Utilisation of novel magnetic resonance imaging features in the diagnosis and understanding of multiple sclerosis

There is no single test clinically available that is independently diagnostic for multiple sclerosis (MS). Currently MS is diagnosed using a combination of clinical evaluation and investigations including magnetic resonance imaging (MRI), interpreted in accordance with diagnostic criteria, to demonstrate the requisite dissemination of lesions in (anatomical) space and time. Lesions comprising inflammatory demyelination in the central nervous system are a core pathological feature of MS. Ultra-high field (e.g. 7 Tesla or 7T) T2*-weighted MRI can demonstrate in vivo a central vein in most of these lesions. This is a histopathologically specific feature which could be exploited to improve diagnostic workup in cases of suspected inflammatory demyelination. Central nervous system white matter not involved in demyelinating lesions is nevertheless affected in MS. The mechanisms inflicting injury to this normal appearing white matter (NAWM) and how they relate to focal lesions are unclear. Damage to NAWM seems important, because it correlates well with disability. Any association between cortical lesions, focal white matter lesions (WML) and diffuse damage to NAWM is difficult to investigate in vivo in MS, principally because MRI is relatively insensitive to cortical lesions. Investigation of such associations may also be confounded by the presence of small focal lesions within the “NAWM” that may remain undetected when using conventional MRI to define NAWM. Advantages inherent to ultra-high field MRI might help mitigate both of these problems

The investigation of early MRI in diagnosis and prognosis in patients presenting with a clinically isolated syndrome characteristic of demyelination

This thesis explores the use of early MRI in prognosis and diagnosis in patients presenting with a clinically isolated syndrome (CIS) characteristic of demyelination. This has been investigated in a cohort recruited within 3 months of CIS onset between 1995 and 2004 and followed up clinically and with MRI (planned at 3 months, 1,3 and 5 years). Current MRI criteria are highly specific for the development of clinically definite multiple sclerosis (CDMS) but have limited sensitivity and are complex. Presented is the evaluation of simplified MRI criteria in my London CIS cohort and in a multicentre CIS cohort. Results from the presented studies show that the MRI criteria can be simplified (dissemination in space: 2 or more lesions in separate but characteristic locations, dissemination in time: an early new T2 lesion) and still maintain high specificity, with improved sensitivity and accuracy. The prognostic role of early MRI was investigated in the optic neuritis (ON) subgroup, as 80% of my cohort presented with ON and some studies have suggested that such a presentation is associated with more benign disease. Whereas baseline lesion number significantly predicted conversion to CDMS and increased disability at 5 years, other MRI parameters, namely baseline lesion location (periventricular lesions increasing the hazard of CDMS and spinal cord and infratentorial lesions increasing the odds of greater disability at 5 years) and lesion activity (new T2 lesion at 3 month follow-up), were stronger predictors. No non-conventional MRI parameters (spectroscopy, magnetisation transfer ratio or atrophy measures) had a significant prognostic role. Overall early MRI findings can aid diagnosis and help identify the CIS patients at greatest risk of conversion to CDMS and subsequent disability, which in turn can help direct treatment and clinical follow-up in specialist MS clinics

Cortical imaging as seen at ultrahigh field MRI

Multiple Sclerosis (MS) has long been considered as White matter (WM) disease. The last decade, the significance of cortical lesions (CL) and their contribution to MS pathology has been intensely investigated. They have been shown to play a major role in physical and cognitive impairment in MS patients. CL detection has proven to be challenging, mainly due to poor contrast between cortical lesion and surrounding normal grey matter (GM) tissue. Various magnetic resonance imaging (MRI) sequences have been used to improve cortical lesion detection in MS patients. In recent years, Double inversion recovery (DIR), Phase sensitive inversion recovery (PSIR) and 7 Tesla T2* have been found to improve CL detection. Magnetization Transfer Imaging (MTI) has the advantage over conventional imaging as it reflects tissue myelin content. In this thesis, I present our studies using MTI at 7 Tesla to study cortical pathology in MS. 1) For a pilot study aiming to validate the use of magnetization transfer ratio (MTR) to detect cortical lesions, We examined the sensitivity of MTR to detect cortical lesions in comparison with 3 T DIR, 7 T PSIR, and 7 T T2* in 18 MS patients and 9 healthy controls. 2) A further 42 patients (11 clinically isolated syndrome (CIS), 11 relapsing remitting MS (RRMS), 10 primary progressive MS (PPMS), and 10 secondary progressive MS (SPMS)) and 8 healthy controls were scanned at baseline, 23 of these patients had a follow up scan at 12 months. MTR at 7 Tesla has increased sensitivity to detect cortical lesions compared to 3T DIR, 7T PSIR and 7T T2*. CL myelin content as measured by the mean MTR lesional values were the lowest in SPMS patients in comparison with the rest of MS phenotypes. CL mean MTR values, more than volume was associated with the degree of physical and cognitive disability in MS patients. When MTR was studied in a longitudinal study, we have seen more changes in average MTR of cortical lesions in SPMS and CIS patients compared to RRMS and PPMS patients

Cortical imaging as seen at ultrahigh field MRI

Multiple Sclerosis (MS) has long been considered as White matter (WM) disease. The last decade, the significance of cortical lesions (CL) and their contribution to MS pathology has been intensely investigated. They have been shown to play a major role in physical and cognitive impairment in MS patients. CL detection has proven to be challenging, mainly due to poor contrast between cortical lesion and surrounding normal grey matter (GM) tissue. Various magnetic resonance imaging (MRI) sequences have been used to improve cortical lesion detection in MS patients. In recent years, Double inversion recovery (DIR), Phase sensitive inversion recovery (PSIR) and 7 Tesla T2* have been found to improve CL detection. Magnetization Transfer Imaging (MTI) has the advantage over conventional imaging as it reflects tissue myelin content. In this thesis, I present our studies using MTI at 7 Tesla to study cortical pathology in MS. 1) For a pilot study aiming to validate the use of magnetization transfer ratio (MTR) to detect cortical lesions, We examined the sensitivity of MTR to detect cortical lesions in comparison with 3 T DIR, 7 T PSIR, and 7 T T2* in 18 MS patients and 9 healthy controls. 2) A further 42 patients (11 clinically isolated syndrome (CIS), 11 relapsing remitting MS (RRMS), 10 primary progressive MS (PPMS), and 10 secondary progressive MS (SPMS)) and 8 healthy controls were scanned at baseline, 23 of these patients had a follow up scan at 12 months. MTR at 7 Tesla has increased sensitivity to detect cortical lesions compared to 3T DIR, 7T PSIR and 7T T2*. CL myelin content as measured by the mean MTR lesional values were the lowest in SPMS patients in comparison with the rest of MS phenotypes. CL mean MTR values, more than volume was associated with the degree of physical and cognitive disability in MS patients. When MTR was studied in a longitudinal study, we have seen more changes in average MTR of cortical lesions in SPMS and CIS patients compared to RRMS and PPMS patients

Rapid magnetization transfer magnetic resonance imaging

Magnetization transfer (MT) imaging provides a contrast reflecting the properties of hydrogen atoms bound to macromolecules in the tissue. These components, which are short-lived in nature, cannot be captured by conventional MRI methods. However, by saturating the magnetization of macromolecules using an off-resonance radio-frequency pulse, a signal intensity drop is induced, enabling the generation of MT contrast. In principle, MT is expressed in two different ways: (a) Magnetization transfer ratio (MTR), which is a semi-quantitative measure, and (b) quantitative magnetization transfer (qMT) which represent quantitative parameters underlying the MT effect. Both methods have demonstrated their usefulness in the diagnosis and prognosis of various pathologies, such as multiple sclerosis (MS). However, the integration of MT imaging into daily clinical practice remains a challenge due to the general long acquisition time of qMT imaging, the transmit field nonuniformities at high field, and the limited signal-to-noise at low fields. This thesis aims to address these issues by developing fast and robust methodologies for MT imaging at both low (0.55 T) and high (3 T) field strengths. To this end, a fast spiral multi-slice spoiled gradient echo (SPGR) sequence, combined with a low-resolution B1-mapping for accurate MTR imaging in less than one minute was implemented. The same method was further developed to obtain accurate and easy-to-calculate whole-brain qMT maps within 5 minutes. Moreover, the feasibility of MT imaging at low field was investigated with an MT-sensitized balanced steady-state free precession (bSSFP) sequence, which slightly outperformed the product SPGR in terms of signal-to-noise ratio (SNR). We further demonstrated that an extremely efficient bSSFP-based sequence, termed bSTAR can be extended to MT imaging at low-field with a submillimeter isotropic resolution within the clinically acceptable scan time. The techniques presented in this thesis facilitate a wider use of MT imaging in clinics for the diagnosis and prognosis of various diseases

Quantitatively Studying Tissue Damage in Multiple Sclerosis Using Gradient Recalled Echo MRI Sequences

Multiple Sclerosis (MS) is an unpredictable, often disabling disease of the central nervous system (CNS) that disrupts the flow of information within the brain, and between the brain the body. MS is the most common progressive neurologic disease of young adults, affecting approximately 2.3 million people worldwide. It is estimated that more than 700,000 individuals are affected by MS in United States. While MS has been studied for decades, the cause of it is still not definite and a fully effective treatment for MS is not yet available. Magnetic resonance imaging (MRI) has been used extensively in MS diagnosis and for monitoring disease. Clinical T1W, T2W and Fluid Attenuated Inversion Recovery (FLAIR) images are able to detect focal WM lesions with high accuracy and are used in MS diagnosis. However, standard clinical MRI lacks specificity to MS pathology and correlates only modestly with MS disability. Many studies have been devoted to the development and experimental validation of quantitative methods sensitive to myelin damage (hallmark of MS), primarily by means of multiexponential T2 imaging of water trapped between myelin layers, magnetization transfer (MT) and diffusion tensor imaging. These techniques have not gained traction in clinical practice, prompting searches for novel, more pathologically specific and efficient approaches. In this thesis, two novel MRI techniques developed in our lab, quantitative Gradient Recalled Echo (qGRE) and Multi-Angular-Relaxometry of Tissue (SMART), were used to quantitatively study MS tissue damage. Our qGRE technique (which is an advanced version of GEPCI – gradient echo plural contrast imaging) is based on quantitative measurements of the transverse relaxation properties of the Gradient Recalled Echo (GRE) MRI signal. This quantitative qGRE approach allows estimation of tissue damage in MS lesions and normal appearing WM and GM. An innovative qGRE method of data analysis allows separation of tissue-cellular-specific (R2t* relaxation rate constant) from Blood Oxygen Level Dependent (BOLD) contributions to the total GRE MRI signal decay rate constant (R2*). Since BOLD effect causes variations in MRI signal that occur with physiological state-dependent changes in blood flow and/or oxygen consumption, the R2t* values more specifically reflect the tissue-cellular component of R2*. The tissue-cellular-specific (R2t*) MRI relaxation parameter depends on the environment of water molecules (the main source of MRI signal): higher concentrations of proteins, lipids, and other constituents of biological tissue and cellular constituents (sources of MRI signal relaxation) leading to higher relaxation rate constants. Our results showed that R2t* can sensitively detect MS-related pathology in cortical NAGM, subcortical NAWM and WM lesions. The method demonstrated tissue damage patterns in the CNS of the MS cohort. Our data shed light on the interrelationships of damage throughout the brain and cervical spinal cord, while supporting the idea of MS as a global CNS disease. In addition, our data demonstrated that while spinal cord CSA is a reliable marker for changes in motor functions, the reduction in the R2t* of GM and WM is a reliable indicator of cognitive dysfunction. The SMART technique is also based on a GRE MRI sequence (but with multiple flip angles) and a model of GRE signal that accounts for cross-relaxation effects between “free” and “bound” water proton pools. Importantly, no MT pulses are used in SMART approach, thus overcoming high RF energy deposition associated with existing qMT approaches for evaluation of tissue macromolecular content. From a single protocol this technique can generate quantitative macromolecular proton fraction (MPF) images along with naturally co-registered quantitative images of longitudinal (R1=1/T1) and transverse (R2*=1/T2*) signal relaxation rate constants, and spin density. The SMART technique allows quantitative assessments of central nervous system (CNS) simultaneously using several tissue contrasts. Our results showed that the SMART metrics can distinguish progressive MS from relapsing-remitting MS (RRMS) and correlate with clinical assessments. Without applying either MT or 180° radiofrequency pulses, SMART MRI generates high resolution quantitative images with various contrasts, and is safe for high-field MRI, making it a useful outcome measure in clinical trials

Quantitatively Studying Tissue Damage in Multiple Sclerosis Using Gradient Recalled Echo MRI Sequences

Multiple Sclerosis (MS) is an unpredictable, often disabling disease of the central nervous system (CNS) that disrupts the flow of information within the brain, and between the brain the body. MS is the most common progressive neurologic disease of young adults, affecting approximately 2.3 million people worldwide. It is estimated that more than 700,000 individuals are affected by MS in United States. While MS has been studied for decades, the cause of it is still not definite and a fully effective treatment for MS is not yet available. Magnetic resonance imaging (MRI) has been used extensively in MS diagnosis and for monitoring disease. Clinical T1W, T2W and Fluid Attenuated Inversion Recovery (FLAIR) images are able to detect focal WM lesions with high accuracy and are used in MS diagnosis. However, standard clinical MRI lacks specificity to MS pathology and correlates only modestly with MS disability. Many studies have been devoted to the development and experimental validation of quantitative methods sensitive to myelin damage (hallmark of MS), primarily by means of multiexponential T2 imaging of water trapped between myelin layers, magnetization transfer (MT) and diffusion tensor imaging. These techniques have not gained traction in clinical practice, prompting searches for novel, more pathologically specific and efficient approaches. In this thesis, two novel MRI techniques developed in our lab, quantitative Gradient Recalled Echo (qGRE) and Multi-Angular-Relaxometry of Tissue (SMART), were used to quantitatively study MS tissue damage. Our qGRE technique (which is an advanced version of GEPCI – gradient echo plural contrast imaging) is based on quantitative measurements of the transverse relaxation properties of the Gradient Recalled Echo (GRE) MRI signal. This quantitative qGRE approach allows estimation of tissue damage in MS lesions and normal appearing WM and GM. An innovative qGRE method of data analysis allows separation of tissue-cellular-specific (R2t* relaxation rate constant) from Blood Oxygen Level Dependent (BOLD) contributions to the total GRE MRI signal decay rate constant (R2*). Since BOLD effect causes variations in MRI signal that occur with physiological state-dependent changes in blood flow and/or oxygen consumption, the R2t* values more specifically reflect the tissue-cellular component of R2*. The tissue-cellular-specific (R2t*) MRI relaxation parameter depends on the environment of water molecules (the main source of MRI signal): higher concentrations of proteins, lipids, and other constituents of biological tissue and cellular constituents (sources of MRI signal relaxation) leading to higher relaxation rate constants. Our results showed that R2t* can sensitively detect MS-related pathology in cortical NAGM, subcortical NAWM and WM lesions. The method demonstrated tissue damage patterns in the CNS of the MS cohort. Our data shed light on the interrelationships of damage throughout the brain and cervical spinal cord, while supporting the idea of MS as a global CNS disease. In addition, our data demonstrated that while spinal cord CSA is a reliable marker for changes in motor functions, the reduction in the R2t* of GM and WM is a reliable indicator of cognitive dysfunction. The SMART technique is also based on a GRE MRI sequence (but with multiple flip angles) and a model of GRE signal that accounts for cross-relaxation effects between “free” and “bound” water proton pools. Importantly, no MT pulses are used in SMART approach, thus overcoming high RF energy deposition associated with existing qMT approaches for evaluation of tissue macromolecular content. From a single protocol this technique can generate quantitative macromolecular proton fraction (MPF) images along with naturally co-registered quantitative images of longitudinal (R1=1/T1) and transverse (R2*=1/T2*) signal relaxation rate constants, and spin density. The SMART technique allows quantitative assessments of central nervous system (CNS) simultaneously using several tissue contrasts. Our results showed that the SMART metrics can distinguish progressive MS from relapsing-remitting MS (RRMS) and correlate with clinical assessments. Without applying either MT or 180° radiofrequency pulses, SMART MRI generates high resolution quantitative images with various contrasts, and is safe for high-field MRI, making it a useful outcome measure in clinical trials

Magnetisation transfer imaging in the study of early relapsing-remitting multiple sclerosis.

Multiple sclerosis is a common cause of neurological disability in the young adult, but, at present, disease modifying medication may have little, if any, effect upon long term clinical impairment. For this reason, there is a continuing need to understand the mechanisms that lead to long term disability and - in the context of clinical trials - to develop reliable surrogate markers of disease progression. It may be especially useful to describe the early evolution of abnormality within normal-appearing white matter (NAWM) and grey matter firstly because pathology in early MS may be a key determinant of later disability, and secondly because there is only a modest relationship between white matter lesion load and clinical impairment. This thesis presents a series of studies, investigating NAWM and grey matter abnormality in a cohort of patients with early relapsing-remitting MS. A key question was whether MRI measures were able to detect accumulating abnormality in NAWM and grey matter early in the clinical course. An initial investigation, using Ti relaxation time estimation, did not detect strong evidence for a net change over time. Attention was therefore turned to the magnetisation transfer ratio (MTR) and results from a series of studies, investigating NAWM, grey matter and thalamic MTR abnormalities in early relapsing-remitting MS are presented. Of note, a clinically relevant reduction in grey matter MTR was apparent, and there was evidence for increasing MTR abnormality in the grey matter, NAWM and the thalamus over a two year follow-up period. In part three of this thesis, a model for the MT effect is used to estimate two underlying MT parameters - the semi-solid proton fraction (/) and the semi-solid T2 (T2B) in sixty patients with clinically-definite MS. The aim was to assess the clinical relevance of these novel parameters

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

Improving longitudinal spinal cord atrophy measurements for clinical trials in multiple sclerosis by using the generalised boundary shift integral (GBSI)

Spinal cord atrophy is a common and clinically relevant feature of multiple sclerosis (MS), and can be used to monitor disease progression and as an outcome measure in clinical trials. Spinal cord atrophy is conventionally estimated with segmentation-based methods (e.g., cross-sectional spinal cord area (CSA)), where spinal cord change is calculated indirectly by numerical difference between timepoints. In this thesis, I validated the generalised boundary shift integral (GBSI), as the first registration-based method for longitudinal spinal cord atrophy measurement. The GBSI registers the baseline and follow-up spinal cord scans in a common half-way space, to directly determine atrophy on the cord edges. First, on a test dataset (9 MS patients and 9 controls), I have found that GBSI presented with lower random measurement error, than CSA, reflected by lower standard deviation, coefficient of variation and median absolute deviation. Then, on multi-centre, multi-manufacturer, and multi–field‐strength scans (282 MS patients and 82 controls), I confirmed that GBSI provided lower measurement variability in all MS subtypes and controls, than CSA, resulting into better separation between MS patients and controls, improved statistical power, and reduced sample size estimates. Finally, on a phase 2 clinical trial (220 primary-progressive MS patients), I demonstrated that spinal cord atrophy measurements on GBSI could be obtained from brain scans, considering their quality and association with corresponding spinal cord MRI-derived measurements. Not least, 1-year spinal cord atrophy measurements on GBSI, but not CSA, were associated with upper and lower limb motor function. In conclusion, spinal cord atrophy on the GBSI had higher measurement precision and stronger clinical correlates, than the segmentation method, and could be derived from high-quality brain acquisitions. Longitudinal spinal cord atrophy on GBSI could become a gold standard for clinical trials including spinal cord atrophy as an outcome measure, but should remain a secondary outcome measure, until further advancements increase the ease of acquisition and processing