Imperial College London

ProfessorRogerGunn

Faculty of MedicineDepartment of Brain Sciences

Professor of Molecular Neuroimaging
 
 
 
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r.gunn

 
 
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Burlington DanesHammersmith Campus

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Summary

 

Publications

Publication Type
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376 results found

Whittington A, Gunn RN, Alzheimers Disease Neuroimaging Initiative, 2021, TauIQ: a canonical image based algorithm to quantify tau PET scans., Journal of Nuclear Medicine, Vol: 62, Pages: 1292-1300, ISSN: 0161-5505

Recently, AmyloidIQ was introduced as a new canonical image-based algorithm to quantify amyloid PET scans and demonstrated increased power over traditional SUV ratio (SUVR) approaches when assessed in cross-sectional and longitudinal analyses. We build further on this mathematical framework to develop a TauIQ algorithm for the quantitative analysis of the more complex spatial distribution displayed by tau PET radiotracers. Methods: Cross-sectional (n = 615) and longitudinal (n = 149) 18F-flortaucipir data were obtained from the Alzheimer's Disease Neuroimaging Initiative along with necessary adjunct amyloid PET and T1-weighted structural MRI data. A subset of these data were used to derive a chronological tau dataset, using AmyloidIQ analysis of associated amyloid PET data to calculate the subject's temporal position in the canonical AD disease process, from which canonical images for the nonspecific and specific binding components of 18F-flortaucipir in AD were calculated. These 2 canonical images were incorporated into the TauIQ algorithm that enables the quantification of both global and local tau outcome measures using an image-based regression and statistical parametric analysis of the initial residual image. Performance of the TauIQ algorithm was compared with SUVR approaches for cross-sectional analyses, longitudinal analyses, and correlation with clinical measures (Alzheimer Disease Assessment Scale-Cognitive Subscale [ADAS-Cog], Clinical Dementia Rating scale-sum of boxes [CDR-SB], and Mini-Mental State Examination [MMSE]). Results: TauIQ successfully calculated global tau load (TauL) in all 791 scans analyzed (range, -3.5% to 185.2%; mean ± SD, 23% ± 20.5%) with a nonzero additional local tau component being required in 31% of all scans (cognitively normal [CN], 22%; mild cognitive impairment [MCI], 35%; dementia, 72%). TauIQ was compared with the best SUVR approach in the cross-sectional analysis (TauL increase in effect size: CN- vs. CN+, +

Journal article

Onwordi EC, Whitehurst T, Mansur A, Statton B, Berry A, Quinlan M, O'Regan D, Rogdaki M, Reis Marques T, Rabiner E, Gunn R, Vernon A, Natesan S, Howes Oet al., 2021, The relationship between synaptic density marker SV2A, glutamate and N-acetyl aspartate levels in healthy volunteers and schizophrenia: a multimodal PET and magnetic resonance spectroscopy brain imaging study, Translational Psychiatry, Vol: 11, Pages: 1-9, ISSN: 2158-3188

Glutamatergic excitotoxicity is hypothesised to underlie synaptic loss in schizophrenia pathogenesis, but it is unknown whether synaptic markers are related to glutamatergic function in vivo. Additionally, it has been proposed that N-acetyl aspartate (NAA) levels reflect neuronal integrity. Here, we investigated whether synaptic vesicle glycoprotein 2 A (SV2A) levels are related to glutamatergic markers and NAA in healthy volunteers (HV) and schizophrenia patients (SCZ). Forty volunteers (SCZ n = 18, HV n = 22) underwent [11C]UCB-J positron emission tomography and proton magnetic resonance spectroscopy (1H-MRS) imaging in the left hippocampus and anterior cingulate cortex (ACC) to index [11C]UCB-J distribution volume ratio (DVR), and creatine-scaled glutamate (Glu/Cr), glutamate and glutamine (Glx/Cr) and NAA (NAA/Cr). In healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glu/Cr, in both the hippocampus and ACC. Furthermore, in healthy volunteers, but not patients, [11C]UCB-J DVR was significantly positively correlated with Glx/Cr, in both the hippocampus and ACC. There were no significant relationships between [11C]UCB-J DVR and NAA/Cr in the hippocampus or ACC in healthy volunteers or patients. Therefore, an appreciable proportion of the brain 1H-MRS glutamatergic signal is related to synaptic density in healthy volunteers. This relationship is not seen in schizophrenia, which, taken with lower synaptic marker levels, is consistent with lower levels of glutamatergic terminals and/or a lower proportion of glutamatergic relative to GABAergic terminals in the ACC in schizophrenia.

Journal article

Calsolaro V, Matthews PM, Donat CK, Livingston NR, Femminella GD, Guedes SS, Myers J, Fan Z, Tyacke RJ, Venkataraman AV, Perneczky R, Gunn R, Rabiner EA, Gentleman S, Parker CA, Murphy PS, Wren PB, Hinz R, Sastre M, Nutt DJ, Edison Pet al., 2021, Astrocyte reactivity with late onset cognitive impairment assessed in-vivo using 11C-BU99008 PET and its relationship with amyloid load, Molecular Psychiatry, ISSN: 1359-4184

11C-BU99008 is a novel positron emission tomography (PET) tracer that enables selective imaging of astrocyte reactivity in vivo. To explore astrocyte reactivity associated with Alzheimer’s disease, 11 older, cognitively impaired (CI) subjects and 9 age-matched healthy controls (HC) underwent 3T magnetic resonance imaging (MRI), 18F-florbetaben and 11C-BU99008 PET. The 8 amyloid (Aβ)-positive CI subjects had higher 11C-BU99008 uptake relative to HC across the whole brain, but particularly in frontal, temporal, medial temporal and occipital lobes. Biological parametric mapping demonstrated a positive voxel-wise neuroanatomical correlation between 11C-BU99008 and 18F-florbetaben. Autoradiography using 3H-BU99008 with post-mortem Alzheimer’s brains confirmed through visual assessment that increased 3H-BU99008 binding localised with the astrocyte protein glial fibrillary acid protein and was not displaced by PiB or florbetaben. This proof-of-concept study provides direct evidence that 11C-BU99008 can measure in vivo astrocyte reactivity in people with late-life cognitive impairment and Alzheimer’s disease. Our results confirm that increased astrocyte reactivity is found particularly in cortical regions with high Aβ load. Future studies now can explore how clinical expression of disease varies with astrocyte reactivity.

Journal article

Marques TR, Natesan S, Rabiner EA, Searle GE, Gunn R, Howes OD, Kapur Set al., 2021, Adenosine A(2A) receptor in schizophrenia: an in vivo brain PET imaging study, PSYCHOPHARMACOLOGY, ISSN: 0033-3158

Journal article

Veronese M, Rizzo G, Belzunce M, Schubert J, Searle G, Whittington A, Mansur A, Dunn J, Reader A, Gunn RN, and the Grand Challenge Participantset al., 2021, Reproducibility of findings in modern PET neuroimaging: insight from the NRM2018 grand challenge., Journal of Cerebral Blood Flow and Metabolism, Pages: 271678X211015101-271678X211015101, ISSN: 0271-678X

The reproducibility of findings is a compelling methodological problem that the neuroimaging community is facing these days. The lack of standardized pipelines for image processing, quantification and statistics plays a major role in the variability and interpretation of results, even when the same data are analysed. This problem is well-known in MRI studies, where the indisputable value of the method has been complicated by a number of studies that produce discrepant results. However, any research domain with complex data and flexible analytical procedures can experience a similar lack of reproducibility. In this paper we investigate this issue for brain PET imaging. During the 2018 NeuroReceptor Mapping conference, the brain PET community was challenged with a computational contest involving a simulated neurotransmitter release experiment. Fourteen international teams analysed the same imaging dataset, for which the ground-truth was known. Despite a plurality of methods, the solutions were consistent across participants, although not identical. These results should create awareness that the increased sharing of PET data alone will only be one component of enhancing confidence in neuroimaging results and that it will be important to complement this with full details of the analysis pipelines and procedures that have been used to quantify data.

Journal article

Bucci M, Savitcheva I, Farrar G, Salvado G, Collij L, Dore V, Gispert JD, Gunn R, Hanseeuw B, Hansson O, Shekari M, Lhommel R, Molinuevo JL, Rowe C, Sur C, Whittington A, Buckley C, Nordberg Aet al., 2021, A multisite analysis of the concordance between visual image interpretation and quantitative analysis of [F-18]flutemetamol amyloid PET images, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, Vol: 48, Pages: 2183-2199, ISSN: 1619-7070

Journal article

Mansur A, Rabiner EA, Tsukada H, Comley RA, Lewis Y, Huiban M, Passchier J, Gunn RNet al., 2021, Test-retest variability and reference region-based quantification of 18F-BCPP-EF for imaging mitochondrial complex I in the human brain, Journal of Cerebral Blood Flow and Metabolism, Vol: 41, Pages: 771-779, ISSN: 0271-678X

Mitochondrial complex I (MC-I) is an essential regulator of brain bioenergetics and can be quantified in the brain using PET radioligand 18F-BCPP-EF. Here we evaluate the test-retest reproducibility of 18F-BCPP-EF in humans, and assess the use of a non-invasive quantification method (standardised uptake value ratio - SUVR). Thirty healthy volunteers had a 90-min dynamic 18F-BCPP-EF scan with arterial blood sampling, five of which received a second scan to be included in the test-retest analysis. Time-activity curves (TAC) were analysed using multilinear analysis 1 (MA1) and the two-tissue compartment model (2TC) to estimate volumes of distribution (VT). Regional SUVR-1 values were calculated from the 70 to 90-min TAC data using the centrum semiovale as a pseudo reference region, and compared to kinetic analysis-derived outcome measures. The mean absolute test-retest variability of VT ranged from 12% to 18% across regions. Both DVR-1and SUVR-1 had improved test-retest variability in the range 2%-7%. SUVR-1 was highly correlated with DVR-1 (r2 = 0.97, n = 30). In conclusion, 18F-BCPP-EF has suitable test-retest reproducibility and can be used to quantify MC-I in clinical studies.

Journal article

Ashok AH, Myers J, Frost G, Turton S, Gunn RN, Passchier J, Colasanti A, Marques TR, Nutt D, Lingford-Hughes A, Howes OD, Rabiner EAet al., 2021, Acute acetate administration increases endogenous opioid levels in the human brain: A [C-11]carfentanil molecular imaging study, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 35, Pages: 606-610, ISSN: 0269-8811

Journal article

Chen DL, Ballout S, Chen L, Cheriyan J, Choudhury G, Denis-Bacelar AM, Emond E, Erlandsson K, Fisk M, Fraioli F, Groves AM, Gunn RN, Hatazawa J, Holman BF, Hutton BF, Iida H, Lee S, MacNee W, Matsunaga K, Mohan D, Parr D, Rashidnasab A, Rizzo G, Subramanian D, Tal-Singer R, Thielemans K, Tregay N, van Beek EJR, Vass L, Melo MFV, Wellen JW, Wilkinson I, Wilson FJ, Winkler Tet al., 2020, Consensus Recommendations on the Use of F-18-FDG PET/CT in Lung Disease, JOURNAL OF NUCLEAR MEDICINE, Vol: 61, ISSN: 0161-5505

Journal article

Onwordi EC, Halff E, Whitehurst T, Mansur A, Statton B, Berry A, Quinlan M, O'Regan D, Rogdaki M, Marques TR, Rabiner EA, Gunn RN, Vernon AC, Natesan S, Howes ODet al., 2020, The relationship between synaptic density marker SV2A and glutamate: a multimodal positron emission tomography and magnetic resonance spectroscopy imaging study, 33rd Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER, Pages: S296-S296, ISSN: 0924-977X

Conference paper

Wang G, Rahmim A, Gunn RN, 2020, PET Parametric Imaging: Past, Present, and Future, IEEE TRANSACTIONS ON RADIATION AND PLASMA MEDICAL SCIENCES, Vol: 4, Pages: 663-675, ISSN: 2469-7311

Journal article

Roussakis AA, Gennaro M, Gordon MF, Reilmann R, Borowsky B, Rynkowski G, Savola JM, Hayden MR, Gunn R, Tabrizi S, Piccini Pet al., 2020, A longitudinal PET study to assess the state of microglia activation in a Phase 2 study of Laquinimod as a treatment for Huntington's disease (LEGATO-HD), Movement-Disorder-Society (MDS) International Virtual Congress, Publisher: WILEY, Pages: S102-S102, ISSN: 0885-3185

Conference paper

Wilson H, Pagano G, de Natale ER, Mansur A, Caminiti SP, Polychronis S, Middleton LT, Price G, Schmidt KF, Gunn RN, Rabiner EA, Politis Met al., 2020, Mitochondrial complex 1, sigma 1, and synaptic vesicle 2A in early drug-naive Parkinson's Disease, Movement Disorders, Vol: 35, Pages: 1416-1427, ISSN: 0885-3185

BackgroundDysfunction of mitochondrial energy generation may contribute to neurodegeneration, leading to synaptic loss in Parkinson's disease (PD). The objective of this study was to find cross‐sectional and longitudinal changes in PET markers of synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1 in drug‐naive PD patients.MethodsTwelve early drug‐naive PD patients and 16 healthy controls underwent a 3‐Tesla MRI and PET imaging to quantify volume of distribution of [11C]UCB‐J, [11C]SA‐4503, and [18F]BCPP‐EF for synaptic vesicle protein 2A, sigma 1 receptor, and mitochondrial complex 1, respectively. Nine PD patients completed approximately 1‐year follow‐up assessments.ResultsReduced [11C]UCB‐J volume of distribution in the caudate, putamen, thalamus, brain stem, and dorsal raphe and across cortical regions was observed in drug‐naive PD patients compared with healthy controls. [11C]UCB‐J volume of distribution was reduced in the locus coeruleus and substantia nigra but did not reach statistical significance. No significant differences were found in [11C]SA‐4503 and [18F]BCPP‐EF volume of distribution in PD compared with healthy controls. Lower brain stem [11C]UCB‐J volume of distribution correlated with Movement Disorder Society Unified Parkinson's Disease Rating Scale part III and total scores. No significant longitudinal changes were identified in PD patients at follow‐up compared with baseline.ConclusionsOur findings represent the first in vivo evidence of mitochondrial, endoplasmic reticulum, and synaptic dysfunction in drug‐naive PD patients. Synaptic dysfunction likely occurs early in disease pathophysiology and has relevance to symptomatology. Mitochondrial complex 1 and sigma 1 receptor pathology warrants further investigations in PD. Studies in larger cohorts with longer follow‐up will determine the validity of these PET markers to track disease progression. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, In

Journal article

Turton S, Myers J, Mick I, Colasanti A, Venkataraman A, Durant C, Waldman A, Brailsford A, Parkin M, Rabiner EA, Gunn R, Lightman S, Nutt D, Lingford-Hughes ARet al., 2020, Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol dependent individuals, Molecular Psychiatry, Vol: 25, Pages: 1749-1758, ISSN: 1359-4184

Addiction has been proposed as a ‘reward deficient’ state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse. However, changes in endogenous opioid tone in AD are poorly characterised and are important to understand as opioid antagonists do not help everyone with AD. We used [11C]carfentanil, a selective MOR agonist positron emission tomography (PET) radioligand, to investigate endogenous opioid tone in AD for the first time. We recruited 13 abstinent male AD and 15 control participants who underwent two [11C]carfentanil PET scans, one before and one 3 h following a 0.5 mg/kg oral dose of dexamphetamine to measure baseline MOR availability and endogenous opioid release. We found significantly blunted dexamphetamine-induced opioid release in 5 out of 10 regions-of-interest including insula, frontal lobe and putamen in AD compared with controls, but no significantly higher MOR availability AD participants compared with HC in any region. This study is comparable to our previous results of blunted dexamphetamine-induced opioid release in gambling disorder, suggesting that this dysregulation in opioid tone is common to both behavioural and substance addictions.

Journal article

Kocagoncu E, Quinn A, Firouzian A, Cooper E, Greve A, Gunn R, Green G, Woolrich MW, Henson RN, Lovestone S, Rowe JBet al., 2020, Tau pathology in early Alzheimer's disease is linked to selective disruptions in neurophysiological network dynamics, Publisher: ELSEVIER SCIENCE INC

Working paper

Kocagoncu E, Quinn A, Firouzian A, Cooper E, Greve A, Gunn R, Green G, Woolrich MW, Henson RN, Lovestone S, Deep and Frequent Phenotyping study team, Rowe JBet al., 2020, Tau pathology in early Alzheimer's disease is linked to selective disruptions in neurophysiological network dynamics, Neurobiology of Aging, Vol: 92, Pages: 141-152, ISSN: 0197-4580

Understanding the role of Tau protein aggregation in the pathogenesis of Alzheimer's disease is critical for the development of new Tau-based therapeutic strategies to slow or prevent dementia. We tested the hypothesis that Tau pathology is associated with functional organization of widespread neurophysiological networks. We used electro-magnetoencephalography with [18F]AV-1451 PET scanning to quantify Tau-dependent network changes. Using a graph theoretical approach to brain connectivity, we quantified nodal measures of functional segregation, centrality, and the efficiency of information transfer and tested them against levels of [18F]AV-1451. Higher Tau burden in early Alzheimer's disease was associated with a shift away from the optimal small-world organization and a more fragmented network in the beta and gamma bands, whereby parieto-occipital areas were disconnected from the anterior parts of the network. Similarly, higher Tau burden was associated with decreases in both local and global efficiency, especially in the gamma band. The results support the translational development of neurophysiological "signatures" of Alzheimer's disease, to understand disease mechanisms in humans and facilitate experimental medicine studies.

Journal article

Popescu SG, Whittington A, Gunn RN, Matthews PM, Glocker B, Sharp DJ, Cole JHet al., 2020, Nonlinear biomarker interactions in conversion from mild cognitive impairment to Alzheimer's disease, Human Brain Mapping, Vol: 41, Pages: 4406-4418, ISSN: 1065-9471

Multiple biomarkers can capture different facets of Alzheimer's disease. However, statistical models of biomarkers to predict outcomes in Alzheimer's rarely model nonlinear interactions between these measures. Here, we used Gaussian Processes to address this, modelling nonlinear interactions to predict progression from mild cognitive impairment (MCI) to Alzheimer's over 3 years, using Alzheimer's Disease Neuroimaging Initiative (ADNI) data. Measures included: demographics, APOE4 genotype, CSF (amyloid‐β42, total tau, phosphorylated tau), [18F]florbetapir, hippocampal volume and brain‐age. We examined: (a) the independent value of each biomarker; and (b) whether modelling nonlinear interactions between biomarkers improved predictions. Each measured added complementary information when predicting conversion to Alzheimer's. A linear model classifying stable from progressive MCI explained over half the variance (R2 = 0.51, p < .001); the strongest independently contributing biomarker was hippocampal volume (R2 = 0.13). When comparing sensitivity of different models to progressive MCI (independent biomarker models, additive models, nonlinear interaction models), we observed a significant improvement (p < .001) for various two‐way interaction models. The best performing model included an interaction between amyloid‐β‐PET and P‐tau, while accounting for hippocampal volume (sensitivity = 0.77, AUC = 0.826). Closely related biomarkers contributed uniquely to predict conversion to Alzheimer's. Nonlinear biomarker interactions were also implicated, and results showed that although for some patients adding additional biomarkers may add little value (i.e., when hippocampal volume is high), for others (i.e., with low hippocampal volume) further invasive and expensive examination may be warranted. Our framework enables visualisation of these interactions, in individual patient biomarker ‘space', providing information for per

Journal article

Sharma PK, Wells L, Rizzo G, Elson JL, Passchier J, Rabiner EA, Gunn RN, Dexter DT, Pienaar ISet al., 2020, DREADD activation of pedunculopontine cholinergic neurons reverses motor deficits and restores striatal dopamine signaling in parkinsonian rats., Neurotherapeutics, Vol: 17, Pages: 1120-1141, ISSN: 1878-7479

The brainstem-based pedunculopontine nucleus (PPN) traditionally associates with motor function, but undergoes extensive degeneration during Parkinson's disease (PD), which correlates with axial motor deficits. PPN-deep brain stimulation (DBS) can alleviate certain symptoms, but its mechanism(s) of action remains unknown. We previously characterized rats hemi-intranigrally injected with the proteasomal inhibitor lactacystin, as an accurate preclinical model of PD. Here we used a combination of chemogenetics with positron emission tomography imaging for in vivo interrogation of discrete neural networks in this rat model of PD. Stimulation of excitatory designer receptors exclusively activated by designer drugs expressed within PPN cholinergic neurons activated residual nigrostriatal dopaminergic neurons to produce profound motor recovery, which correlated with striatal dopamine efflux as well as restored dopamine receptor 1- and dopamine receptor 2-based medium spiny neuron activity, as was ascertained with c-Fos-based immunohistochemistry and stereological cell counts. By revealing that the improved axial-related motor functions seen in PD patients receiving PPN-DBS may be due to stimulation of remaining PPN cholinergic neurons interacting with dopaminergic ones in both the substantia nigra pars compacta and the striatum, our data strongly favor the PPN cholinergic-midbrain dopaminergic connectome as mechanism for PPN-DBS's therapeutic effects. These findings have implications for refining PPN-DBS as a promising treatment modality available to PD patients.

Journal article

Onega M, Parker CA, Coello C, Rizzo G, Keat N, Ramada-Magalhaes J, Moz S, Tang S-P, Plisson C, Wells L, Ashworth S, Slack RJ, Vitulli G, Wilson FJ, Gunn R, Lukey PT, Passchier Jet al., 2020, Preclinical evaluation of [F-18]FB-A20FMDV2 as a selective marker for measuring alpha(V)beta(6) integrin occupancy using positron emission tomography in rodent lung, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 47, Pages: 958-966, ISSN: 0340-6997

PurposeIntegrin αvβ6 belongs to the RGD subset of the integrin family, and its expression levels are a prognostic and theranostic factor in some types of cancer and pulmonary fibrosis. This paper describes the GMP radiolabelling of the synthetic 20 amino acid peptide A20FMDV2 (NAVPNLRGDLQVLAQKVART), derived from the foot-and-mouth disease virus, and characterises the use of [18F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αvβ6 in rodent lung to support human translational studies.MethodsThe synthesis of [18F]FB-A20FMDV2 was performed using a fully automated and GMP-compliant process. Sprague-Dawley rats were used to perform homologous (unlabelled FB-A20FMDV2) and heterologous (anti-αvβ6 antibody 8G6) blocking studies. In order to generate a dosimetry estimate, tissue residence times were generated, and associated tissue exposure and effective dose were calculated using the Organ Level Internal Dose Assessment/Exponential Modelling (OLINDA/EXM) software.Results[18F]FB-A20FMDV2 synthesis was accomplished in 180 min providing ~800 MBq of [18F]FB-A20FMDV2 with a molar activity of up to 150 GBq/μmol and high radiochemical purity (> 97%). Following i.v. administration to rats, [18F]FB-A20FMDV2 was rapidly metabolised with intact radiotracer representing 5% of the total radioactivity present in rat plasma at 30 min. For the homologous and heterologous block in rats, lung-to-heart SUV ratios at 30–60 min post-administration of [18F]FB-A20FMDV2 were reduced by 38.9 ± 6.9% and 56 ± 19.2% for homologous and heterologous block, respectively. Rodent biodistribution and dosimetry calculations using OLINDA/EXM provided a whole body effective dose in humans 33.5 μSv/MBq.Conclusion[18F]FB-A20FMDV2 represents a specific and selective PET ligand to measure drug-associated αvβ6 integrin occupancy in lung. The ef

Journal article

Onwordi EC, Halff E, Whitehurst T, Mansur A, Cotel M-C, Wells L, Creeney H, Bonsall D, Rogdaki M, Shatalina E, Marques TR, Rabiner E, Gunn R, Natesan S, Vernon A, Howes ODet al., 2020, SYNAPTIC MARKER PROTEIN SV2A IS REDUCED IN SCHIZOPHRENIA IN VIVO AND UNAFFECTED BY ANTIPSYCHOTICS IN RATS, Congress of the Schizophrenia-International-Research-Society (SRIS), Publisher: OXFORD UNIV PRESS, Pages: S28-S28, ISSN: 0586-7614

Conference paper

Lukey PT, Coello C, Gunn R, Parker C, Wilson FJ, Saleem A, Garman N, Costa M, Kendrick S, Onega M, Kang'ombe AR, Listanco A, Davies J, Ramada-Magalhaes J, Moz S, Fahy WA, Maher TM, Jenkins G, Passchier J, Marshall RPet al., 2020, Clinical quantification of the integrin αvβ6 by [18F]FB-A20FMDV2 positron emission tomography in healthy and fibrotic human lung (PETAL Study), European Journal of Nuclear Medicine and Molecular Imaging, Vol: 47, Pages: 967-979, ISSN: 0340-6997

PURPOSE: The RGD-integrin, αvβ6, plays a role in the pathogenesis of pulmonary fibrosis through activation of transforming growth factor beta (TGFβ). This study sought to quantify expression of αvβ6 in the lungs of healthy humans and subjects with pulmonary fibrosis using the αvβ6-selective [18F]FB-A20FMDV2 PET ligand. METHODS: [18F]FB-A20FMDV2 PET/CT scans were performed in healthy subjects and those with fibrotic lung disease. Standard uptake values (SUV) and volume of distribution (VT) were used to quantify αvβ6 expression. In subjects with fibrotic lung disease, qualitative assessment of the relationship between αvβ6 expression and the distribution of fibrosis on high resolution computed tomography was conducted. RESULTS: A total of 15 participants (6 healthy, 7 with idiopathic pulmonary fibrosis (IPF) and 2 with connective tissue disease (CTD) associated PF) were enrolled. VT and SUV of [18F]FB-A20FMDV2 were increased in the lungs of subjects with pulmonary fibrosis (PF) compared with healthy subjects. Geometric mean VT (95% CI) was 0.88 (0.60, 1.29) mL/cm3 for healthy subjects, and 1.40 (1.22, 1.61) mL/cm3 for subjects with IPF; and SUV was 0.54 (0.36, 0.81) g/mL for healthy subjects and 1.03 (0.86, 1.22) g/mL for subjects with IPF. The IPF/healthy VT ratio (geometric mean, (95% CI of ratio)) was 1.59 (1.09, 2.32) (probability ratio > 1 = 0.988)) and the SUV ratio was 1.91 (1.27, 2.87) (probability ratio > 1 = 0.996). Increased uptake of [18F]FB-A20FMDV2 in PF was predominantly confined to fibrotic areas. [18F]FB-A20FMDV2 measurements were reproducible at an interval of 2 weeks. [18F]FB-A20FMDV2 was safe and well tolerated. CONCLUSIONS: Lung uptake of [18F]FB-A20FMDV2, a measure of expression of the integrin αvβ6, was markedly increased in subjects with PF compared with healthy subjects.

Journal article

Knudsen GM, Ganz M, Appelhoff S, Boellaard R, Bormans G, Carson RE, Catana C, Doudet D, Gee AD, Greve DN, Gunn RN, Halldin C, Herscovitch P, Huang H, Keller SH, Lammertsma AA, Lanzenberger R, Liow J-S, Lohith TG, Lubberink M, Lyoo CH, Mann JJ, Matheson GJ, Nichols TE, Nørgaard M, Ogden T, Parsey R, Pike VW, Price J, Rizzo G, Rosa-Neto P, Schain M, Scott PJ, Searle G, Slifstein M, Suhara T, Talbot PS, Thomas A, Veronese M, Wong DF, Yaqub M, Zanderigo F, Zoghbi S, Innis RBet al., 2020, Guidelines for the content and format of PET brain data in publications and archives: A consensus paper., Journal of Cerebral Blood Flow and Metabolism, ISSN: 0271-678X

It is a growing concern that outcomes of neuroimaging studies often cannot be replicated. To counteract this, the magnetic resonance (MR) neuroimaging community has promoted acquisition standards and created data sharing platforms, based on a consensus on how to organize and share MR neuroimaging data. Here, we take a similar approach to positron emission tomography (PET) data. To facilitate comparison of findings across studies, we first recommend publication standards for tracer characteristics, image acquisition, image preprocessing, and outcome estimation for PET neuroimaging data. The co-authors of this paper, representing more than 25 PET centers worldwide, voted to classify information as mandatory, recommended, or optional. Second, we describe a framework to facilitate data archiving and data sharing within and across centers. Because of the high cost of PET neuroimaging studies, sample sizes tend to be small and relatively few sites worldwide have the required multidisciplinary expertise to properly conduct and analyze PET studies. Data sharing will make it easier to combine datasets from different centers to achieve larger sample sizes and stronger statistical power to test hypotheses. The combining of datasets from different centers may be enhanced by adoption of a common set of best practices in data acquisition and analysis.

Journal article

Onwordi EC, Halff EF, Whitehurst T, Mansur A, Cotel M-C, Wells L, Creeney H, Bonsall D, Rogdaki M, Shatalina E, Marques TR, Rabiner E, Gunn R, Natesan S, Vernon A, Howes Oet al., 2020, Synaptic density marker SV2A is reduced in schizophrenia patients and unaffected by antipsychotics in rats, Nature Communications, Vol: 11, ISSN: 2041-1723

Synaptic dysfunction is hypothesised to play a key role in schizophrenia pathogenesis, but this has not been tested directly in vivo. Here, we investigated synaptic vesicle glycoprotein 2A (SV2A) levels and their relationship to symptoms and structural brain measures using[11 C]UCB-J positron emission tomography in 18 patients with schizophrenia and 18 controls. We found significant group and group-by-region interaction effects on volume of distribution(VT). [11 C]UCB-J VT was significantly lower in the frontal and anterior cingulate cortices in schizophrenia with large effect sizes (Cohen’s d = 0.8-0.9), but there was no significant difference in the hippocampus. We also investigated the effects of antipsychotic drugadministration on SV2A levels in Sprague-Dawley rats using western blotting, [3 H]UCB-J autoradiography and immunostaining with confocal microscopy, finding no significant effects on any measure. These findings indicate that there are lower synaptic terminal protein levels in schizophrenia in vivo and that antipsychotic drug exposure is unlikely to account for them.

Journal article

Mansur A, Rabiner EA, Comley RA, Lewis Y, Middleton LT, Huiban M, Passchier J, Tsukada H, Gunn RNet al., 2020, Characterization of 3 PET tracers for Quantification of Mitochondrial and Synaptic function in Healthy Human Brain: 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, Journal of Nuclear Medicine, Vol: 61, Pages: 96-103, ISSN: 1535-5667

Mitochondrial complex 1 (MC1) is involved in maintaining brain bioenergetics, the sigma 1 receptor (σ1R) responds to neuronal stress and synaptic vesicle protein 2A (SV2A) reflects synaptic integrity. Expression of each of these proteins is altered in neurodegenerative diseases. Here we characterise the kinetic behaviour of three positron emission tomography (PET) radioligands 18F-BCPP-EF, 11C-SA-4503 and 11CUCB- J, for the measurement of MC1, σ1R and SV2A, respectively, and determine appropriate analysis workflows for their application in future studies of the in vivo molecular pathology of these diseases. Methods: Twelve human subjects underwent dynamic PET scans including associated arterial blood sampling with each radioligand. A range of kinetic models were investigated to identify an optimal kinetic analysis method for each radioligand and a suitable acquisition duration. Results: All three radioligands readily entered the brain and yielded heterogeneous uptake consistent with the known distribution of the targets. The optimal models determined for the regional estimates of volume of distribution (VT) were multilinear analysis 1 (MA1) and the 2-tissue compartment (2TC) model for 18F-BCPP-EF, MA1 for 11C-SA- 4503, and both MA1 and the 1-tissue compartment (1TC) model for 11C-UCB-J. Acquisition times of 70, 80 and 60 minutes for 18F-BCPP-EF, 11C-SA-4503, 11C-UCB-J, respectively, provided good estimates of regional VT values. An effect of age was observed on 18F-BCPP-EF and 11C-UCB-J signal in the caudate. Conclusion: These ligands can be assessed for their potential to stratify patients or monitor the progression of molecular neuropathology in neurodegenerative diseases.

Journal article

Wadhwa P, Thielemans K, Efthimiou N, Wangerin K, Keat N, Emond E, Deller T, Bertolli O, Deidda D, Delso G, Tohme M, Jansen F, Gunn RN, Hallett W, Tsoumpas Cet al., 2020, PET image reconstruction using physical and mathematical modelling for time of flight PET-MR scanners in the STIR library, METHODS, Vol: 185, Pages: 110-119, ISSN: 1046-2023

Journal article

Convery RS, Jiao J, Clarke MTM, Moore KM, Koriath CAM, Woollacott IOC, Weston PSJ, Gunn R, Rabiner I, Cash DM, Rossor MN, Warren JD, Fox NC, Ourselin S, Bocchetta M, Rohrer JDet al., 2020, Longitudinal (F-18)AV-1451 PET imaging in a patient with frontotemporal dementia due to a Q351R MAPT mutation, JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY, Vol: 91, Pages: 106-108, ISSN: 0022-3050

Journal article

Erritzoe D, Godlewska BR, Rizzo G, Searle GE, Lewis Y, Ashok A, Howes O, Passchier J, Gunn RN, Nutt DJ, Cowen PJ, Knudsen GM, Rabiner EAet al., 2019, Brain serotonin release reduced among patients with severe depression: a pet study with [11c]cimbi-36 and d-amphetamine challenge, 32nd Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER, Pages: S258-S258, ISSN: 0924-977X

Conference paper

McCluskey S, Haslop A, Coello C, Gunn R, Tate E, Southworth R, Plisson C, Long NJ, Wells Let al., 2019, Imaging chemotherapy induced acute cardiotoxicity with 18F-labelled lipophilic cations, Journal of Nuclear Medicine, Vol: 60, Pages: 1750-1756, ISSN: 1535-5667

Many chemotherapy agents are toxic to the heart, such that increasing numbers of cancer survivors are now living with the potentially lethal cardiovascular consequences of their treatment. Earlier and more sensitive detection of chemotherapy-induced cardiotoxicity may allow improved treatment strategies and increase long-term survival. Lipophilic cation positron emission tomography (PET) tracers may be suitable for early detection of cardiotoxicity. This study aims to evaluate an 18F-labelled lipophilic phosphonium cation e.g. 18F-Mitophos, as a cardiac imaging agent, comparing it to leading PET and SPECT lipophilic cationic tracers before further assessing its potential for imaging cardiotoxicity in an acute doxorubicin (DOX) model.

Journal article

Wilson H, Niccolini F, Dervenoulas G, Tyacke R, Myers J, Gunn R, Nutt D, Rabiner E, Tabrizi S, Politis Met al., 2019, Evaluation of Imidazoline 2 binding sites reflecting astroglia pathology in Huntington's Disease: An in vivo [11C]BU99008 PET study, International Congress of Parkinson's Disease and Movement Disorders, Publisher: WILEY, Pages: S836-S836, ISSN: 0885-3185

Conference paper

Wilson H, Dervenoulas G, Pagano G, Tyacke R, Myers J, Gunn R, Rabiner E, Nutt D, Politis Met al., 2019, Evaluation of Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's Disease: An in vivo [11C]BU99008 PET study, International Congress of Parkinson's Disease and Movement Disorders, Publisher: WILEY, Pages: S835-S836, ISSN: 0885-3185

Conference paper

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