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

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

Evaluation of Upper Motor Neuron Pathology in Amyotrophic Lateral Sclerosis by Mri;Towards Identifying Noninvasive Biomarkers of the Disease

Amyotrophic lateral sclerosis (ALS) is the commonest adult motor neuron disease (MND) which causes progressive muscle paralysis and death usually within 5 years of symptom onset. As a result, only ̃30,000 individuals in the United States are afflicted at any one time even though 5,000 or more individuals are diagnosed yearly. The diagnosis of ALS requires evidence of degeneration in upper motor neurons (UMNs) in the brain and in lower motor neurons (LMNs) that exit the brainstem and spinal cord to innervate skeletal muscles. Diagnosis can be incorrect or delayed when disease is early or atypical because non-invasive objective tests of UMN involvement do not exist, unlike electromyography to assess the LMN. Although magnetic resonance imaging (MRI) of brain and spinal cord is used primarily to identify conditions which mimic ALS, novel MRI sequences and post-processing techniques can identify macroscopic and even sub-macroscopic changes in ALS brain related to neuronoaxonal degeneration (e.g., in corticospinal motor tracts). MRI-based techniques like diffusion tensor imaging (DTI) and proton magnetic resonance spectroscopy (1H-MRS), as well as nuclear medicine modalities like positron emission tomography (PET) and single photon emission tomography (SPECT) are being used to study brains of patients with ALS. Many previous MRI studies of ALS brain are limited either in methodology or information obtained being primarily qualitative, i.e. changes visible to the naked eye (macroscopic). This study employed both routine and novel MRI sequences to objectively assess gray and white matter pathology of the brain in ALS patients, including T2 relaxometry, DTI, and voxel based morphometry (VBM) of 3D high resolution T1-weighted images. DTI metrics showed significant (p\u3c 0.05) changes in rostral extent of corticospinal tract (CST) in ALS patients with predominantly UMN symptoms and signs, and the ALS-dementia patients, whereas more caudal involvement was observed in ALS patients with classic findings of UMN and LMN

A novel multiparametric approach to 3D quantitative MRI of the brain

Magnetic Resonance properties of tissues can be quantified in several respects: relaxation processes, density of imaged nuclei, magnetism of environmental molecules, etc. In this paper, we propose a new comprehensive approach to obtain 3D high resolution quantitative maps of arbitrary body districts, mainly focusing on the brain. The theory presented makes it possible to map longitudinal (R1), pure transverse (R2) and free induction decay (R2 ) rates, along with proton density (PD) and magnetic susceptibility (χ), from a set of fast acquisition sequences in steady-state that are highly insensitive to flow phenomena. A novel denoising scheme is described and applied to the acquired datasets to enhance the signal to noise ratio of the derived maps and an information theory approach compensates for biases from radio frequency (RF) inhomogeneities, if no direct measure of the RF field is available. Finally, the results obtained on sample brain scans of healthy controls and multiple sclerosis patients are presented and discussed

Magnetic Resonance Imaging of Iron in Early Multiple Sclerosis at 3 Tesla

Multiple sclerosis (MS) is the most common neurological disease in young Canadians, yet its etiology remains obscure. Two possibly related findings in MS are brain iron deposition and the presence of small veins in white matter lesions. This thesis concerns the development and application of 3 Tesla magnetic resonance imaging tools to image iron and veins in early multiple sclerosis. To facilitate measurements of iron concentration as well as production of cerebral venograms, we first optimized multi-echo susceptibility weighted imaging (SWI), using numerical simulations and input from physicians. We validated measurements of R2*, an MRI parameter that scales linearly with iron concentration. Subsequently, we proposed quantification of the caliber of the internal jugular veins (IJVs) from magnetic resonance venograms. IJVs are implicated in the chronic cerebrospinal venous insufficiency model of MS, an increasingly disputed theory that attributes iron deposition in MS to venous abnormalities. We report that the coefficient of variation of measurements of average cross-sectional area of the IJVs is on the order of 7%. We performed quantitative investigations of iron concentration in a cohort of patients at risk of MS diagnosis, compared to healthy controls. We report increased R2* (putative iron) in deep as well as cortical grey matter in patients. We subsequently measured IJV area, finding a trend for reduced total IJV caliber in patients; however, we found no correlation between R2* changes and IJV area. We investigated the ability of multi-echo SWI to detect central veins within white matter hyperintensities (WMHs). We found that patients who converted from clinically isolated syndrome (CIS) to MS had a larger fraction of lesions with central veins compared to patients with non-converted CIS and healthy controls. Moreover, all patients who received a diagnosis of MS within the study window had \u3e40% lesions with central veins at their CIS baselines, suggesting there may be predictive value in this biomarker. The subjects from these last two studies represent a subset of our cohort in an ongoing longitudinal study. Using methodology described herein, we are equipped to further investigate different biomarkers of disease to better understand early pathology in MS

The UTE and ZTE Sequences at Ultra-High Magnetic Field Strengths: A Survey

UTE (Ultrashort Echo Time) and ZTE (Zero Echo Time) sequences have been developed to detect short T2 relaxation signals coming from regions that are unable to be detected by conventional MRI methods. Due to the high dipole-dipole interactions in solid and semi-solid tissues, the echo time generated is simply not enough to produce a signal using conventional imaging method, often leading to void signal coming from the discussed areas. By the application of these techniques, solid and semi-solid areas can be imaged which can have a profound impact in clinical imaging. High and Ultra-high field strength (UHF) provides a vital advantage in providing better sensitivity and specificity of MR imaging. When coupled with the UTE and ZTE sequences, the image can recover void signals as well as a much-improved signal quality. To further this strategy, secondary data from various research tools was obtained to further validate the research while addressing the drawbacks to this approach. It was found that UTE and ZTE sequences coupled with some techniques such as qualitative imaging and new trajectories are very crucial for accurate image depiction of the areas of the musculoskeletal system, neural system, lung imaging and dental imaging

Quantitative signal properties from standardized MRIs correlate with multiple sclerosis disability

OBJECTIVE: To enable use of clinical magnetic resonance images (MRIs) to quantify abnormalities in normal appearing (NA) white matter (WM) and gray matter (GM) in multiple sclerosis (MS) and to determine associations with MS-related disability. Identification of these abnormalities heretofore has required specialized scans not routinely available in clinical practice. METHODS: We developed an analytic technique which normalizes image intensities based on an intensity atlas for quantification of WM and GM abnormalities in standardized MRIs obtained with clinical sequences. Gaussian mixture modeling is applied to summarize image intensity distributions from T1-weighted and 3D-FLAIR (T2-weighted) images from 5010 participants enrolled in a multinational database of MS patients which collected imaging, neuroperformance and disability measures. RESULTS: Intensity distribution metrics distinguished MS patients from control participants based on normalized non-lesional signal differences. This analysis revealed non-lesional differences between relapsing MS versus progressive MS subtypes. Further, the correlation between our non-lesional measures and disability was approximately three times greater than that between total lesion volume and disability, measured using the patient derived disease steps. Multivariate modeling revealed that measures of extra-lesional tissue integrity and atrophy contribute uniquely, and approximately equally, to the prediction of MS-related disability. INTERPRETATION: These results support the notion that non-lesional abnormalities correlate more strongly with MS-related disability than lesion burden and provide new insight into the basis of abnormalities in NA WM. Non-lesional abnormalities distinguish relapsing from progressive MS but do not distinguish between progressive subtypes suggesting a common progressive pathophysiology. Image intensity parameters and existing biomarkers each independently correlate with MS-related disability

Qualitative and quantitative MR imaging in preterm infants: relation to neurodevelopmental outcome

Despite improved survival of extremely preterm infants within the last two decades, long term cognitive, motor and behavioural impairment remain a significant burden for preterm born children. Motor impairment includes cerebral palsy (CP) and minor motor dysfunction occurring in 5-10% and 40% of very preterm born children respectively. A meta-analysis showed that children born preterm might manifest moderate to severe deficits in academic achievement, attention problems, internalizing problems and poor executive functions. Recent neuroimaging studies have helped to understand the nature of brain injuries in preterm infants. Various brain lesions occur in preterm infants, most commonly white matter (WM) injury and accompanying neuronal/axonal deficits that involve the cerebral WM, thalamus, basal ganglia, cerebral cortex, brainstem and cerebellum. However, precise prediction of outcome with conventional MRI is to date lacking. Quantitative MR has been mainly used to show normal and abnormal brain development, however few studies have tried to correlate quantitative MR at term equivalent age with later neurodevelopmental outcome. A better understanding of the mechanisms leading to neurodevelopmental impairment in preterm born children is critical in order to develop and monitor neuroprotective strategies. The aim of this thesis was to evaluate whether quantitative MRI at term corrected age is more predictive than conventional MRI of neurodevelopmental outcome in preterm infants. 80 preterm infants born < 32 weeks were recruited from the neonatal intensive care unit. MRI data was acquired on a Siemens (Erlangen, Germany) Avanto 1.5T scanner using the Siemens CP extremity coil. T1 weighted 3D-FLASH, T2-weighted fast spin echo, T2 relaxometry and diffusion weighted images were acquired. The infants were assessed at one and two years of age with Bayley III. Correlation between clinical data, conventional and quantitative MR findings and neurodevelopmental outcome at one and two years was evaluated with the focus on how quantitative MR measures might provide more information on outcome compared to conventional MRI. WM and GM T2 values showed significant differences between preterm subgroups and between control and preterm infants with regional variation in preterm infants. T2 values correlated well with cognitive, motor and language outcome at two years of age, even after multiple corrections for clinical and MR variables. At two years of age, caudate ADC correlated significantly with language and expressive language outcome, and periventricular frontal WM ADC correlated significantly with receptive language outcome. Splenium FA correlated with cognitive, language and receptive communication outcome at two years of age. Cognitive outcome correlated with the presence of IVH, cerebellar haemorrhage, HPI and cPVL. Small CC and DEHSI were independent risk factors for expressive language and HPI, small CC and PWML were associated with motor outcome

Simultaneous T(2) and T(2)* mapping of multiple sclerosis lesions with radial RARE-EPI

PURPOSE: The characteristic MRI features of multiple sclerosis (MS) lesions make it conceptually appealing to pursue parametric mapping techniques that support simultaneous generation of quantitative maps of 2 or more MR contrast mechanisms. We present a modular rapid acquisition with relaxation enhancement (RARE)‐EPI hybrid that facilitates simultaneous T(2) and T(2)* mapping (2in1‐RARE‐EPI). METHODS: In 2in1‐RARE‐EPI the first echoes in the echo train are acquired with a RARE module, later echoes are acquired with an EPI module. To define the fraction of echoes covered by the RARE and EPI module, an error analysis of T(2) and T(2)* was conducted with Monte Carlo simulations. Radial k‐space (under)sampling was implemented for acceleration (R = 2). The feasibility of 2in1‐RARE‐EPI for simultaneous T(2) and T(2)* mapping was examined in a phantom study mimicking T(2) and T(2)* relaxation times of the brain. For validation, 2in1‐RARE‐EPI was benchmarked versus multi spin‐echo (MSE) and multi gradient‐echo (MGRE) techniques. The clinical applicability of 2in1‐RARE‐EPI was demonstrated in healthy subjects and MS patients. RESULTS: There was a good agreement between T(2)/T(2)* values derived from 2in1‐RARE‐EPI and T(2)/T(2)* reference values obtained from MSE and MGRE in both phantoms and healthy subjects. In patients, MS lesions in T(2) and T(2)* maps deduced from 2in1‐RARE‐EPI could be just as clearly delineated as in reference maps calculated from MSE/MGRE. CONCLUSION: This work demonstrates the feasibility of radially (under)sampled 2in1‐RARE‐EPI for simultaneous T(2) and T(2)* mapping in MS patients