Inter subject variability and reproducibility of diffusion tensor imaging within and between different imaging sessions.

The aim of these studies was to provide reference data on intersubject variability and reproducibility of diffusion tensor imaging. Healthy volunteers underwent imaging on two occasions using the same 3T Siemens Verio magnetic resonance scanner. At each session two identical diffusion tensor sequences were obtained along with standard structural imaging. Fractional anisotropy, apparent diffusion coefficient, axial and radial diffusivity maps were created and regions of interest applied in normalised space. The baseline data from all 26 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were different across the brain. The regional mean (range) coefficient of variation figures for within session reproducibility were 2.1 (0.9-5.5%), 1.2 (0.4-3.9%), 1.2 (0.4-3.8%) and 1.8 (0.4-4.3%) for fractional anisotropy, apparent diffusion coefficient, axial and radial diffusivity, and were lower than between session reproducibility measurements (2.4 (1.1-5.9%), 1.9 (0.7-5.7%), 1.7 (0.7-4.7%) and 2.4 (0.9-5.8%); p<0.001). The calculated overall and within session 95% prediction intervals for zero change were similar. This study provides additional reference data concerning intersubject variability and reproducibility of diffusion tensor imaging conducted within the same imaging session and different imaging sessions. These data can be utilised in interventional studies to quantify change within a single imaging session, or to assess the significance of change in longitudinal studies of brain injury and disease.RCUK, Wellcome, OtherThis is the published version. It was originally published by PLoS in PLoS ONE here: http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0065941

Comparison of inter subject variability and reproducibility of whole brain proton spectroscopy.

The aim of these studies was to provide reference data on intersubject variability and reproducibility of metabolite ratios for Choline/Creatine (Cho/Cr), N-acetyl aspartate/Choline (NAA/Cho) and N-acetyl aspartate/Creatine (NAA/Cr), and individual signal-intensity normalised metabolite concentrations of NAA, Cho and Cr. Healthy volunteers underwent imaging on two occasions using the same 3T Siemens Verio magnetic resonance scanner. At each session two identical Metabolic Imaging and Data Acquisition Software (MIDAS) sequences were obtained along with standard structural imaging. Metabolite maps were created and regions of interest applied in normalised space. The baseline data from all 32 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were variable across the different brain regions. The within and between session reproducibility measurements were similar for Cho/Cr, NAA/Choline, Cho and Cr (11.8%, 11.4%, 14.3 and 10.6% vs. 11.9%, 11.4%, 13.5% and 10.5% respectively), but for NAA/Creatine and NAA between session reproducibility was lower (9.3% and 9.1% vs. 10.1% and 9.9%; p <0.05). This study provides additional reference data that can be utilised in interventional studies to quantify change within a single imaging session, or to assess the significance of change in longitudinal studies of brain injury and disease.TV Veenith was supported by clinical research training fellowship from the National Institute of Academic Anaesthesia and Raymond Beverly Sackler studentship. VFJN is supported by an NIHR academic clinical fellowship. JPC was supported by Wellcome trust project grant. DKM is supported by an NIHR Senior Investigator Award. This work was supported by a Medical Research Council (UK) Program Grant (Acute brain injury: heterogeneity of mechanisms, therapeutic targets and outcome effects (G9439390 ID 65883)), the UK National Institute of Health Research Biomedical Research Centre at Cambridge, and the Technology Platform funding provided by the UK Department of Health.This article was originally published in PLoS ONE (Veenith TV, Mada M, Carter E, Grossac J, Newcombe V, et al. (2014) Comparison of Inter Subject Variability and Reproducibility of Whole Brain Proton Spectroscopy. PLoS ONE 9(12): e115304. doi:10.1371/journal.pone.0115304

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

Inter subject variability and reproducibility of diffusion tensor imaging within and between different imaging sessions

The aim of these studies was to provide reference data on intersubject variability and reproducibility of diffusion tensor imaging. Healthy volunteers underwent imaging on two occasions using the same 3T Siemens Verio magnetic resonance scanner. At each session two identical diffusion tensor sequences were obtained along with standard structural imaging. Fractional anisotropy, apparent diffusion coefficient, axial and radial diffusivity maps were created and regions of interest applied in normalised space. The baseline data from all 26 volunteers were used to calculate the intersubject variability, while within session and between session reproducibility were calculated from all the available data. The reproducibility of measurements were used to calculate the overall and within session 95% prediction interval for zero change. The within and between session reproducibility data were lower than the values for intersubject variability, and were different across the brain. The regional mean (range) coefficient of variation figures for within session reproducibility were 2.1 (0.9–5.5%), 1.2 (0.4–3.9%), 1.2 (0.4–3.8%) and 1.8 (0.4–4.3%) for fractional anisotropy, apparent diffusion coefficient, axial and radial diffusivity, and were lower than between session reproducibility measurements (2.4 (1.1–5.9%), 1.9 (0.7–5.7%), 1.7 (0.7–4.7%) and 2.4 (0.9–5.8%); p<0.001). The calculated overall and within session 95% prediction intervals for zero change were similar. This study provides additional reference data concerning intersubject variability and reproducibility of diffusion tensor imaging conducted within the same imaging session and different imaging sessions. These data can be utilised in interventional studies to quantify change within a single imaging session, or to assess the significance of change in longitudinal studies of brain injury and disease

Normobaric hyperoxia does not improve derangements in diffusion tensor imaging found distant from visible contusions following acute traumatic brain injury

Abstract We have previously shown that normobaric hyperoxia may benefit peri-lesional brain and white matter following traumatic brain injury (TBI). This study examined the impact of brief exposure to hyperoxia using diffusion tensor imaging (DTI) to identify axonal injury distant from contusions. Fourteen patients with acute moderate/severe TBI underwent baseline DTI and following one hour of 80% oxygen. Thirty-two controls underwent DTI, with 6 undergoing imaging following graded exposure to oxygen. Visible lesions were excluded and data compared with controls. We used the 99% prediction interval (PI) for zero change from historical control reproducibility measurements to demonstrate significant change following hyperoxia. Following hyperoxia DTI was unchanged in controls. In patients following hyperoxia, mean diffusivity (MD) was unchanged despite baseline values lower than controls (p < 0.05), and fractional anisotropy (FA) was lower within the left uncinate fasciculus, right caudate and occipital regions (p < 0.05). 16% of white and 14% of mixed cortical and grey matter patient regions showed FA decreases greater than the 99% PI for zero change. The mechanistic basis for some findings are unclear, but suggest that a short period of normobaric hyperoxia is not beneficial in this context. Confirmation following a longer period of hyperoxia is required

Variability in fractional anisotropy measurements.

<p>Box and whisker plot for fractional anisotropy values (mm²/second) for the white matter region of interest (ROI) measurements. The spread of data within each ROI reflects inter subject variation, while the difference between runs 1–2 and 3–4 reflects within session reproducibility, and the change from first to second sessions reflects between session reproducibility. The central lines in each box denote median values, the lower and upper boundaries the 25th and 75th centile, the error bars the 10th and 90th centile, and the closed circles outlying data points. Anterior corpus callosum (ACC), body corpus callosum (BCC), posterior corpus callosum (PCC), left anterior thalamic radiation (ATR L), right anterior thalamic radiation (ATR R), left superior longitudinal fasciculus (SLF L), right superior longitudinal fasciculus (SLF R), left inferior longitudinal fasciculus (ILF L), right inferior longitudinal fasciculus (ILF R), left cingulum (Cingulum L), right cingulum (Cingulum R), left uncinate fasciculus (UFL), right uncinate fasciculus (UFR), left corticospinal tract (CST L), right corticospinal tract (CST R), dorsal midbrain (dorsal MB), ventral midbrain (ventral midbrain), left cerebral peduncle (CP L), right cerebral peduncle (CP R), left pons (pons L) and right pons (pons R).</p

Pathophysiologic Mechanisms of Cerebral Ischemia and Diffusion Hypoxia in Traumatic Brain Injury.

IMPORTANCE: Combined oxygen 15-labeled positron emission tomography (15O PET) and brain tissue oximetry have demonstrated increased oxygen diffusion gradients in hypoxic regions after traumatic brain injury (TBI). These data are consistent with microvascular ischemia and are supported by pathologic studies showing widespread microvascular collapse, perivascular edema, and microthrombosis associated with selective neuronal loss. Fluorine 18-labeled fluoromisonidazole ([18F]FMISO), a PET tracer that undergoes irreversible selective bioreduction within hypoxic cells, could confirm these findings. OBJECTIVE: To combine [18F]FMISO and 15O PET to demonstrate the relative burden, distribution, and physiologic signatures of conventional macrovascular and microvascular ischemia in early TBI. DESIGN, SETTING, AND PARTICIPANTS: This case-control study included 10 patients who underwent [18F]FMISO and 15O PET within 1 to 8 days of severe or moderate TBI. Two cohorts of 10 healthy volunteers underwent [18F]FMISO or 15O PET. The study was performed at the Wolfson Brain Imaging Centre of Addenbrooke's Hospital. Cerebral blood flow, cerebral blood volume, cerebral oxygen metabolism (CMRO2), oxygen extraction fraction, and brain tissue oximetry were measured in patients during [18F]FMISO and 15O PET imaging. Similar data were obtained from control cohorts. Data were collected from November 23, 2007, to May 22, 2012, and analyzed from December 3, 2012, to January 6, 2016. MAIN OUTCOMES AND MEASURES: Estimated ischemic brain volume (IBV) and hypoxic brain volume (HBV) and a comparison of their spatial distribution and physiologic signatures. RESULTS: The 10 patients with TBI (9 men and 1 woman) had a median age of 59 (range, 30-68) years; the 2 control cohorts (8 men and 2 women each) had median ages of 53 (range, 41-76) and 45 (range, 29-59) years. Compared with controls, patients with TBI had a higher median IBV (56 [range, 9-281] vs 1 [range, 0-11] mL; P < .001) and a higher median HBV (29 [range, 0-106] vs 9 [range, 1-24] mL; P = .02). Although both pathophysiologic tissue classes were present within injured and normal appearing brains, their spatial distributions were poorly matched. When compared with tissue within the IBV compartment, the HBV compartment showed similar median cerebral blood flow (17 [range, 11-40] vs 14 [range, 6-22] mL/100 mL/min), cerebral blood volume (2.4 [range, 1.6- 4.2] vs 3.9 [range, 3.4-4.8] mL/100 mL), and CMRO2 (44 [range, 27-67] vs 71 [range, 34-88] μmol/100 mL/min) but a lower oxygen extraction fraction (38% [range, 29%-50%] vs 89% [range, 75%-100%]; P < .001), and more frequently showed CMRO2 values consistent with irreversible injury. Comparison with brain tissue oximetry monitoring suggested that the threshold for increased [18F]FMISO trapping is probably 15 mm Hg or lower. CONCLUSIONS AND RELEVANCE: Tissue hypoxia after TBI is not confined to regions with structural abnormality and can occur in the absence of conventional macrovascular ischemia. This physiologic signature is consistent with microvascular ischemia and is a target for novel neuroprotective strategies.TVV was supported by a clinical research training fellowship from National Institute of Academic Anaesthesia and Raymond Beverly Sackler studentship. TG was supported by a clinical research training fellowship from The Société Française d’Anesthésie et de Réanimation (SFAR). VFJN is supported by a Health Foundation / Academy of Medical Sciences Clinician Scientist Fellowship. DKM is supported by an NIHR Senior Investigator Award. This work was supported by a Wellcome Trust Project Grant (WT093267) and Medical Research Council (UK) Program Grant (Acute brain injury: heterogeneity of mechanisms, therapeutic targets and outcome effects (G9439390 ID 65883)), the UK National Institute of Health Research Biomedical Research Centre at Cambridge, and the Technology Platform funding provided by the UK Department of Health (JPC, DKM, TDF and FIA)

Within and between session variability of diffusion tensor imaging region of interest measurements.

<p>Individual white matter region of interest measurements for within session reproducibility obtained in the first and second imaging sessions in 26 and 22 subjects respectively, and the between session reproducibility for those 22 subjects who underwent imaging at both sessions. Data displayed are standard deviation of measurements for fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial (AD) and radial (RD) diffusivity.</p

Within and between session variability of diffusion tensor imaging region of interest measurements.

<p>Individual mixed cortical and deep grey matter region of interest measurements for within session reproducibility obtained in the first and second imaging sessions in 26 and 22 subjects respectively, and the between session reproducibility for those 22 subjects who underwent imaging at both sessions. Data displayed are standard deviation of measurements for fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial (AD) and radial (RD) diffusivity.</p