Decreased brain venous vasculature visibility on susceptibility-weighted imaging venography in patients with multiple sclerosis is related to chronic cerebrospinal venous insufficiency.

BACKGROUND: The potential pathogenesis between the presence and severity of chronic cerebrospinal venous insufficiency (CCSVI) and its relation to clinical and imaging outcomes in brain parenchyma of multiple sclerosis (MS) patients has not yet been elucidated. The aim of the study was to investigate the relationship between CCSVI, and altered brain parenchyma venous vasculature visibility (VVV) on susceptibility-weighted imaging (SWI) in patients with MS and in sex- and age-matched healthy controls (HC). METHODS: 59 MS patients, 41 relapsing-remitting and 18 secondary-progressive, and 33 HC were imaged on a 3T GE scanner using pre- and post-contrast SWI venography. The presence and severity of CCSVI was determined using extra-cranial and trans-cranial Doppler criteria. Apparent total venous volume (ATVV), venous intracranial fraction (VIF) and average distance-from-vein (DFV) were calculated for various vein mean diameter categories: .9 mm. RESULTS: CCSVI criteria were fulfilled in 79.7% of MS patients and 18.2% of HC (p < .0001). Patients with MS showed decreased overall ATVV, ATVV of veins with a diameter < .3 mm, and increased DFV compared to HC (all p < .0001). Subjects diagnosed with CCSVI had significantly increased DFV (p < .0001), decreased overall ATVV and ATVV of veins with a diameter < .3 mm (p < .003) compared to subjects without CCSVI. The severity of CCSVI was significantly related to decreased VVV in MS (p < .0001) on pre- and post-contrast SWI, but not in HC. CONCLUSIONS: MS patients with higher number of venous stenoses, indicative of CCSVI severity, showed significantly decreased venous vasculature in the brain parenchyma. The pathogenesis of these findings has to be further investigated, but they suggest that reduced metabolism and morphological changes of venous vasculature may be taking place in patients with MS

Anatomic & metabolic brain markers of the m.3243A>G mutation: A multi-parametric 7T MRI study

One of the most common mitochondrial DNA (mtDNA) mutations, the A to G transition at base pair 3243, has been linked to changes in the brain, in addition to commonly observed hearing problems, diabetes and myopathy. However, a detailed quantitative description of m.3243A>G patients' brains has not been provided so far. In this study, ultra-high field MRI at 7T and volume- and surface-based data analyses approaches were used to highlight morphology (i.e. atrophy)-, microstructure (i.e. myelin and iron concentration)- and metabolism (i.e. cerebral blood flow)-related differences between patients (N = 22) and healthy controls (N = 15). The use of quantitative MRI at 7T allowed us to detect subtle changes of biophysical processes in the brain with high accuracy and sensitivity, in addition to typically assessed lesions and atrophy. Furthermore, the effect of m.3243A>G mutation load in blood and urine epithelial cells on these MRI measures was assessed within the patient population and revealed that blood levels were most indicative of the brain's state and disease severity, based on MRI as well as on neuropsychological data. Morphometry MRI data showed a wide-spread reduction of cortical, subcortical and cerebellar gray matter volume, in addition to significantly enlarged ventricles. Moreover, surface-based analyses revealed brain area-specific changes in cortical thickness (e.g. of the auditory cortex), and in T1, T2* and cerebral blood flow as a function of mutation load, which can be linked to typically m.3243A>G-related clinical symptoms (e.g. hearing impairment). In addition, several regions linked to attentional control (e.g. middle frontal gyrus), the sensorimotor network (e.g. banks of central sulcus) and the default mode network (e.g. precuneus) were characterized by alterations in cortical thickness, T1, T2* and/or cerebral blood flow, which has not been described in previous MRI studies. Finally, several hypotheses, based either on vascular, metabolic or astroglial implications of the m.3243A>G mutation, are discussed that potentially explain the underlying pathobiology. To conclude, this is the first 7T and also the largest MRI study on this patient population that provides macroscopic brain correlates of the m.3243A>G mutation indicating potential MRI biomarkers of mitochondrial diseases and might guide future (longitudinal) studies to extensively track neuropathological and clinical changes

Ultrahigh field MRI in clinical neuroimmunology: a potential contribution to improved diagnostics and personalised disease management

Conventional magnetic resonance imaging (MRI) at 1.5 Tesla (T) is limited by modest spatial resolution and signal-to-noise ratio (SNR), impeding the identification and classification of inflammatory central nervous system changes in current clinical practice. Gaining from enhanced susceptibility effects and improved SNR, ultrahigh field MRI at 7 T depicts inflammatory brain lesions in great detail. This review summarises recent reports on 7 T MRI in neuroinflammatory diseases and addresses the question as to whether ultrahigh field MRI may eventually improve clinical decision-making and personalised disease management

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

New MR imaging techniques in epilepsy

This thesis is concerned with the application of three magnetic resonance (MR) techniques in epilepsy: i.) Fluid attenuated inversion recovery prepared (FLAIR) imaging, ii.) diffusion imaging including diffusion tensor imaging (DTI) and iii.) serial and high resolution imaging of the hippocampus. I assessed the clinical value of fast FLAIR in epilepsy in a study involving 128 patients and of 3D FLAIR in a study involving 10 patients. The conspicuity of neocortical lesions and hippocampal sclerosis was increased. New lesions were detected in 5% of patients. The extent of low grade tumours was best assessed on 3D fast FLAIR images. Fast FLAIR was inferior to standard MR techniques for identifying and heterotopia. I applied newly developed, experimental diffusion imaging techniques. In eight studies using different diffusion imaging techniques involving a total of 50 patients and 54 control subjects I investigated the mobility of water molecules in the human epileptic brain in vivo. I used spin echo diffusion imaging in two studies, echo planar imaging (EPI) based DTI in four studies and EPI diffusion imaging in a patient during focal status epilepticus. Finally, in a preliminary study I attempted to use EPI diffusion imaging as a contrast to visualise transient changes associated with frequent lateralizing spikes. Our findings were: i.) diffusion is increased in hippocampal sclerosis suggesting a loss of structural organization and expansion of the extracellular space, ii.) displaying the directionality (anisotropy) of diffusion is superior to standard imaging to visualise tracts, iii.) anisotropy is reduced in the pyramidal tract in patients with hemiparesis and iv.) in the optic radiation in patients with hemianopia after temporal lobectomy suggesting wallerian degeneration, v.) both developmental and acquired structural abnormalities have a lower anisotropy than normal white matter, vi.) diffusion abnormalities in blunt head trauma are widespread and may include regions which are normal on standard imaging, indicating micro structural damage suggestive of diffuse axonal injury, vii.) focal status epilepticus can be associated with a reduced difflision in the affected cortex, viii.) diffusion imaging may be useful as a contrast for event-related (spike triggered) functional MR imaging. With serial MRI I demonstrated hippocampal volume loss in a patient after generalized status epilepticus and with high resolution imaging of an anatomical specimen and a control subject I showed hippocampal layers on MR images. The results presented in this thesis emphasised the flexibility of MR imaging and its ability to demonstrate abnormalities in vivo. FLAIR imaging is now part of the clinical work up of patients with epilepsy. Diffusion imaging has been shown to be superior to standard imaging to visualise tracts which has far-reaching implications for neurological applications. Diffusion imaging also provides an exciting window to study cerebral micro structure in vivo. Serial imaging allows for the first time the visualisation of temporal changes and high resolution imaging has the prospect of demonstrating hippocampal layers in vivo. MR imaging is a constantly progressing technique. It is hoped that this thesis will help to formulate hypotheses for new MR experiments to study the relationship of dysfunction and structural abnormalities

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

Key clinical benefits of neuroimaging at 7 T

The growing interest in ultra-high field MRI, with more than 35.000 MR examinations already performed at 7 T, is related to improved clinical results with regard to morphological as well as functional and metabolic capabilities. Since the signal-to-noise ratio increases with the field strength of the MR scanner, the most evident application at 7 T is to gain higher spatial resolution in the brain compared to 3 T. Of specific clinical interest for neuro applications is the cerebral cortex at 7 T, for the detection of changes in cortical structure, like the visualization of cortical microinfarcts and cortical plaques in Multiple Sclerosis. In imaging of the hippocampus, even subfields of the internal hippocampal anatomy and pathology may be visualized with excellent spatial resolution. Using Susceptibility Weighted Imaging, the plaque-vessel relationship and iron accumulations in Multiple Sclerosis can be visualized, which may provide a prognostic factor of disease. Vascular imaging is a highly promising field for 7 T which is dealt with in a separate dedicated article in this special issue. The static and dynamic blood oxygenation level-dependent contrast also increases with the field strength, which significantly improves the accuracy of pre-surgical evaluation of vital brain areas before tumor removal. Improvement in acquisition and hardware technology have also resulted in an increasing number of MR spectroscopic imaging studies in patients at 7 T. More recent parallel imaging and short-TR acquisition approaches have overcome the limitations of scan time and spatial resolution, thereby allowing imaging matrix sizes of up to 128×128. The benefits of these acquisition approaches for investigation of brain tumors and Multiple Sclerosis have been shown recently. Together, these possibilities demonstrate the feasibility and advantages of conducting routine diagnostic imaging and clinical research at 7 T

A Prospective Advanced Magnetic Resonance Imaging Study of Newly Diagnosed Epilepsy

According to the World Health Organization (WHO), approximately 50 million people in the world have active epilepsy. Epilepsy is the most common neurological disorder after migraine, stroke and Alzheimer’s disease. Epilepsy disorder affects men and women of all ages, races and social classes. There is an extensive neuroimaging literature describing patients with chronic epilepsy. However, few studies have investigated brain structural changes in patients with newly diagnosed epilepsy (NDE) using quantitative magnetic resonance imaging (MRI). The main goal of this thesis was to determine the nature and extent of brain structural and functional differences in patients with NDE using different MRI techniques compared with healthy controls. The first study was to determine the morphometric changes in patients with NDE compared to healthy controls using quantitative MRI analysis. The second study was to identify functional connectivity differences (in the whole brain and regions of interest) in patients with NDE and healthy controls using resting state functional magnetic resonance imaging (RS-fMRI). All study participants were recruited from the Walton Centre NHS Foundation Trust, Liverpool. All had been diagnosed with focal epilepsy by a consultant neurologist and recruited for MRI scanning within 12 months of diagnosis. Twenty-seven patients with NDE were recruited (14 male, 13 female, with mean age (M)=33.2) and 32 healthy matched controls (14 male, 18 female, M=33.07).Control and NDE study participants were matched for age, handedness and gender. All participants were scanned using a Siemens 3T Trio whole-body scanner (Siemens, Erlangen, Germany) with eight-channel radiofrequency (RF) head coil together with foam padding to comfortably restrict head motion at the Magnetic Resonance and Image Analysis Research Centre (MARIARC), University of Liverpool. Various MRI sequences were conducted including: 3D MPRAGE T1-weighted anatomical data, and RS-fMRI In the first study, shape, surface based, and voxel based morphometry analysis were applied, and the results suggested differences to the morphology of the brain stem and both the right and left thalami in patients with NDE. The independent component analysis of RS-fMRI showed abnormal different functional connectivity in visual and attention networks in patients with NDE relative to healthy controls while ROI-ROI demonstrated increased functional connectivity between the subcallosal cortex and both thalami in NDE patients. This is the first extensive programme of research to employ various analysis techniques and advanced MRI sequences to study structural and functional differences in patients with NDE compared to healthy controls. The results of this thesis show that structural and functional differences occur in both thalami in patients with NDE. These findings suggest that the thalamus plays a very important role in epilepsy pathophysiology. The results of this thesis offer further understanding regarding the role of structural and functional differences in NDE. They highlight the need for future quantitative MRI analysis studies of NDE to help patients avoid the chronic stage of the disorder and improve their quality of life