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

An assessment of small vessel disease in human post-mortem tissue through radiology and histology

Sporadic human cerebral small vessel disease (SVD) is a significant problem in our aging population. It is the most common cause of haemorrhagic stroke, causes one quarter of all ischaemic strokes, causes vascular dementia and synergistically worsens other dementias. It also causes a range of other psychological and physical problems and is increasingly common with increased age. SVD is well characterised on neuroimaging, with lesions throughout the brain, and particularly in the white matter. The cause(s) and pathophysiological mechanisms underlying the development of SVD, however, remain poorly understood with poor correlations between the abnormalities seen at the cellular level, on neuroimaging, and clinically. There are many theories as to the cause of SVD. However, observational studies and experimental evidence point towards an abnormality in the small vasculature of the brain initiating a cascade of events leading to a variety of vascular and brain parenchymal lesions. What these abnormalities are, and how exactly they result in the pathology seen, is unknown. Different structural components of the vessel wall and parenchymal brain cells appear to be involved, as well as functional abnormalities such as abnormal vascular reactivity. Risk factors also play a role, hypertension being the most significant, but how these interact with the normal vasculature is not fully understood. To provide an overview of our current understanding of SVD in human tissue I first completed a systematic review of the literature comparing the appearances of SVD on post-mortem imaging and histology. This revealed the inconsistency in methods and reporting in these studies and the lack of histopathology agreement on SVD terminology and definitions. I then studied the histological appearances of the lesions identified by post-mortem imaging to provide a reliable precise histological-imaging correlation. I developed a new protocol for ex vivo 7 Tesla magnetic resonance imaging (7T MRI) scanning of human brain tissue on post-mortem material and developed a grading system to assess SVD burden on MRI and histology with histological definitions, to try to encourage standardised, comprehensive and transparent reporting so that results in small studies can be more easily compared. I studied human post-mortem brain tissue to better investigate the disease in the appropriate context. In our cases from individuals with haemorrhagic SVD, normal aging and young controls, the most severe SVD pathology on ex vivo imaging and histology was, as expected, in the haemorrhagic SVD group. The normal aging group also had significant levels of pathology, perhaps representing the increasing burden of disease present but not necessarily detected clinically with increased age. It is possible the underlying pathophysiology in this group might develop by different mechanisms compared to the haemorrhagic group. Directly comparing the imaging and histological lesions confirmed the histological appearances of some lesions on imaging such as enlarged perivascular spaces, lacunes, microinfarcts and microbleeds. However, making direct comparisons is complex. Some lesions, such as small vessel fibrinoid necrosis, presumed to be below the resolution for detection on 7T MRI, were identified on both histology and imaging. Some features seen on histology in association with recognised SVD lesions, such as perivascular inflammation in an area of white matter rarefaction, were present in a variety of different histological contexts with no apparent correlation on imaging. And some lesions, such as white matter rarefaction around enlarged perivascular spaces, were present often on both imaging and histology, but their significance and contribution to SVD is unknown. To try to further understand the mechanisms underlying SVD and the lesions seen on imaging I undertook biochemical studies of protein expression in the deep white matter of the haemorrhagic SVD group, young controls and an Alzheimer’s disease group, who also have white matter pathology on neuroimaging. Increased fibrinogen levels suggested vascular leakage in both disease groups. However, haemorrhagic SVD had more severe white matter hypoxic changes and increased vasoconstrictor levels while in Alzheimer’s disease there was increased amyloid 42 and levels of a pericyte marker, possibly reflecting different pathophysiological mechanisms causing the similar appearing radiological changes. When assessing radiologically defined white matter hyperintensities (WMH) I found hypoxic-induced changes throughout brains with WMH, including in normal appearing areas of white matter. This suggests these brains have abnormalities in areas that appear radiologically normal, as found in in vivo imaging studies. To conclude, this work has confirmed the importance of reaching a consensus in histopathological reporting, terminology and definitions which is a basic requirement before we can better understand the pathophysiology of SVD. This has led to the formation of definitions and a practical grading system that could be used as a basis upon which to build a future agreement. The complexity of the histological lesions underlying radiological SVD changes was apparent, and the frequency with which some other potentially important histological changes were identified suggests these have not, to date, been fully appreciated. Investigating the underlying mechanisms of white matter hyperintensities showed vascular leakage was a shared abnormality in two different diseases with white matter changes on imaging, suggesting it may be a common factor upon which variable pathways converge. Future work is needed to further understand the importance of these less well characterised histological features. Investigating the role of vascular leakage and exploring drugs that maintain or improve vascular integrity could be a potential route for helping to treat SVD. Studies into underlying transcriptomic abnormalities around vascular leakage in human tissue may be informative

Blast Injury Outcome Study in Armed forces Personnel (BIOSAP) and Blast injury in pigs study (BIIPs)

No abstrac

Neuroinflammation and neurodegeneration following blast traumatic brain injury

Blast traumatic brain injury (bTBI) is the signature injury from conflicts in Iraq and Afghanistan. Although chronic neuroinflammation has been detected following TBI, little is known about this following bTBI. This thesis investigates TBI in UK military personnel before measuring neuroinflammation and neurodegeneration in personnel and an animal bTBI model. Outcomes following TBI during those conflicts were analysed. This preceded a study involving ten personnel following bTBI. A single-centre MRS and [18F]GE180 PET case-control study assessed biomarkers of neuroinflammation. Furthermore, an animal bTBI model assessed immunohistochemical and neuroimaging markers of neuroinflammation and neurodegeneration. Results showed survival improved year-on-year, except following severe TBI. Poor outcomes were driven by penetrating TBI. There were no significant changes related to neuroinflammation seen on MRS or PET, however the animal model demonstrated neuroinflammatory and neurodegenerative changes. While improved survival rates endorse the success of the UK Defence Medical Services, there remains potential to improve outcomes following severe TBI in future conflicts. Multi-centre in vivo MRS and PET studies could be useful in detecting neuroinflammation but would require PET radioligands with improved VT. Ex vivo work validates DTI for detecting injury following bTBI, identifying areas for future study. Prognostication of poor outcome following TBI is no longer a self-fulfilling prophecy

Neuroimaging - Clinical Applications

Modern neuroimaging tools allow unprecedented opportunities for understanding brain neuroanatomy and function in health and disease. Each available technique carries with it a particular balance of strengths and limitations, such that converging evidence based on multiple methods provides the most powerful approach for advancing our knowledge in the fields of clinical and cognitive neuroscience. The scope of this book is not to provide a comprehensive overview of methods and their clinical applications but to provide a "snapshot" of current approaches using well established and newly emerging techniques

Spinal cord grey matter pathology in multiple sclerosis

Background: Traditionally, Multiple Sclerosis (MS) has been considered to be a predominantly white matter (WM) disease. More recent studies have revealed considerable grey matter (GM) involvement in the brain. However there is a paucity of literature examining GM pathology in the spinal cord. Objectives and methods: We use human post-mortem material to explore various aspects of spinal cord GM pathology in MS including (i) the extent and pattern of spinal cord demyelination, (ii) the relative contributions of GM and WM volume loss to spinal cord atrophy, (iii) the extent of neuronal pathology within the spinal cord and (iv) the sensitivity of post-mortem MRI for detecting spinal cord GM plaques. Results: Within the spinal cord, GM demyelination is more extensive than WM demyelination with many lesions showing a novel morphological pattern whereby the plaque borders maintain a strict respect for the GM/WM boundary. Demyelination is more extensive in the spinal cord GM than in other brain regions examined. Post-mortem MR imaging at 4.7 Tesla is highly sensitive for detecting the spinal cord GM plaques. We demonstrate substantial neuronal loss in the spinal cord in MS, observing reductions in both interneuron and motoneuron numbers. This neuronal loss occurs predominantly within GM plaques. We also observe reductions in interneuron size, both within plaques and in the myelinated GM. Despite this, we find no evidence of spinal cord GM atrophy. Conclusions: This study represents the first detailed examination of spinal cord GM involvement in MS. We demonstrate substantial GM pathology in the spinal cord, further challenging the concept that MS is a predominantly WM disease. A greater understanding of this pathology may provide important insights into MS pathogenesis and mechanisms of disability in the disease

Malformations of the Human Cerebral Cortex: patterns and causes

Malformations of cortical development (MCD) are a group of disorders characterized by a congenital abnormal structure of the cerebral cortex. In general, malformations are defined as structural abnormalities caused by a disturbance in cell organization or function within a tissue type. When a disturbance results in an abnormal structure of the cerebral cortex we call this: malformations of cortical development. MCD are heterogeneous as a group, as they include several different structural abnormalities, and they have a diverse array of causes, both genetic and environmental

Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors

A dramatic increase in knowledge regarding the molecular biology of brain tumors has been established over the past few years, and this has lead to the development of novel therapeutic strategies for these patients. In this book a review of the options available for the clinical management of patients with these tumors are outlined. In addition advances in radiology both for pre-operative diagnostic purposes along with surgical planning are described. Furthermore a review of newer developments in chemotherapy along with the evolving field of photodynamic therapy both for intra-operative management and subsequent therapy is provided. A discussion of certain surgical management issues along with tumor induced epilepsy is included. Finally a discussion of the management of certain unique problems including brain metastases, brainstem glioma, central nervous system lymphoma along with issues involving patients with a brain tumor and pregnancy is provided