Quantitative MRI in the diagnosis and monitoring of human prion diseases

This thesis examines the application of cerebral diffusion weighted imaging (DWI) and short echo time (TE) proton magnetic resonance spectroscopy (1H-MRS) for the evaluation of patients with different forms of human prion disease. Human prion diseases are progressive, uniformly fatal neurodegenerative diseases and as treatments are developed, early diagnosis is essential. Particularly important is the diagnosis of presymptomatic cases and prediction of disease onset in these individuals. In this thesis I demonstrate that MRI measures of Apparent Diffusion Coefficient (ADC) at low and high b-value and short TE 1H-MRS are potential neuroimaging biomarkers of prion disease activity. I show that ex-vivo MRI at high field provides important insights into the microstructural changes underlying the sensitivity of some of these quantitative MRI methods to prion disease pathology. The findings presented here exemplify the potential of quantitative MRI in both increasing our understanding of the pathophysiology of prion diseases and in providing neuroimaging biomarkers which will be of great importance for the future evaluation of treatment efficacy

Imaging and CSF analyses effectively distinguish CJD from its mimics

OBJECTIVE: To review clinical and investigation findings in patients referred to a specialist prion clinic who were suspected to have sporadic Creutzfeldt-Jakob disease (sCJD) and yet were found to have an alternative final diagnosis. METHODS: Review the clinical findings and investigations in 214 patients enrolled into the UK National Prion Monitoring Cohort Study between October 2008 and November 2015 who had postmortem confirmed sCJD and compare these features with 50 patients referred over the same period who had an alternative final diagnosis (CJD mimics). RESULTS: Patients with an alternative diagnosis and those with sCJD were of similar age, sex and frequency of dementia but CJD mimics had a longer clinical history. Myoclonus, rigidity and hallucinations were more frequent in patients with sCJD but these features were not helpful in classifying individual patients. Alzheimer's disease, dementia with Lewy bodies and genetic neurodegenerative disorders were alternative diagnoses in more than half of the CJD mimic cases, and 10% had an immune-mediated encephalopathy; lymphoma, hepatic encephalopathy and progressive multifocal leukoencephalopathy were seen more than once. Diffusion-weighted MRI was the most useful readily available test to classify cases correctly (92% CJD, 2% CJD mimics). The CSF cell count, 14-3-3 protein detection and S100B were of limited value. A positive CSF RT-QuIC test, introduced during the course of the study, was found in 89% of tested CJD cases and 0% CJD mimics. CONCLUSION: The combination of diffusion-weighted MRI analysis and CSF RT-QuIC allowed a perfect classification of sCJD versus its mimics in this study

The autonomic brain: multi-dimensional generative hierarchical modelling of the autonomic connectome

The autonomic nervous system governs the body's multifaceted internal adaptation to diverse changes in the external environment, a role more complex than is accessible to the methods — and data scales — hitherto used to illuminate its operation. Here we apply generative graphical modelling to large-scale multimodal neuroimaging data encompassing normal and abnormal states to derive a comprehensive hierarchical representation of the autonomic brain. We demonstrate that whereas conventional structural and functional maps identify regions jointly modulated by parasympathetic and sympathetic systems, only graphical analysis discriminates between them, revealing the cardinal roles of the autonomic system to be mediated by high-level distributed interactions. We provide a novel representation of the autonomic system — a multidimensional, generative network — that renders its richness tractable within future models of its function in health and disease

Extensive subclinical sinusitis leading to Moraxella osloensis meningitis.

We report a case of a 31 year old male with extensive subclinical sinusitis leading to erosion in the cribriform plate and subsequent meningitis caused by the organism Moraxella osloensis. The patient presented to the emergency department with rapid onset confusion, neck stiffness and headache. Inflammatory markers, renal and liver function, and a chest radiograph were all normal. CT Head showed extensive polyp disease in the paranasal sinuses with expansion of the left frontal sinus and CT Sinuses revealed an area of low attenuation in the cribriform plate consistent with bony erosion. MRI Head showed thick loculated sinus inflammation. Lumbar puncture yielded CSF with a high white cell count of predominantly mononuclear cells, no visible organisms and an elevated protein. CSF microscopy, culture and viral PCR were not diagnostic, and so the CSF was sent for 16S rDNA PCR screening, which identified the rDNA of Moraxella osloensis. Moraxella osloensis is a rare cause of bacterial meningitis, with only a few reported cases. This case illustrates that sinusitis, while a common condition, when severe can predispose to intracranial infection with atypical and low virulence organisms such as Moraxella species, which do not commonly cause invasive CNS disease. This case represents the first case of Moraxella osloensis meningitis reported from the United Kingdom

Predicting outcome in childhood diffuse midline gliomas using magnetic resonance imaging based texture analysis

BACKGROUND: Diffuse midline gliomas (DMG) are aggressive brain tumours, previously known as diffuse intrinsic pontine gliomas (DIPG), with 10% overall survival (OS) at 18 months. Predicting OS will help refine treatment strategy in this patient group. MRI based texture analysis (MRTA) is novel image analysis technique that provides objective information about spatial arrangement of MRI signal intensity (heterogeneity) and has potential to be imaging biomarker. OBJECTIVES: To investigate MRTA in predicting OS in childhood DMG. METHODS: Retrospective study of patients diagnosed with DMG, based on radiological features, treated at our institution 2007-2017. MRIs were acquired at diagnosis and 6 weeks after radiotherapy (54Gy in 30 fractions). MRTA was performed using commercial available TexRAD research software on T2W sequence and Apparent Diffusion Coefficient (ADC) maps encapsulating tumour in the largest single axial plane. MRTA comprised filtration-histogram technique using statistical and histogram metrics for quantification of texture. Kaplan-Meier survival analysis determined association of MRI texture parameters with OS. RESULTS: 32 children 2-14 years (median 7 years) were included. MRTA was undertaken on T2W (n=32) and ADC (n=22). T2W-MRTA parameters were better at prognosticating than ADC-MRTA. Children with homogenous tumour texture, at medium scale on diagnostic T2W MRI, had worse prognosis (Mean of Positive Pixels (MPP): p=0.005, mean: p=0.009, SD: p=0.011, kurtosis: p=0.037, entropy: p=0.042). Best predictor MPP was able to stratify patients into poor and good prognostic groups with median survival of 7.5 months versus 17.5 months, respectively. CONCLUSIONS: DMG with more homogeneous texture on diagnostic MRI is associated with worse prognosis. Texture parameter MPP is the most predictive marker of OS in childhood DMG

The autonomic brain: Multi-dimensional generative hierarchical modelling of the autonomic connectome.

The autonomic nervous system governs the body's multifaceted internal adaptation to diverse changes in the external environment, a role more complex than is accessible to the methods-and data scales-hitherto used to illuminate its operation. Here we apply generative graphical modelling to large-scale multimodal neuroimaging data encompassing normal and abnormal states to derive a comprehensive hierarchical representation of the autonomic brain. We demonstrate that whereas conventional structural and functional maps identify regions jointly modulated by parasympathetic and sympathetic systems, only graphical analysis discriminates between them, revealing the cardinal roles of the autonomic system to be mediated by high-level distributed interactions. We provide a novel representation of the autonomic system-a multidimensional, generative network-that renders its richness tractable within future models of its function in health and disease

Brain tumour genetic network signatures of survival

Tumour heterogeneity is increasingly recognized as a major obstacle to therapeutic success across neuro-oncology. Gliomas are characterised by distinct combinations of genetic and epigenetic alterations, resulting in complex interactions across multiple molecular pathways. Predicting disease evolution and prescribing individually optimal treatment requires statistical models complex enough to capture the intricate (epi)genetic structure underpinning oncogenesis. Here, we formalize this task as the inference of distinct patterns of connectivity within hierarchical latent representations of genetic networks. Evaluating multi-institutional clinical, genetic, and outcome data from 4023 glioma patients over 14 years, across 12 countries, we employ Bayesian generative stochastic block modelling to reveal a hierarchical network structure of tumour genetics spanning molecularly confirmed glioblastoma, IDH- wildtype; oligodendroglioma, IDH-mutant and 1p/19q codeleted; and astrocytoma, IDH- mutant. Our findings illuminate the complex dependence between features across the genetic landscape of brain tumours, and show that generative network models reveal distinct signatures of survival with better prognostic fidelity than current gold standard diagnostic categories.Comment: Main article: 52 pages, 1 table, 7 figures. Supplementary material: 13 pages, 11 supplementary figure

Evolution of Diffusion-Weighted Magnetic Resonance Imaging Signal Abnormality in Sporadic Creutzfeldt-Jakob Disease, With Histopathological Correlation

IMPORTANCE: Prion diseases represent the archetype of brain diseases caused by protein misfolding, with the most common subtype being sporadic Creutzfeldt-Jakob disease (sCJD), a rapidly progressive dementia. Diffusion-weighted imaging (DWI) has emerged as the most sensitive magnetic resonance imaging (MRI) sequence for the diagnosis of sCJD, but few studies have assessed the evolution of MRI signal as the disease progresses. OBJECTIVES: To assess the natural history of the MRI signal abnormalities on DWI in sCJD to improve our understanding of the pathogenesis and to investigate the potential of DWI as a biomarker of disease progression, with histopathological correlation. DESIGN, SETTING, AND PARTICIPANTS: Gray matter involvement on DWI was assessed among 37 patients with sCJD in 26 cortical and 5 subcortical subdivisions per hemisphere using a semiquantitative scoring system of 0 to 2 at baseline and follow-up. A total brain score was calculated as the summed scores in the individual regions. In 7 patients, serial mean diffusivity measurements were obtained. Age at baseline MRI, disease duration, atrophy, codon 129 methionine valine polymorphism, Medical Research Council Rating Scale score, and histopathological findings were documented. The study setting was the National Prion Clinic, London, England. All participants had a probable or definite diagnosis of sCJD and had at least 2 MRI studies performed during the course of their illness. The study dates were October 1, 2008 to April 1, 2012. The dates of our analysis were January 19 to April 20, 2012. MAIN OUTCOMES AND MEASURES: Correlation of regional and total brain scores with disease duration. RESULTS: Among the 37 patients with sCJD in this study there was a significant increase in the number of regions demonstrating signal abnormality during the study period, with 59 of 62 regions showing increased signal intensity (SI) at follow-up, most substantially in the caudate and putamen (P < .001 for both). The increase in the mean (SD) total brain score from 30.2 (17.3) at baseline to 40.5 (20.6) at follow-up (P = .001) correlated with disease duration (r = 0.47, P = .003 at baseline and r = 0.35, P = .03 at follow-up), and the left frontal SI correlated with the degree of spongiosis (r = 0.64, P = .047). Decreased mean diffusivity in the left caudate at follow-up was seen (P < .001). Eight patients demonstrated decreased SI in cortical regions, including the left inferior temporal gyrus and the right lingual gyrus. CONCLUSIONS AND RELEVANCE: Magnetic resonance images in sCJD show increased extent and degree of SI on DWI that correlates with disease duration and the degree of spongiosis. Although cortical SI may fluctuate, increased basal ganglia SI is a consistent finding and is due to restricted diffusion. Diffusion-weighted imaging in the basal ganglia may provide a noninvasive biomarker in future therapeutic trials