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

The tryptophan pathway and nicotinamide supplementation in ischaemic acute kidney injury

International audienceAbstract Background Down-regulation of the enzymes involved in tryptophan-derived nicotinamide (NAM) adenine dinucleotide (NAD+) production was identified after acute kidney injury (AKI), leading to the hypothesis that supplementation with NAM may increase the kidney NAD+ content, rescuing tryptophan pathways and subsequently improving kidney outcomes. Methods Urinary measurement of tryptophan and kynurenin using liquid chromatography–mass spectrometry metabolomics was used in a cohort of 167 cardiac bypass surgery patients along with tests for correlation to the development of postoperative AKI. A mouse model of ischaemic AKI using ischaemia–reperfusion injury (bilateral clamping of renal arteries for 25 min) was also used. Results We identified a significant decrease in urinary tryptophan and kynurenin in patients developing AKI, irrespective of the Kidney Disease: Improving Global Outcomes (KDIGO) stage. Although a significant difference was observed, tryptophan and kynurenin moderately discriminated for the development of all AKI KDIGO stages {area under the curve [AUC] 0.82 [95% confidence interval (CI) 0.75–0.88] and 0.75 [0.68–0.83], respectively} and severe KDIGO Stages 2–3 AKI [AUC 0.71 (95% CI 0.6–0.81) and 0.66 (0.55–0.77), respectively]. Sparked by this confirmation in humans, we aimed to confirm the potential preventive effect of NAM supplementation in wild-type male and female C57BL/6 mice subjected to ischaemic AKI. NAM supplementation had no effect on renal function (blood urea nitrogen at Day 1, sinistrin–fluorescein isothiocyanate glomerular filtration rate), architecture (periodic acid–Schiff staining) and injury or inflammation (kidney injury molecule 1 and IL18 messenger RNA expression). In addition, NAM supplementation did not increase post-AKI NAD+ kidney content. Conclusion Notwithstanding the potential role of NAM supplementation in the setting of basal NAD+ deficiency, our findings in mice and the reanalysis of published data do not confirm that NAM supplementation can actually improve renal outcomes after ischaemic AKI in unselected animals and probably patients

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

Importance We have previously combined oxygen-15 positron emission tomography (15O PET) and brain tissue oximetry (BptO2) to demonstrate increased oxygen diffusion gradients in hypoxic regions following traumatic brain injury (TBI). These data are consistent with microvascular ischaemia and are supported by pathological studies showing widespread microvascular collapse, perivascular oedema and microthrombosis associated with selective neuronal loss. 18F-fluoromisonidazole ([18F]FMISO), a PET tracer that undergoes irreversible selective bioreduction within hypoxic cells, could confirm these findings. Objective Combine ([18F]FMISO) and 15O PET to demonstrate the relative burden, distribution and physiological signatures of conventional macrovascular and microvascular ischaemia in early TBI. Design Observational. Setting Neurosciences Critical Care Unit. Participants Ten patients of median age 59 years (range 30–68) within 1-8 days of severe/moderate TBI, and two cohorts of 10 healthy volunteers aged 53 (41–76) and 45 (29–59) years. Exposures Cerebral blood flow (CBF), blood volume (CBV), oxygen metabolism (CMRO2), oxygen extraction fraction (OEF), and brain tissue hypoxia were measured in patients during combined 15O and [18F]FMISO PET imaging. Similar data were obtained from two cohorts of healthy volunteers who underwent either 15O or [18F]FMISO PET. Main Outcome Measures We estimated ischaemic brain volume (IBV) and hypoxic brain volume (HBV), and compared their spatial distribution and physiological signatures. Results Compared to controls, patients showed higher IBV (56(9 – 281) ml vs. 1(0 – 11) ml; p <0.001) and HBV (29 (0 – 106) ml vs. 9(1 – 24) ml; p < 0.05). While both pathophysiological tissue classes were present within injured and normal brain, their spatial distributions were poorly matched. When compared to tissue within the IBV compartment, the HBV compartment showed similar CBF, CBV and CMRO2, but lower OEF (p < 0.001), and more frequently showed CMRO2 values consistent with irreversible injury. Comparison with BptO2 monitoring suggested that the threshold for increased [18F]FMISO trapping is probably < 15 mmHg. Conclusions and relevance Tissue hypoxia following TBI is not confined to regions with structural abnormality, and can occur in the absence of conventional macrovascular ischaemia. This physiological signature is consistent with microvascular ischaemia 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)

Analysis of variance table for diffusion tensor imaging parameters.

<p>Data (mm²/second) were obtained from 26 volunteers using the region of interest (ROI) template for fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD). Degrees of freedom (DF).</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)

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

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

Region of interest template.

<p>T1 weighted magnetic resonance image in MNI152 space (2 mm resolution) showing frontal lobe left (Frontal L), frontal lobe right (Frontal R), anterior corpus callosum (ACC), caudate left (Caudate L), caudate right (Caudate R), thalamus left (Thalamus L), thalamus right (Thalamus R), posterior corpus callosum (PCC), occipital left (Occipital L) and occipital right (Occipital R). Additional regions not shown include body corpus callosum, ventral midbrain, dorsal midbrain, forceps minor, forceps major and bilateral regions covering the hippocampus, parietal lobe, temporal lobe, cerebral peduncle, pons, cerebellum, anterior thalamic radiation, superior longitudinal fasciculus, inferior longitudinal fasciculus, cingulum, uncinate fasciculus and corticospinal tract.</p