Quantitative Susceptibility Imaging of Tissue Microstructure Using Ultra-High Field MRI

This thesis has used ultra-high field (UHF) magnetic resonance imaging (MRI) to investigate the fundamental relationships between tissue microstructure and such susceptibility-based contrast parameters as the apparent transverse relaxation rate (R2*), the local Larmor frequency shift (LFS) and quantitative volume magnetic susceptibility (QS). The interaction of magnetic fields with biological tissues results in shifts in the LFS which can be used to distinguish underlying cellular architecture. The LFS is also linked to the relaxation properties of tissues in a gradient echo MRI sequence. Equally relevant, histological analysis has identified iron and myelin as two major sources of the LFS. As a result, computation of LFS and the associated volume magnetic susceptibility from MRI phase data may serve as a significant method for in vivo monitoring of changes in iron and myelin associated with normal, healthy aging, as well as neurological disease processes. In this research, the cellular level underpinnings of the R2* and LFS signals were examined in a model rat brain system using 9.4 T MRI. The study was carried out using biophysical modeling and correlation with quantitative histology. For the first time, multiple biophysical modeling schemes were compared in both gray and white matter of excised rat brain tissue. Suprisingly, R2* dependence on tissue orientation has not been fully understood. Accordingly, scaling relations were derived for calculating the reversible, mesoscopic magnetic field component, R2\u27, of the apparent transverse relaxation rate from the orientation dependence in gray and white matter. Our results demonstrate that the orientation dependence of R2* and LFS in both white and cortical gray matter has a sinusoidal dependence on tissue orientation and a linear dependence on the volume fraction of myelin in the tissue. A susceptibility processing pipeline was also developed and applied to the calculation of phase-combined LFS and QS maps. The processing pipeline was subsequently used to monitor myelin and iron changes in multiple sclerosis (MS) patients compared to healthy, age and gender-matched controls. With the use of QS and R2* mapping, evidence of statistically significant increases in iron deposition in sub-cortical gray matter, as well as myelin degeneration along the white matter skeleton, were identified in MS patients. The magnetic susceptibility-based MRI methods were then employed as potential clinical biomarkers for disease severity monitoring of MS. It was demonstrated that the combined use of R2* and QS, obtained from multi-echo gradient echo MRI, could serve as an improved metric for monitoring both gray and white matter changes in early MS

Regional grey matter microstructural changes and volume loss according to disease duration in multiple sclerosis patients

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER, "Otra manera de hacer Europa", "Investing in your future"); Red Española de Esclerosis Múltiple (REEM - RD16/0015/0002, RD16/0015/0003, RD12/0032/0002, RD12/0060/01-02); TEVA Spain; Fundación Merck Salud (Ayudas Merck de Investigación 2017); Proyecto Societat Catalana Neurologia 2017; CIBERNED program (Program 1, Alzheimer Disease and SIGNAL study); National Institutes of Health (NIA grants 1R01AG056850-01A1, R21AG056974, R01AG061566;, Fundació La Marató de TV3 (20142030, 20141210); Fundació Catalana Síndrome de Down; Fundació Víctor Grífols i Lucas; Generalitat de Catalunya (SLT006/17/00119); Universitat de Barcelona (APIF Pre-doctoral grant); Hospital Clinic Emili Letang).The spatio-temporal characteristics of grey matter (GM) impairment in multiple sclerosis (MS) are poorly understood. We used a new surface-based diffusion MRI processing tool to investigate regional modifications of microstructure, and we quantified volume loss in GM in a cohort of patients with MS classified into three groups according to disease duration. Additionally, we investigated the relationship between GM changes with disease severity. We studied 54 healthy controls and 247 MS patients classified regarding disease duration: MS1 (less than 5 years, n = 67); MS2 (5-15 years, n = 107); and MS3 (more than15 years, n = 73). We compared GM mean diffusivity (MD), fractional anisotropy (FA) and volume between groups, and estimated their clinical associations. Regional modifications in diffusion measures (MD and FA) and volume did not overlap early in the disease, and became widespread in later phases. We found higher MD in MS1 group, mainly in the temporal cortex, and volume reduction in deep GM and left precuneus. Additional MD changes were evident in cingulate and occipital cortices in the MS2 group, coupled to volume reductions in deep GM and parietal and frontal poles. Changes in MD and volume extended to more than 80% of regions in MS3 group. Conversely, increments in FA, with very low effect size, were observed in the parietal cortex and thalamus in MS1 and MS2 groups, and extended to the frontal lobe in the later group. MD and GM changes were associated with white matter lesion load and with physical and cognitive disability. Microstructural integrity loss and atrophy present differential spatial predominance early in MS and accrual over time, probably due to distinct pathogenic mechanisms that underlie tissue damage

Combining tractography and cortical measures to test system-specific hypotheses in multiple sclerosis

The objective was to test three motor system-specific hypotheses in multiple sclerosis patients: (i) corticospinal tract and primary motor cortex imaging measures differ between multiple sclerosis patients and controls; (ii) in patients, these measures correlate with disability; (iii) in patients, corticospinal tract measures correlate with measures of the ipsilateral primary motor cortex

Graph theoretical framework of brain networks in multiple sclerosis: a review of concepts

Network science provides powerful access to essential organizational principles of the human brain. It has been applied in combination with graph theory to characterize brain connectivity patterns. In multiple sclerosis (MS), analysis of the brain networks derived from either structural or functional imaging provides new insights into pathological processes within the gray and white matter. Beyond focal lesions and diffuse tissue damage, network connectivity patterns could be important for closely tracking and predicting the disease course. In this review, we describe concepts of graph theory, highlight novel issues of tissue reorganization in acute and chronic neuroinflammation and address pitfalls with regard to network analysis in MS patients. We further provide an outline of functional and structural connectivity patterns observed in MS, spanning from disconnection and disruption on one hand to adaptation and compensation on the other. Moreover, we link network changes and their relation to clinical disability based on the current literature. Finally, we discuss the perspective of network science in MS for future research and postulate its role in the clinical framework

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

Increased cortical curvature reflects white matter atrophy in individual patients with early multiple sclerosis

AbstractObjectiveWhite matter atrophy occurs independently of lesions in multiple sclerosis. In contrast to lesion detection, the quantitative assessment of white matter atrophy in individual patients has been regarded as a major challenge. We therefore tested the hypothesis that white matter atrophy (WMA) is present at the very beginning of multiple sclerosis (MS) and in virtually each individual patient. To find a new sensitive and robust marker for WMA we investigated the relationship between cortical surface area, white matter volume (WMV), and whole-brain-surface-averaged rectified cortical extrinsic curvature. Based on geometrical considerations we hypothesized that cortical curvature increases if WMV decreases and the cortical surface area remains constant.MethodsIn total, 95 participants were enrolled: 30 patients with early and advanced relapsing–remitting MS; 30 age-matched control subjects; 30 patients with Alzheimer's disease (AD) and 5 patients with clinically isolated syndrome (CIS).Results29/30 MS and 5/5 CIS patients showed lower WMV than expected from their intracranial volume (average reduction 13.0%, P<10−10), while the cortical surface area showed no significant differences compared with controls. The estimated WMV reductions were correlated with an increase in cortical curvature (R=0.62, P=0.000001). Discriminant analysis revealed that the curvature increase was highly specific for the MS and CIS groups (96.7% correct assignments between MS and control groups) and was significantly correlated with reduction of white matter fractional anisotropy, as determined by diffusion tensor imaging and the Expanded Disability Status Scale. As expected by the predominant gray and WM degeneration in AD, no systematic curvature increase was observed in AD.ConclusionWhole-brain-averaged cortical extrinsic curvature appears to be a specific and quantitative marker for a WMV–cortex disproportionality and allows us to assess “pure” WMA without being confounded by intracranial volume. WMA seems to be a characteristic symptom in early MS and can already occur in patients with CIS and should thus be considered in future MS research and clinical studies

Tract-specific white matter correlates of fatigue and cognitive impairment in benign multiple sclerosis

Background: Although benign multiple sclerosis (BMS) is traditionally defined by the presence of mild motor involvement decades after disease onset, symptoms of fatigue and cognitive impairment are very common. Objective: To investigate the association between micro-structural damage in the anterior thalamic (AT) tracts and in the corpus callosum (CC), as measured by diffusion tensor imaging (DTI) tractography, and fatigue and cognitive deficits. Methods: DTI data were acquired from 26 BMS patients and 24 sex- and age-matched healthy controls. Results: General and mental fatigue scores were significantly impaired in patients compared with controls (p≤0.05 for both) and 38% of patients resulted cognitively impaired. Mean diffusivity (MD) of the AT and CC tracts was significantly higher and fractional anisotropy (FA) was lower in patients compared with controls (p&lt;0.001 for all). Fatigue was associated with increased MD (p=0.01) of the AT tracts whereas deficit of executive functions and verbal learning were associated with decreased FA in the body (p=0.004) and genu (p=0.008) of the CC. Deficits in processing speed and attention were associated with the T2 lesion volume of the AT tracts (p&lt;0.01 for all). Discussion: These findings suggest that fatigue and cognitive impairment are quite frequent in BMS patients and are, at least in part, related to micro-structural damage and T2LV of WM tracts connecting the brain cortical and sub-cortical regions of the two hemispheres