Medical Research Council Clinical science Center

London, United Kingdom

Medical Research Council Clinical science Center

London, United Kingdom
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McGinnity C.J.,Imperial College London | McGinnity C.J.,Medical Research Council Clinical science Center | McGinnity C.J.,King's College London | Shidahara M.,Tohoku University | And 19 more authors.
NeuroImage | Year: 2013

Previous positron emission tomography (PET) studies in refractory temporal lobe epilepsy (TLE) using the non-selective opioid receptor antagonist [11C]diprenorphine (DPN) did not detect any changes in mesial temporal structures, despite known involvement of the hippocampus in seizure generation. Normal binding in smaller hippocampi is suggestive of increased receptor concentration in the remaining grey matter. Correction for partial-volume effect (PVE) has not been used in previous DPN PET studies. Here, we present PVE-corrected DPN-PET data quantifying post-ictal and interictal opioid receptor availability in humans with mTLE.Eight paired datasets of post-ictal and interictal DPN PET scans and eleven test/retest control datasets were available from a previously published study on opioid receptor changes in TLE following seizures (Hammers et al., 2007a). Five of the eight participants with TLE had documented hippocampal sclerosis. Data were re-analyzed using regions of interest and a novel PVE correction method (structural functional synergistic-resolution recovery (SFS-RR); (Shidahara et al., 2012)). Data were denoised, followed by application of SFS-RR, with anatomical information derived via precise anatomical segmentation of the participants' MRI (MAPER; (Heckemann et al., 2010)). [11C]diprenorphine volume-of-distribution (VT) was quantified in six regions of interest.Post-ictal increases were observed in the ipsilateral fusiform gyri and lateral temporal pole. A novel finding was a post-ictal increase in [11C]DPN VT relative to the interictal state in the ipsilateral parahippocampal gyrus, not observed in uncorrected datasets. As for voxel-based (SPM) analyses, correction for global VT values was essential in order to demonstrate focal post-ictal increases in [11C]DPN VT.This study provides further direct human in vivo evidence for changes in opioid receptor availability in TLE following seizures, including changes that were not evident without PVE correction. Denoising, resolution recovery and precise anatomical segmentation can extract valuable information from PET studies that would be missed with conventional post-processing procedures. © 2013.

Meyer P.T.,University Hospital Freiburg | Bhagwagar Z.,Bristol Myers Squibb | Cowen P.J.,University of Oxford | Cunningham V.J.,Imperial College London | And 2 more authors.
NeuroImage | Year: 2010

Background: [11C]MDL100,907 is a promising positron emission tomography (PET) ligand for 5-HT2A receptor quantification in vivo. Studies suggest that [11C]MDL100,907 PET may be quantified by non-invasive reference tissue analyses using cerebellum as reference region. We systematically investigated the validity of such analyses. Methods: Five healthy volunteers underwent [11C]MDL100,907 PET at baseline and after mirtazapine pre-treatment. Regional time-activity curves of 10 regions of interest (ROI) were analyzed for binding potential (BPND) and mirtazapine receptor occupancy (Occ) using: simplified reference tissue model (SRTM), multi-linear reference tissue model (MRTM), their two-parameter versions (SRTM2/MRTM2), non-invasive graphical analysis (NIGA) and a tissue activity concentration ratio. NIGA was also applied voxel-wise to generate BPND maps. These methods were compared with a two-tissue compartment model with arterial input function (2TCM) Results: SRTM and MRTM frequently failed to yield reliable results. SRTM2 and MRTM2 gave virtually identical estimates of BPND, which were highly correlated with 2TCM analyses (R2 ≥ 0.86) although with negative bias (- 29 ± 27% at baseline across all ROI). NIGA was less biased (- 19 ± 16%) and better correlated with 2TCM (R2 ≥ 0.93). Regarding Occ, NIGA and SRTM2/MRTM2 showed comparable mean biases (- 11 ± 27% vs. - 7 ± 47%) but correlation with 2TCM was higher for NIGA (R2 = 0.90 vs. 0.77). NIGA parametric maps (analysed using identical ROI) resulted in moderate bias in BPND (- 26 ± 22%; R2 ≥ 0.88) and Occ (- 17 ± 36%; R2 = 0.78). Estimates obtained from tissue ratios performed least favourably. Conclusions: NIGA is well suited for analysis of [11C]MDL100,907 PET studies, yielding estimates of 5-HT2A receptor availability and changes that are highly correlated with results from invasive 2TCM analyses. This should greatly enhance the applicability of 5-HT2A receptor PET studies. © 2010 Elsevier Inc. All rights reserved.

Sanders R.D.,Intensive Care and Pain Medicine and Leucocyte Biology | Manning H.J.,Intensive Care and Pain Medicine | Robertson N.J.,Medical Research Council Clinical science Center | Ma D.,Imperial College London | And 4 more authors.
Anesthesiology | Year: 2010

Perinatal hypoxic-ischemic encephalopathy can be a devastating complication of childbirth. Herein, the authors review the pathophysiology of hypoxic-ischemic encephalopathy and the current status of neuroprotective strategies to ameliorate the injury centering on four themes: (1) monitoring in the perinatal period, (2) rapid identification of affected neonates to allow timely institution of therapy, (3) preconditioning therapy (a therapeutic that reduces the brain vulnerability) before hypoxic-ischemic encephalopathy, and (4) prompt institution of postinsult therapies to ameliorate the evolving injury. Recent clinical trials have demonstrated the significant benefit for hypothermic therapy in the postnatal period; furthermore, there is accumulating preclinical evidence that adjunctive therapies can enhance hypothermic neuroprotection. Advances in the understanding of preconditioning may lead to the administration of neuroprotective agents earlier during childbirth. Although most of these neuroprotective strategies have not yet entered clinical practice, there is a significant hope that further developments will enhance hypothermic neuroprotection. Copyright © 2010, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins.

McGinnity C.J.,Imperial College London | McGinnity C.J.,Medical Research Council Clinical science Center | McGinnity C.J.,King's College London | Koepp M.J.,University College London | And 20 more authors.
Journal of Neurology, Neurosurgery and Psychiatry | Year: 2015

Objective: To demonstrate altered N-methyl-D-aspartate (NMDA) receptor availability in patients with focal epilepsies using positron emission tomography (PET) and [18 F]GE-179, a ligand that selectively binds to the open NMDA receptor ion channel, which is thought to be overactive in epilepsy. Methods: Eleven patients (median age 33 years, 6 males) with known frequent interictal epileptiform discharges had an [18F]GE-179 PET scan, in a crosssectional study. MRI showed a focal lesion but discordant EEG changes in two, was non-localising with multifocal EEG abnormalities in two, and was normal in the remaining seven patients who all had multifocal EEG changes. Individual patient [18F]GE-179 volume-of distribution (VT) images were compared between individual patients and a group of 10 healthy controls (47 years, 7 males) using Statistical Parametric Mapping. Results: Individual analyses revealed a single cluster of focal VT increase in four patients; one with a single and one with multifocal MRI lesions, and two with normal MRIs. Post hoc analysis revealed that, relative to controls, patients not taking antidepressants had globally increased [18F]GE-179 VT (+28%; p<0.002), and the three patients taking an antidepressant drug had globally reduced [18F]GE-179 VT (-29%; p<0.002). There were no focal abnormalities common to the epilepsy group. Conclusions: In patients with focal epilepsies, we detected primarily global increases of [18F]GE-179 VT consistent with increased NMDA channel activation, but reduced availability in those taking antidepressant drugs, consistent with a possible mode of action of this class of drugs. [18F]GE-179 PET showed focal accentuations of NMDA binding in 4 out of 11 patients, with difficult to localise and treat focal epilepsy.

Van Breevoort D.,Sanquin AMC Landsteiner Laboratory | Snijders A.P.,Medical Research Council Clinical science Center | Hellen N.,UK National Institute for Medical Research | Hellen N.,Imperial College London | And 14 more authors.
Blood | Year: 2014

Vascular endothelial cells contain unique rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs), which contain the hemostatic protein von Willebrand factor (VWF) and a cocktail of angiogenic and inflammatory mediators. We have shown that the Rab27A effector synaptotagmin-like protein 4-a (Slp4-a) plays a critical role in regulating hormoneevoked WPB exocytosis. Using a nonbiased proteomic screen for targets for Slp4-a, we now identify syntaxin-binding protein 1 (STXBP1) and syntaxin-2 and -3 as endogenous Slp4-a binding partners in endothelial cells. Coimmunoprecipitations showed that STXBP1 interacts with syntaxin-2 and -3, but not with syntaxin-4. Small interfering RNA-mediated silencing of STXBP1 expression impaired histamine- and forskolin-induced VWF secretion. To further substantiate the role of STXBP1, we isolated blood outgrowth endothelial cells (BOECs) from an early infantile epileptic encephalopathy type 4 (EIEE4) patient carrying a de novo mutation in STXBP1. STXBP1-haploin sufficient EIEE4 BOECs contained similar numbers of morphologically normal WPBs compared with control BOECs of healthy donors; however, EIEE4 BOECs displayed significantly impaired histamine- and forskolin-stimulated VWF secretion. Based on these findings, we propose that the Rab27A-Slp4- a complex on WPB promotes exocytosis through an interaction with STXBP1, thereby controlling the release of vaso-active substances in the vasculature. © 2014 by The American Society of Hematology.

Rimoldi O.,Medical Research Council Clinical science Center | Rimoldi O.,Imperial College London | Rimoldi O.,CNR Institute of Molecular Bioimaging and Physiology | Rosen S.D.,Imperial College London | And 3 more authors.
Journal of Hypertension | Year: 2014

Background: Hypertensive patients show a blunted coronary flow reserve (CFR) that, in the absence of epicardial disease, is an index of microvascular dysfunction. We aimed at assessing subendocardial and subepicardial myocardial blood flow (MBF) and CFR using high-resolution PET and determine the influence of haemodynamic load and ventricular mass in patients with arterial hypertension and left ventricular hypertrophy. Methods: We measured MBF (ml/min per g) using PET with oxygen-15 labelled water. Thirty patients (56 ± 8 years, 21 men) with stage 1-2 hypertension in therapy wash-out, except for thiazides, and 10 healthy volunteers were studied at baseline and during dipyridamole-induced hyperaemia (0.56 mg/kg over 4 min). Data are mean ± SD. Results: In patients, left ventricular mass index was 144 ± 40 g/m2 and septal thickness 14.8 ± 1.9mm. Baseline MBF was similar in patients and healthy volunteers in subendocardial (ENDO) (P = 0.08) and subepicardial (EPI) (P = 0.5), but patients had significantly lower hyperaemic MBF-EPI and MBF-ENDO (P < 0.001) and significantly lower CFR (EPI P < 0.001; ENDO P = 0.003). In patients, the degree of impairment of CFR-EPI (R = 0.52, P = 0.003) and CFR-ENDO (R = 0.51, P = 0.004) was inversely related to SBP, but not to left ventricular mass index. Conclusion: In patients with stage 1-2 hypertension and left ventricular hypertrophy, CFR is transmurally blunted due to a reduced hyperaemic response to stress, which is inversely related to SBP. In the absence of coronary stenosis, this phenomenon is most likely the expression of severe coronary microvascular dysfunction. Copyright © Lippincott Williams & Wilkins.

Cuhlmann S.,National Science Foundation | Cuhlmann S.,Biological Imaging Center | Van Der Heiden K.,National Science Foundation | Saliba D.,Kennedy Institute of Rheumatology | And 12 more authors.
Circulation Research | Year: 2011

Rationale: The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain. Objective: We studied the signaling mechanisms that regulate RelA NF-κB subunit expression in endothelial cells (ECs) and their role in arterial inflammation. Methods and Results: Gene silencing and chromatin immunoprecipitation revealed that RelA expression was positively regulated by c-Jun N-terminal kinase (JNK) and the downstream transcription factor ATF2 in ECs. We concluded that this pathway promotes focal arterial inflammation as genetic deletion of JNK1 reduced NF-κB expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-κB may be controlled by mechanical forces because atherosusceptibility is associated with exposure to disturbed blood flow. This was assessed by positron emission tomography imaging of carotid arteries modified with a constrictive cuff, a method that was developed to study the effects of disturbed flow on vascular physiology in vivo. This approach coupled to en face staining revealed that disturbed flow elevates NF-κB expression and inflammation in murine carotid arteries via JNK1. Conclusions: We demonstrate that disturbed blood flow promotes arterial inflammation by inducing NF-κB expression in endothelial cells via JNK-ATF2 signaling. Thus, our findings illuminate a novel form of JNK-NF-κB crosstalk that may determine the focal nature of arterial inflammation and atherosclerosis. © 2011 American Heart Association, Inc.

Rinne J.O.,Clinical Research Services Turku | Brooks D.J.,Medical Research Council Clinical science Center | Rossor M.N.,University College London | Fox N.C.,University College London | And 13 more authors.
The Lancet Neurology | Year: 2010

Background: Carbon-11-labelled Pittsburgh compound B (11C-PiB) PET is a marker of cortical fibrillar amyloid-β load in vivo. We used 11C-PiB PET to investigate whether bapineuzumab, a humanised anti-amyloid-β monoclonal antibody, would reduce cortical fibrillar amyloid-β load in patients with Alzheimer's disease. Methods: Patients with mild-to-moderate Alzheimer's disease were randomly assigned to receive intravenous bapineuzumab or placebo in a ratio of seven to three in three ascending dose groups (0·5, 1·0, or 2·0 mg/kg). Each dose group was enrolled after safety review of the previous group. Randomisation was by interactive voice response system; masking was achieved with numbered kit allocation. Patients, investigators, study site personnel, sponsor staff, and carers were masked to treatment. Patients received up to six infusions, 13 weeks apart, and had 11C-PiB PET scans at baseline and at weeks 20, 45, and 78. The primary outcome was the difference between the pooled bapineuzumab group and the pooled placebo group in mean change from screening to week 78 in 11C-PiB cortical to cerebellar retention ratio averaged across six cortical regions of interest. Analysis was by modified intention to treat. This study is registered with EudraCT, number 2004-004120-12; ISRCTN17517446. Findings: 28 patients were assigned to bapineuzumab (n=20) or placebo (n=8). 19 patients in the bapineuzumab group and seven in the placebo group were included in the modified intention-to-treat analysis. Estimated mean 11C-PiB retention ratio change from baseline to week 78 was -0·09 (95% CI -0·16 to -0·02; p=0·014) in the bapineuzumab group and 0·15 (95% CI 0·02 to 0·28; p=0·022) in the placebo group. Estimated mean difference in 11C-PiB retention ratio change from baseline to week 78 between the bapineuzumab group and the placebo group was -0·24 (95% CI -0·39 to -0·09; p=0·003). Differences between the bapineuzumab group and the placebo group in the individual regions of interest were similar to the overall mean difference. Adverse events were typically mild to moderate in severity and transient. Two patients in the 2·0 mg/kg bapineuzumab group had transient cerebral vasogenic oedema. Interpretation: Treatment with bapineuzumab for 78 weeks reduced cortical 11C-PiB retention compared with both baseline and placebo. 11C-PiB PET seems to be useful in assessing the effects of potential Alzheimer's disease treatments on cortical fibrillar amyloid-β load in vivo. Funding: Elan Pharmaceuticals and Wyeth Research. © 2010 Elsevier Ltd. All rights reserved.

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