptibility weighted imaging (SWI) compared to other conventional MR techniques and rapid-scanning X-ray fluorescence in MS cadaver brains. Then, we use SWI phase images to assess iron content in the deep gray matter structures of MS patients compared to normal controls. Finally, we assess the possibility of developing a new MS vascular animal model to study the link between vascular abnormalities, iron deposition and sclerotic lesions. As a result of this work, we show that SWI provides a better contrast to image the structures and substructures of the brain based on their iron content compared to conventional MR techniques. The power of SWI in imaging iron content was validated by the use of X-Ray fluorescence (which is known to be an element specific imaging method), showing similar contrast and making SWI the method of choice to image iron content in vivo. Using SWI, we show a clear separation between MS patients and normal subjects, when we assessed iron content in the midbrain, thalamus and basal ganglia. We report that out of the seven structures studied, two were more susceptible to abnormal iron deposition (the pulvinar thalamus in young adults, and the red nucleus in elderly people). Finally, in an MR based study, we show that the swine and the human share a similar cerebrovascular drainage system starting from the superficial cerebral veins and deep cervical veins all the way to the heart, as a means to test the vascular involvement in MS

Diseases of the Brain, Head and Neck, Spine 2020–2023

This open access book offers an essential overview of brain, head and neck, and spine imaging. Over the last few years, there have been considerable advances in this area, driven by both clinical and technological developments. Written by leading international experts and teachers, the chapters are disease-oriented and cover all relevant imaging modalities, with a focus on magnetic resonance imaging and computed tomography. The book also includes a synopsis of pediatric imaging. IDKD books are rewritten (not merely updated) every four years, which means they offer a comprehensive review of the state-of-the-art in imaging. The book is clearly structured and features learning objectives, abstracts, subheadings, tables and take-home points, supported by design elements to help readers navigate the text. It will particularly appeal to general radiologists, radiology residents, and interventional radiologists who want to update their diagnostic expertise, as well as clinicians from other specialties who are interested in imaging for their patient care

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

Advanced MRI methods for probing disease severity and functional decline in multiple sclerosis

Multiple sclerosis (MS) is a chronic and severe disease of the central nervous system characterized by complex pathology including inflammatory demyelination and neurodegeneration. MS impacts >2.8 million people worldwide, with most starting with a relapsing-remitting form (RRMS) in young adulthood, and many of them worsening to a secondary-progressive course (SPMS) despite treatment. So, there is a clear need for improved disease characterization. MRI is an ideal tool for non-invasive assessment of MS pathology, but there is still no established measure of disease activity and functional consequences. This project aims to overcome the challenge by developing novel imaging measures based on brain diffusion MRI and phase congruency texture analysis of conventional MRI. Through advanced modeling and analysis of clinically feasible brain MRI, this thesis investigates whether and how the derived measures differentiate MS pathology types and disease severity and predict functional outcomes in MS. The overall process has led to important technical innovations in several aspects. These include: innovative modeling of simple diffusion acquisitions to generate high angular resolution diffusion imaging (HARDI) measures; new optimization and harmonization techniques for diffusion MRI; innovative neural network models to create new diffusion data for comprehensive HARDI modeling; and novel methods and a graphic user interface for optimizing phase congruency analyses. Assisted by different machine learning methods, collective findings show that advanced measures from both diffusion MRI and phase congruency are highly sensitive to subtle differences in MS pathology, which differentiate disease severity between RRMS and SPMS through multi-dimensional analyses including chronic active lesions, and predict functional outcomes especially in physical and neurocognitive domains. These results are clinically translational and the new measures and techniques can help improve the evaluation and management of both MS and similar diseases