Energy failure following traumatic brain injury: Potential mechanisms and impact of normobaric hyperoxia

Cerebral ischaemia is a frequent finding in post mortem studies following traumatic brain injury (TBI), but clinical studies using 15oxygen positron emission tomography (15O PET) suggest that classical ischaemia is uncommon beyond the first 24 hours after injury. Evidence of metabolic failure in the absence of classical ischaemia may represent ongoing neuronal dysfunction and progressive neuronal loss. Any therapeutic intervention that mitigates such metabolic derangements before they result in irreversible neuronal injury may improve tissue fate and improve the functional outcome for patients. Energy failure was spatially defined, characterised, and mapped using 15O and 18Fluoromisinidazole ([18F] FMISO) positron emission tomography. This enabled differentiation of classical ischaemia, diffusion hypoxia, and established infarction, and provided data on the dominant local mechanism at any given time after TBI. My thesis also aimed to examine the utility of diffusion tensor imaging and whole-brain proton MR spectroscopy (WB 1H MRS) as imaging biomarkers to investigate normobaric hyperoxia as a therapeutic option following traumatic brain injury (TBI). Using ([18F] FMISO PET evidence of tissue hypoxia consistent with microvascular ischaemia was found across the injured brain. The impact of normobaric hyperoxia (NBH) was examined in a clinical TBI cohort using diffusion tensor imaging and WB 1H MRS. Some evidence of benefit was found within the perilesional brain, but further studies should examine the value of a longer period of exposure to NBH and whether this has implications for functional outcome.AAGBI, MRC, Wellcome trus

Fluoxetine as disease modifying treatment in multiple sclerosis : rationale, evaluation of the use of MRI to monitor treatment, and preliminary findings

Patients with multiple sclerosis (MS) lack astrocytic β2-adrenergic receptors and this may contribute to the focal inflammatory demyelinating lesions and axonal degeneration that characterize this disease. We hypothesized that the antidepressant fluoxetine might be able to compensate for the loss of the β2-adrenergic receptors. In this thesis we evaluated the use of cerebral MRI scans to monitor disease activity and we performed several exploratory studies to evaluate effects of fluoxetine on patients with MS. A convenient way to find out whether a drug is able to reduce disease activity in MS is by measuring the development of new focal lesions on serial MRI scans of the brain. MS patients who received fluoxetine during 6 months had a trend towards the development of less new focal lesions compared to patients receiving placebo. To assess whether preventing new lesions formation reduces disability on the long term, we studied the relationship between the focal (T2) lesions and disease progression. The number of focal lesions predicted progression of disability and conversion to a progressive disease course in patients with relapsing remitting MS. However, once patients had entered the progressive phase, T2 lesions were no longer predictive for further progression of disability. In another study, we found that 2 weeks use of fluoxetine resulted in an increase in NAA/Cr (a marker of axonal function) in the white matter of MS patients. These preliminary studies suggest that fluoxetine reduces new focal lesion formation and may improve axonal metabolism in MS patients.

Proton magnetic resonance spectroscopy in multiple sclerosis.

Proton magnetic resonance spectroscopy ((1)H-MRS) provides tissue metabolic information in vivo. This article reviews the role of MRS-determined metabolic alterations in lesions, normal-appearing white matter, gray matter, and spinal cord in advancing our knowledge of pathologic changes in multiple sclerosis (MS). In addition, the role of MRS in objectively evaluating therapeutic efficacy is reviewed. This potential metabolic information makes MRS a unique tool to follow MS disease evolution, understand its pathogenesis, evaluate the disease severity, establish a prognosis, and objectively evaluate the efficacy of therapeutic interventions

Novel approaches to MRI of glioma

Gliomas are extremely heterogeneous, both morphologically and biologically, which contributes to a very poor prognosis. Current imaging of glioma is insufficient for a thorough diagnosis, therapy assessment and prognosis prediction. Moreover, refined and more sophisticated imaging technique could help in furthering our knowledge of gliomas. In order to facilitate proliferation, cancer cells undergo a change in structure and an increase in metabolism that results in distortion and disruption of tissue architecture. Gliomas are characterised by an increase in cells of variable sizes, as well as changes in the tissue microstructure. Diffusion-Weighted Imaging (DWI) and the apparent diffusion coefficient (ADC), have been extensively studied as potential imaging biomarkers for cellularity and tissue architecture. However, several studies have shown partial overlap in the measured values between tumour subtypes. Moreover, ADC is influenced by several factors and does not provide detailed information on the tissue microstructure. The Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumours (VERDICT) is a novel diffusion model that infers tissue microstructure compartment from conventional DWI measurements. This model derives metrics for the intracellular, intravascular and extracellular– extravascular spaces providing a more detailed interpretation of the tissue microstructure. To date, VERDICT has been applied to xenograft models of colorectal cancer, patient studies of prostate cancer and recently its feasibility in glioma has been shown. In this PhD I have applied a shortened version of the VERDICT method to image intratumoral and intertumoral heterogeneity in glioma. The results have also been validated with histology as part of a prospective study. Gliomas also exhibit a significant increase in mitotic activity within the tumour. The increased number of mitosis alters cell density which, in turn, affects the total concentration of tissue sodium as the concentration of tissue sodium is approximately ten-fold higher in the extracellular compared to the intracellular space. In addition, there is a decrease in Na+/K+-ATPase activity in tumours due to ATP depletion, which contributes to disturb sodium homeostasis. Non-invasive detection of 23Na with MRI has the potential to quantify sodium concentration and therefore could be an imaging probe of cell morphology and membrane function within the tumour microenvironment, as well as a method of probing tissue heterogeneity. During my PhD, a novel 23Na-MRI technique has been used to evaluate sodium distribution within glioma and in the surrounding tissue. Metabolic reprogramming is one of the major driving forces for determining glioma growth and invasion. Therefore, the non-invasive characterization of metabolic intratumoral, peritumoral and intertumoral heterogeneity in vivo could help to better stratify patients and to develop novel therapeutic strategies targeting cancer-specific metabolic pathways. 13C magnetic resonance imaging (MRI) using dynamic nuclear polarization (DNP) is a novel technique that allows non-invasive assessment of the metabolism of hyperpolarized (HP) 13C-labelled molecules in vivo, such as the exchange of [1-13C]pyruvate to [1-13C]lactate in tumours (Warburg effect). Part of my PhD has focused on developing and translating HP [1-13C]pyruvate MRI to explore metabolic reprogramming in glioma and the surrounding microenvironment. The overall aim of my PhD has been to develop novel approaches to imaging glioma with MRI to probe both the architectural and metabolic changes of Glioma. The preliminary evidence suggests that these tools can more deeply phenotype tumours than conventional imaging approaches. Although the main focus of this work has been gliomas, the techniques developed and presented here may be applied to study other pathological conditions within the brain, which raises the possibility of other potential clinical applications for this work

Positron emissiontomography imaging of neuroinflammation in Multiple Sclerosis with a second generation translocator protein PET radioligand

This thesis describes a new approach for molecular imaging of neuroinflammation in Multiple Sclerosis (MS). My aim was to use the 2nd generation TSPO radioligand 18F-PBR111 to explore the potential of Positron Emission Tomography (PET) targeting the 18-kDa Translocator Protein (TSPO), as an in vivo biomarker of activated microglia in MS patients. This thesis addresses three research objectives. First, I characterised 18F-PBR111 PET signal in healthy controls’ brains and tested how it is affected by the TSPO gene polymorphism at rs6971. Second, I measured 18F-PBR111 uptake across white matter volumes segmented using structural MRI measures related to MS neuropathology. Third, I explored how 18F-PBR111 uptake in the hippocampus correlated with depressive symptoms and to the brain functional connectivity of the hippocampus. Eleven patients with relapsing-remitting MS and 22 age-matched healthy controls underwent 18F-PBR111 PET and MRI scans. Structural and functional MRI sequences were used to define conventional MS neuropathological markers and for the assessment of functional connectivity, respectively. I discovered that white matter 18F-PBR111 PET signal in healthy volunteers varied with TSPO genotype and correlated positively with age. In patients with MS, signal intensity in MRI-defined lesions was higher than that in normal-appearing white matter and correlated with the historical rate of progression of their disability. Hippocampal 18F-PBR111 uptake was higher in the MS patient group than in healthy volunteers and correlated with both depressive symptoms and functional connectivity of the hippocampus with frontal, temporal and parietal cortex. I thus discovered that this 2nd generation TSPO PET radiotracer, used in humans for the first time in our study, is sensitive to MS neuropathology consistent with recognized patterns of microglial activation and that differences between subjects can be related to disability progression. I also have discovered a novel relationship between this measure of hippocampal microglial activation and affective symptoms of MS.Open Acces

Magnetic resonance imaging in relapsing-remitting multiple sclerosis.

The work presented in this thesis employed magnetic resonance imaging (MRI) techniques to determine the volume and metabolite profile of brain grey matter (GM) and white matter (WM) in people with clinically early relapsing-remitting multiple sclerosis (MS). Cross-sectional MRI and clinical data was obtained from 27 subjects with relapsing-remitting MS within 3 years of first symptom onset, and compared with MRI data from 29 normal control subjects. Subsets of these groups also provided longitudinal data over 18 months for volumetric analysis. The principal observations were that: GM and WM atrophy may be observed early in the clinical course of the disease: WM atrophy was more apparent at baseline, but over the period of follow-up GM atrophy occurred more rapidly than that of WM: changes in metabolite concentrations were found in GM and WM suggesting neuronal and axonal damage, and WM glial activation and or proliferation: WM lesion loads explained a fraction of GM and WM atrophy and metabolite variability: clinical outcome related more closely to tissue metabolite changes (GM glutamate and glutamine, and normal-appearing WM inositol) than atrophy at this stage of the disease

Analysis of the blood-to-brain tracer exchange in [18F]DPA714 PET imaging

openPositron Emission Tomography (PET) imaging has emerged as a valuable tool for non-invasive investigation of various brain disorders. One area of interest is the analysis of blood-to-brain tracer exchange, which provides insights into the integrity of the blood-brain barrier (BBB) and its potential alterations in neurological conditions. The effects of aging, gender, genotype, body mass index (BMI), and dose over weight (DW) on K1 have been examined in healthy people using a general mixed linear model and step-wise regression. An ANOVA test was then used to examine the K1 values in subjects with and without multiple sclerosis. A reduced compartmental model has been used to extract the value of K1 from 80 healthy controls and 45 patients with multiple sclerosis in the cortex and subcortex areas.Positron Emission Tomography (PET) imaging has emerged as a valuable tool for non-invasive investigation of various brain disorders. One area of interest is the analysis of blood-to-brain tracer exchange, which provides insights into the integrity of the blood-brain barrier (BBB) and its potential alterations in neurological conditions. The effects of aging, gender, genotype, body mass index (BMI), and dose over weight (DW) on K1 have been examined in healthy people using a general mixed linear model and step-wise regression. An ANOVA test was then used to examine the K1 values in subjects with and without multiple sclerosis. A reduced compartmental model has been used to extract the value of K1 from 80 healthy controls and 45 patients with multiple sclerosis in the cortex and subcortex areas