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PubMed | Imperial College London, Imanova Center for Imaging science, University College London and King's College London
Type: Journal Article | Journal: Biological psychiatry | Year: 2016

Depression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand [(18)F]PBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging.The Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher [(18)F]PBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between [(18)F]PBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS.Patients with MS had an increased hippocampal [(18)F]PBR111 distribution volume ratio relative to healthy control subjects (p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS (r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and [(18)F]PBR111 distribution volume ratio.Our results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of the role of inflammatory processes in the pathogenesis of depression more generally.

Russo E.A.,Imperial College London | Khan S.,Imperial College London | Janisch R.,Imanova Center for Imaging science | Gunn R.N.,Imperial College London | And 6 more authors.
Inflammatory Bowel Diseases | Year: 2016

Background: 18Fluorine-fluorodeoxyglucose positron emission tomography (18F-FDG PET) has recently attracted interest for the measurement of disease activity in Crohn's disease (CD). The aim of this study was to assess the utility of FDG-PET as a marker of progression of inflammatory activity and its response to treatment in patients with CD. Methods: Twenty-two patients with active CD were recruited prospectively to undergo FDG-PET scanning at 2 time points. All 22 index scans were used to assess sensitivity and specificity against a reference standard magnetic resonance imaging measure. Correlations with clinicopathological markers of severity (Harvey-Bradshaw Index, C-reactive protein, and calprotectin) were also performed. Of note, 17/22 patients participated in the longitudinal component and underwent scanning before and 12 weeks after the initiation of anti-tumor necrosis factor alpha therapy. Patients were subcategorized on the basis of a clinically significant response, and responsiveness of the PET measures was assessed using previously described indices. Of note, 5/22 patients took part in the test-retest component of the study and underwent scanning twice within a target interval of 1 week, to assess the reproducibility of the PET measures. Results: The sensitivity and specificity of 18F-FDG PET were 88% and 70%, respectively. Standardized uptake value (SUV)-related PET measures correlated significantly both with C-reactive protein and Harvey-Bradshaw Index in cross-sectional and longitudinal analyses. (G)SUVMAX and (G)SUV MEAN demonstrated favorable responsiveness and reliability characteristics (responsiveness ratio of Guyatt >0.80 and % variability <20%) compared with volume-dependent FDG-PET measures. A proportion of the FDG signal (10%-30%) was found to originate from the lumen of diseased segments. Conclusions: 18F-FDG PET may be useful for longitudinal monitoring of inflammatory activity in CD. Copyright © 2016 Crohn's & Colitis Foundation of America, Inc.

PubMed | Imperial College London, Imanova Center for Imaging science and King's College London
Type: | Journal: NeuroImage. Clinical | Year: 2016

Age of onset in multiple sclerosis (MS) exerts an influence on the course of disease. This study examined whether global and regional brain volumes differed between younger and older onset MS subjects who were matched for short disease duration, mean 1.9years and burden as measured by the MS Severity Score and relapses. 21 younger-onset MS subjects (age 30.43.2years) were compared with 17 older-onset (age 48.73.3years) as well as age-matched controls (

Varrone A.,Karolinska Institutet | Oikonen V.,University of Turku | Forsberg A.,Karolinska Institutet | Joutsa J.,University of Turku | And 19 more authors.
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2014

Purpose: Imaging of the 18-kDa translocator protein (TSPO) is a potential tool for examining microglial activation and neuroinflammation in early Alzheimer’s disease (AD). [18F]FEMPA is a novel high-affinity second-generation TSPO radioligand that has displayed suitable pharmacokinetic properties in preclinical studies. The aims of this study were to quantify the binding of [18F]FEMPA to TSPO in AD patients and controls and to investigate whether higher [18F]FEMPA binding in AD patients than in controls could be detected in vivo. Methods: Ten AD patients (five men, five women; age 66.9 ± 7.3 years; MMSE score 25.5 ± 2.5) and seven controls (three men, four women; age 63.7 ± 7.2 years, MMSE score 29.3 ± 1.0) were studied using [18F]FEMPA at Turku (13 subjects) and at Karolinska Institutet (4 subjects). The in vitro binding affinity for TSPO was assessed using PBR28 in a competition assay with [3H]PK11195 in seven controls and eight AD patients. Cortical and subcortical regions of interest were examined. Quantification was performed using a two-tissue compartment model (2TCM) and Logan graphical analysis (GA). The outcome measure was the total distribution volume (VT). Repeated measures analysis of variance was used to assess the effect of group and TSPO binding status on VT. Results: Five AD patients and four controls were high-affinity binders (HABs). Three AD patients and three controls were mixed-affinity binders. VT estimated with Logan GA was significantly correlated with VT estimated with the 2TCM in both controls (r = 0.97) and AD patients (r = 0.98) and was selected for the final analysis. Significantly higher VT was found in the medial temporal cortex in AD patients than in controls (p = 0.044) if the TSPO binding status was entered as a covariate. If only HABs were included, significantly higher VT was found in the medial and lateral temporal cortex, posterior cingulate, caudate, putamen, thalamus and cerebellum in AD patients than in controls (p < 0.05). Conclusion: [18F]FEMPA seems to be a suitable radioligand for detecting increased TSPO binding in AD patients if their binding status is taken into account. © 2014, Springer-Verlag Berlin Heidelberg.

Libri V.,Imperial College London | Brown A.P.,Imanova Center for Imaging science | Gambarota G.,Imperial College London | Haddad J.,Sirtris Pharmaceuticals | And 9 more authors.
PLoS ONE | Year: 2012

Background: SRT2104 has been developed as a selective small molecule activator of SIRT1, a NAD+-dependent deacetylase involved in the regulation of energy homeostasis and the modulation of various metabolic pathways, including glucose metabolism, oxidative stress and lipid metabolism. SIRT1 has been suggested as putative therapeutic target in multiple age-related diseases including type 2 diabetes and dyslipidemias. We report the first clinical trial of SRT2104 in elderly volunteers. Methods: Oral doses of 0.5 or 2.0 g SRT2104 or matching placebo were administered once daily for 28 days. Pharmacokinetic samples were collected through 24 hours post-dose on days 1 and 28. Multiple pharmacodynamic endpoints were explored with oral glucose tolerance tests (OGTT), serum lipid profiles, magnetic resonance imaging (MRI) for assessment of whole body visceral and subcutaneous fat, maximal aerobic capacity test and muscle 31P magnetic resonance spectroscopy (MRS) for estimation of mitochondrial oxidative capacity. Results: SRT2104 was generally safe and well tolerated. Pharmacokinetic exposure increased less than dose-proportionally. Mean Tmax was 2-4 hours with elimination half-life of 15-20 hours. Serum cholesterol, LDL levels and triglycerides decreased with treatment. No significant changes in OGTT responses were observed. 31P MRS showed trends for more rapid calculated adenosine diphosphate (ADP) and phosphocreatine (PCr) recoveries after exercise, consistent with increased mitochondrial oxidative phosphorylation. Conclusions: SRT2104 can be safely administered in elderly individuals and has biological effects in humans that are consistent with SIRT1 activation. The results of this study support further development of SRT2104 and may be useful in dose selection for future clinical trials in patients. Trial Registration: NCT00964340. © 2012 Libri et al.

Pinato D.J.,Imperial College London | Stavraka C.,Imperial College London | Tanner M.,Imanova Center for Imaging science | Esson A.,Imperial College London | And 3 more authors.
PLoS ONE | Year: 2012

Background: The detection of incidental findings (IF) in magnetic resonance imaging (MRI) studies is common and increases as a function of age. Responsible handling of IF is required, with implications for the conduct of research and the provision of good clinical care. Aim: To investigate the prevalence and clinical significance of IF in a prospective cohort of healthy elderly volunteers who underwent MRI of the torso as a baseline investigation for a phase I trial. We assessed the follow-up pathway with consequent cost implications and impact on trial outcomes. Methods: A total of 29 elderly healthy volunteers (mean age 67, range 61-77, 59% female) were eligible at screening and underwent MRI for assessment of visceral and subcutaneous fat. Results: IF were detected in 19 subjects (66%). Suspected IF of high and low clinical significance were found in 14% and 52% of participants, respectively. Follow up of IF was conducted in 18 individuals, confirming abnormalities in 13 subjects, 3 of whom were recommended for deferred clinical re-evaluation. The remaining 5 subjects had false positive IF based on second line imaging tests. Costs of follow-up medical care were considerable. Conclusion: MRI abnormalities are common in elderly individuals, as a result of age and non-diagnostic quality of research scans. In the presence of IF in the context of clinical trials, immediate referrals and follow up assessments may be required to rule out suspected pathology prior to exposing trial participants to investigational medicine products (IMP). Unanticipated costs, ethical implication and the possible impact of IF on trial outcomes need to be taken into account when designing and conducting trials with an IMP. © 2012 Pinato et al.

Kaggie J.D.,University of Utah | Hadley J.R.,University of Utah | Badal J.,Brigham Young University | Campbell J.R.,Brigham Young University | And 7 more authors.
Magnetic Resonance in Medicine | Year: 2014

Purpose: The objective of this study was to determine whether a sodium phased array would improve sodium breast MRI at 3 T. The secondary objective was to create acceptable proton images with the sodium phased array in place. Methods: A novel composite array for combined proton/sodium 3 T breast MRI is compared with a coil with a single proton and sodium channel. The composite array consists of a 7-channel sodium receive array, a larger sodium transmit coil, and a 4-channel proton transceive array. The new composite array design utilizes smaller sodium receive loops than typically used in sodium imaging, uses novel decoupling methods between the receive loops and transmit loops, and uses a novel multichannel proton transceive coil. The proton transceive coil reduces coupling between proton and sodium elements by intersecting the constituent loops to reduce their mutual inductance. The coil used for comparison consists of a concentric sodium and proton loop with passive decoupling traps. Results: The composite array coil demonstrates a 2-5× improvement in signal-to-noise ratio for sodium imaging and similar signal-to-noise ratio for proton imaging when compared with a simple single-loop dual resonant design. Conclusion: The improved signal-to-noise ratio of the composite array gives breast sodium images of unprecedented quality in reasonable scan times. © 2013 Wiley Periodicals, Inc.

Challapalli A.,Imperial College London | Sharma R.,Imperial College London | Hallett W.A.,Imanova Center for Imaging science | Kozlowski K.,Imperial College London | And 5 more authors.
Journal of Nuclear Medicine | Year: 2014

11C-choline and 18F-fluoromethylcholine ( 18F-FCH) have been used in patients to study tumor metabolic activity in vivo; however, both radiotracers are readily oxidized to respective betaine analogs, with metabolites detectable in plasma soon after injection of the radiotracer. A more metabolically stable FCH analog, 18F- fluoromethyl- [1,2-2H4]choline (18F-D4-FCH), based on the deuterium isotope effect, has been developed. We report the safety, biodistribution, and internal radiation dosimetry profiles of 18F-D4-FCH in 8 healthy human volunteers. Methods: 18F-D4-FCH was intravenously administered as a bolus injection (mean ± SD, 161 ± 2.17 MBq; range, 156-163 MBq) to 8 healthy volunteers (4 men, 4 women). Whole-body (vertex to mid thigh) PET/CT scans were acquired at ± time points, up to 4 h after tracer injection. Serial whole-blood, plasma, and urine samples were collected for radioactivity measurement and plasma radiotracer metabolites. Tissue 18F radioactivities were determined fromquantitative analysis of the images, and time-activity curves were generated. The total numbers of disintegrations in each organ normalized to injected activity (residence times) were calculated as the area under the curve of the time-activity curve normalized to injected activities and standard organ volumes. Dosimetry calculations were performed using OLINDA/EXM 1.1. Results: The injection of 18F-D4-FCH was well tolerated in all subjects, with no radiotracer-related serious adverse event reported. The mean effective dose averaged over both men and women (6SD) was estimated to be 0.025 ± 0.004 (men, 0.022 ± 0.002; women, 0.027 ± 0.002) mSv/MBq. The = organs receiving the highest absorbed dose (mGy/MBq) were the kidneys (0.106 ± 0.03), liver (0.094 ± 0.03), pancreas (0.066 ± 0.01), urinary bladder wall (0.047 ± 0.02), and adrenals (0.046 ± 0.01). Elimination was through the renal and hepatic systems. Conclusion: 18F-D4-FCH is a safe PET radiotracer with a dosimetry profile comparable to other common 18F PET tracers. These data support the further development of 18F-D4-FCH for clinical imaging of choline metabolism. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

PubMed | Imperial College London and Imanova Center for Imaging science
Type: Journal Article | Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine | Year: 2016

We conducted the first-in-human study of (18)F-fluoroethyl triazole [Tyr(3)] octreotate ((18)F-FET-AG-TOCA) in patients with neuroendocrine tumors (NETs) to evaluate biodistribution, dosimetry, and safety. Despite advances in clinical imaging, detection and quantification of NET activity remains a challenge, with no universally accepted imaging standard.Nine patients were enrolled. Eight patients had sporadic NETs, and 1 had multiple endocrine neoplasia type 1 syndrome. Patients received 137-163 MBq (mean SD, 155.7 8 MBq) of (18)F-FET-AG-TOCA. Safety data were obtained during and 24 h after radioligand administration. Patients underwent detailed whole-body PET/CT multibed scanning over 4 h with sampling of venous bloods for radioactivity and radioactive metabolite quantification. Regions of interest were defined to derive individual and mean organ residence times; effective dose was calculated with OLINDA 1.1.All patients tolerated (18)F-FET-AG-TOCA with no adverse events. Over 60% parent radioligand was present in plasma at 60 min. High tumor (primary and metastases)-to-background contrast images were observed. Physiologic distribution was seen in the pituitary, salivary glands, thyroid, and spleen, with low background distribution in the liver, an organ in which metastases commonly occur. The organs receiving highest absorbed dose were the gallbladder, spleen, stomach, liver, kidneys, and bladder. The calculated effective dose over all subjects (mean SD) was 0.029 0.004 mSv/MBq.The favorable safety, imaging, and dosimetric profile makes (18)F-FET-AG-TOCA a promising candidate radioligand for staging and management of NETs. Clinical studies in an expanded cohort are ongoing to clinically qualify this agent.

PubMed | Imperial College London and Imanova Center for Imaging science
Type: | Journal: Journal of neuroimaging : official journal of the American Society of Neuroimaging | Year: 2016

Demyelination is a core pathological feature of multiple sclerosis (MS) and spontaneous remyelination appears to be an important mechanism for repair in the disease. Magnetization transfer ratio imaging (MTR) has been used extensively to evaluate demyelination, although limitations to its specificity are recognized. MT saturation imaging (MTsat) removes some of the T1 dependence of MTR. We have performed a comparative evaluation of MTR and MTsat imaging in a mixed group of subjects with active MS, to explore their relative sensitivity to pathology relevant to explaining clinical outcomes.A total of 134 subjects underwent MRI of their brain and cervical spinal cord. Isotropic 3-dimensional pre- and postcontrast T1-weighted and T2-weighted fluid-attenuated inversion recovery (FLAIR) volumes were segmented into brain normal appearing white matter (NAWM), brain WM lesions (WML), normal appearing spinal cord (NASC), and spinal cord lesions. Volumes and metrics for MTR and MTsat histograms were calculated for each region.Significant Spearman correlations were found with the Expanded Disability Status Scale and timed 25-foot walk for the whole brain and WML MTR, but not in that from the NAWM or any cervical spinal cord region. By contrast, the MTsat was correlated with both disability metrics in all these regions in both the brain and spine.This study extends prior work relating atrophy and lesion load with disability, by characterization of MTsat parameters. MTsat is practical in routine clinical applications and may be more sensitive to tissue damage than MTR for both brain and cervical spinal cord.

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