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+{"file": "ukeme0701_NBK553477/s3.nxml", "text": "Scanning sessions\nAll of the participants were scanned at the Wolfson Molecular Imaging Centre 18 to 63 days (median 34.5 days) after their stroke. The participants underwent magnetic resonance imaging (MRI) (Philips 1.5\u2009T; Philips, Amsterdam, the Netherlands) and PET (Siemens HRRT; Siemens, Munich, Germany) scanning using [18F]-GE180 and [11C]-(R)-PK11195 tracers.\nThe two PET scans were performed on two separate sessions as close to each other as possible (mean 3.4 days) but at least 1 day apart. Five participants were randomised to receive the [11C]-(R)-PK11195 at the first session (arm A) and five participants were randomised to receive the [18F]-GE180 scan at the first session (arm B).\nThe MRI scan was performed either during session 1 (nine participants) or during session 2 (one participant). Eight participants completed T1 inversion recovery, T2 fluid-attenuated inversion recovery (FLAIR) and post-contrast-enhanced T1 sequence. Two participants completed the non-contrast sequences only because of safety reasons (allergy or impaired renal function).\nPositron emission tomography image processing and analysis\nThe volume of interest (VOI) of ischaemic lesions (target) were defined manually using ANALYZE software (Overland Park, KS, USA) on co-registered T2-weighted FLAIR magnetic resonance (MR) scans, separately for contrast-enhancing and non-contrast-enhancing areas on co-registered T1-weighted MR scans. Contralateral mirror VOIs were then drawn manually as a reference.\nA set of standard anatomical VOIs was placed on the individual PET images by warping the 83-region probabilistic brain atlas15 from template space. Using the segmented T1-weighted MR scans, a set of standard grey matter anatomical VOIs was obtained, including left and right cerebellum.\nThe [11C]-(R)-PK11195 PET data were acquired for 60 minutes following the administration of a 740-MBq activity intravenous bolus. Parametric maps of binding potentials were generated with the simplified reference tissue model using a bilateral grey matter cerebellar reference tissue input function.16,17 For better comparability with the [18F]-GE180 data, [11C]-(R)-PK11195 binding potentials were converted into [11C]-(R)-PK11195 distribution volume ratios by adding the value of 1.18\nThe [18F]-GE180 PET data were acquired for 30 minutes following the administration of a 200-MBq activity intravenous bolus. This short measurement time is not sufficient to calculate binding potentials. Instead, two summed images were calculated: (1) a late summed image 15\u201330 minutes post injection; and (2) an early summed image 0\u20135 minutes post injection, representing predominantly vascular activity. As shown in a previous study,13 the signal from intravascular activity of [18F]-GE180 remains very high during the scanning time. In addition to tissue activity without correction obtained from the late summed images, we estimated intravascular activity from the early summed images and then calculated tissue activity corrected for intravascular activity by subtracting the estimated intravascular activity from the late summed images.\nTarget-to-reference ratios (TRRs) of [18F]-GE180 were then calculated from the readouts of the late summed images without or with correction for vascular activity. TRRs of [11C]-(R)-PK11195 were obtained by dividing distribution volume ratios of the target (infarct) region through the corresponding reference (contralateral mirror) region.\nBlood tests\nEach participant was genotyped for the rs6971 polymorphism of the TSPO gene [single nucleotide polymorphism analysis at rs6971 locus using isolated deoxyribonucleic acid by LCG genomics (Hoddesdon, UK)] and categorised as a HAB, a MAB or a LAB.14 Spearman\u2019s rank-order correlation and unpaired t-tests were used to test for association of imaging parameters with genotype.\nBlood samples were taken from each patient for systemic inflammatory marker [high-sensitivity C-reactive protein (CRP) and interleukin 6] analysis at the [18F]-GE180 PET session (18\u201355 days after stroke onset).\nSafety and tolerability\nEach participant completed a questionnaire after receiving [18F]-GE180 PET to evaluate the tolerability of scanning. The questionnaire contained five questions asking the participant to grade the discomfort associated with the [18F]-GE180 PET procedure on a five-point scale (1 \u2013 the most discomfort, 5 \u2013 the least discomfort).\nAll adverse events related to trial-specific procedures were collected.", "pairs": [], "interleaved": []}
+{"file": "ukeme0701_NBK553477/ack1.nxml", "text": "As a clinical trial, the study was sponsored by The Christie NHS Foundation Trust, Manchester, and managed by the clinical trials unit of the University of Manchester at The Christie NHS Foundation Trust. The authors are very grateful to their staff, to the principal investigators at patient recruitment sites and their staff, to GE HealthCare staff for helpful advice, and to all staff involved in production of [11C]-(R)-PK11195, scanning and study management at the Wolfson Molecular Imaging Centre. We also thank the members of the Independent Data Monitoring Committee for its support and advice. Particular thanks go to the patient volunteers who participated in the study.\nContributions of authors\nEszter Visi (https://orcid.org/0000-0001-5589-4740) (MD, neurologist) was the clinical fellow for this study. She was responsible for data acquisition and for patient care at Wolfson Molecular Imaging Centre. She also contributed significantly to data analysis and drafted the report.\nRainer Hinz (https://orcid.org/0000-0002-7808-9207) (PhD, physicist) led on imaging physics and analysis of radiotracer kinetics.\nMartin Punter (https://orcid.org/0000-0002-6800-891X) (MD, neurologist) provided critical support to Eszter Visi as the clinical lead principal investigator at the Salford Royal Foundation Trust hyperacute stroke centre.\nArshad Majid (MD, PhD, neurologist, professor for stroke research), Alexander Gerhard and Karl Herholz jointly designed the study. Arshad Majid also provided links to patient representatives and the national and regional stroke networks to support patient recruitment.\nAlexander Gerhard (https://orcid.org/0000-0002-8071-6062) (MD, neurologist) was a senior lecturer, provided guidance and provided training on image data analysis to Eszter Visi.\nKarl Herholz (https://orcid.org/0000-0002-8658-0151) (MD, neurologist) was a professor for clinical neuroscience, was the chief investigator for the study, designed the principal concept for data analysis, ensured compliance with regulatory requirements, and finalised the report.\nAll authors provided a critical review of the data and the manuscript.\nData-sharing statement\nAll data requests should be submitted to the corresponding author for consideration. Please note exclusive use will be retained until the publication of major outputs. Access to anonymised data may be granted following review.\nPatient data\nThis work uses data provided by patients and collected by the NHS as part of their care and support. Using patient data is vital to improve health and care for everyone. There is huge potential to make better use of information from people\u2019s patient records, to understand more about disease, develop new treatments, monitor safety, and plan NHS services. Patient data should be kept safe and secure, to protect everyone\u2019s privacy, and it\u2019s important that there are safeguards to make sure that it is stored and used responsibly. Everyone should be able to find out about how patient data are used. #datasaveslives You can find out more about the background to this citation here: https://understandingpatientdata.org.uk/data-citation.\nDisclaimers\nThis report presents independent research. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the MRC, NETSCC, the EME programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, NETSCC, the EME programme or the Department of Health and Social Care.", "pairs": [], "interleaved": []}
+{"file": "ukeme0701_NBK553477/s6.nxml", "text": "The study was discussed with a patient representative prior to finalising. This helped to confirm that the scanning protocol was practical and tolerable and that patient information sheets provided all of the necessary information in an appropriate manner to ensure that proper informed consent of participants was obtained. The interaction did not result in changes to the protocol. Owing to the very technical nature of the results, publications will be primarily aimed at a specialist audience and we do not anticipate support by public and patient involvement for dissemination of the results.", "pairs": [], "interleaved": []}
+{"file": "ukeme0701_NBK553477/s1.nxml", "text": "Stroke is the third most common cause of disability in the developed world and the second leading cause of death worldwide.1 According to the Stroke Association (London, UK), stroke is responsible for >\u2009100,000 hospital admissions per year in the UK and the annual cost to UK society is around \u00a326B.\nAcute ischaemic stroke is typically caused by a cerebral artery occlusion because of local thrombosis or thromboembolism from a remote source. Duration and severity of the diminished cerebral blood flow are the major factors that determine the degree of the ischaemic injury. Hence, prompt reperfusion therapy using either systemic thrombolysis or endovascular mechanical thrombectomy is the mainstay of acute treatment. However, given the narrow therapeutic window, only a minority of patients are eligible and can benefit from these procedures.\nExperimental and clinical studies have demonstrated the complex role of the immune system in the molecular, cellular and tissue changes that occur after acute ischaemic stroke from the early to the late phases.2 Thus, targeting neuroinflammation became a potential novel therapeutic strategy. The broader therapeutic window could enable a wide range of patients (relative to the reperfusion procedures) to receive anti-inflammatory agents, but it might also increase the rate of systemic infectious complications.3 Another potential pitfall can result from the complex character of the inflammatory process. Often referred to as \u2018the double-edged sword\u2019, neuroinflammation can contribute to tissue damage but also promote repair in the subacute and chronic phase.2,4 Therefore, understanding the correlation between the grade and extent of neuroinflammation and the functional outcome could help to establish the optimum timing and monitor the anti-inflammatory treatment.\nMicroglia are the major resident immune cells of the brain. Activated microglia respond to pathogens and neuronal damage and then play a crucial role in mediating the inflammatory response in the brain.5 Hence, microglial activation is a hallmark of neuroinflammation. The 18-kDa translocator protein (TSPO) is expressed within activated microglia, infiltrating macrophages, astrocytes and endothelial cells. Although macrophage infiltration is high in acute stroke, in the subacute phase microglia are the predominant TSPO-expressing cell type.6 Thus, TSPO imaging by positron emission tomography (PET) has been considered an in vivo marker of activated microglia levels in the brain.7\nThe first-generation TSPO ligand radiotracer 11C-labelled PK11195 has been successfully used to image activated microglia in several neurological disorders, including ischaemic stroke.8\u201311 However, its short physical half-life (20 minutes) makes it impractical for routine clinical application. In contrast, 18F-labelled radiopharmaceuticals have a longer half-life, enabling transport from production to clinical sites to occur. Therefore, they can potentially be applied as diagnostic tools in routine clinical settings.\nWe therefore studied microglial activation in the human brain using [18F]-GE180 PET in patients after mild to moderate stroke. In the pilot study we evaluated safety, tolerability and technical feasibility by intraindividual comparison with [11C]-(R)-PK11195 and assessing the effect of the genotype on the binding. [18F]-GE180 binds with high specificity to TSPO12 but, similar to second-generation TSPO ligand tracers, affinity is influenced by a genetic polymorphism (Ala147Thr) on the TSPO gene (rs6971).13 High-affinity binders (HABs) and low-affinity binders (LABs) express a single binding site for TSPO with either high or low affinity, respectively, whereas mixed-affinity binders (MABs) express approximately equal numbers of the HAB and LAB-binding sites.14 The highest specific binding of [18F]-GE180 is expected in HABs, lower but still detectable binding is expected in MABs, and negligible binding is expected in LABs. If successful, this pilot study was intended to be followed by a second phase to assess the correlation between the imaging finding and clinical outcome in a larger patient sample.", "pairs": [], "interleaved": []}
+{"file": "ukeme0701_NBK553477/g1.nxml", "text": "flutriciclamide\nblood\u2013brain barrier\nconfidence interval\nC-reactive protein\ncomputed tomography\nfluid-attenuated inversion recovery\nhigh-affinity binder\nlow-affinity binder\nmixed-affinity binder\nmagnetic resonance\nmagnetic resonance imaging\npositron emission tomography\nstandard deviation\ntarget-to-reference ratio\n18-kDa translocator protein\nvolume of interest", "pairs": [], "interleaved": []}
+{"file": "ukeme0701_NBK553477/s5.nxml", "text": "To our knowledge, this is the first study to analyse the properties of [18F]-GE180 in patients with ischaemic stroke and to compare it with [11C]-(R)-PK11195 in human participants. As to be expected with the very small amounts of injected PET radiotracer, we did not observe any serious adverse events. Although [18F]-GE180 provided very good contrast in ischaemic lesions with BBB damage, we also observed some limitations that had not been seen in the generally favourable outcome of a previous stroke study in rats.19\nSimilar to previous studies of the kinetics of [18F]-GE180 in healthy human participants13,20 and in patients with glioma21 and multiple sclerosis,22 but in contrast to rodent studies,19 we found that the uptake of [18F]-GE180 in normal tissue across the intact BBB was very low.\nPerfusion and blood volume in subacute ischaemic lesions can be highly variable, depending on the extent of reperfusion.23 We therefore performed corrections for intravascular activity. We had opted for scanning times not exceeding 30 minutes, as this length of time is typically required for clinically applicable procedures in functionally impaired patients. The procedure was regarded as well tolerated as indicated by patient responses in the questionnaire. However, because of the short data acquisition time, we could not perform standard kinetic modelling and so estimated intravascular activity from data obtained during the first 5 minutes after radiotracer injection. The correction improved signal-to-background contrast of [18F]-GE180, but did not change the correlations between [18F]-GE180 and [11C]-(R)-PK11195 substantially.\nAs demonstrated in Figures 3 and 4, correlation was generally very good and lesion-to-background ratios were comparable, suggesting that [18F]-GE180 could possibly be used instead of [11C]-(R)-PK11195 to assess microglial activity in clinical stroke studies. We also found a correlation between systemic inflammation markers and radiotracer uptake in lesions with both tracers, confirming observations previously seen in normal participants with vascular risk factors.24 Neither systemic nor PET markers were related to clinical outcome. However, the small sample in our pilot study had not been powered to address this question and functional deficits had been mild already at study inclusion, leaving limited room for further improvement of functional scores.\nRecent infarcts showed higher radiotracer uptake with both tracers than old infarcts. In contrast with the recent lesions, most of the old infarcts demonstrated less radiotracer uptake (i.e. TRR <\u20091) than the contralateral reference region. In the absence of previous scans or obviously relevant clinical events, we could not establish the exact age of the old infarcts. But some details in the clinical history (e.g. an episode of possibly transitory ischaemic attack in the case of P011 and a few episodes of paroxysmal atrial fibrillation in the case of P014) suggested that these might have been acquired many years before. A previous longitudinal study9 demonstrated increased [11C]-(R)-PK11195 binding 150 days after the stroke onset. The lack of inflammation in our case could perhaps be explained by the presence of an already established glial scar.\nSubstantial limitations for clinical use of [18F]-GE180 became obvious when analysing the effects of the genetic polymorphism and BBB damage. We found a significant association of [18F]-GE180 tissue activity concentration with genotype in both the healthy contralateral tissue and the ischaemic lesions, but not with [11C]-(R)-PK11195. When applying correction for intravascular activity of [18F]-GE180, the difference between MABs and HABs was no longer significant in healthy tissue. A similar effect was seen in other studies13,25 but not in all studies20 conducted on healthy volunteers, perhaps because of the small magnitude of the signal in a normal brain. The differences in binding of second-generation tracers across HAB/MAB/LAB classes vary depending on ligand affinity.26 In vitro [18F]-GE180 demonstrates a binding affinity of 15\u2009:\u20091 between HABs and LABs, which suggests negligible specific binding in PET scans obtained in LABs.\nOwing to the limited ability of [18F]-GE180 to cross the intact BBB and, therefore, the poor penetration of the brain tissue, a significant amount of the signal in a brain region of interest is in fact from the vascular activity. As the spatial resolution of human brain imaging is unable to resolve the vasculature, we sought to apply an approximate correction for the contribution of the vascular signal by subtracting an early image. Our results suggest that a significant portion (up to 50%) of the signal seen in the infarcts in MAB and HAB patients may be caused by spillover from the vasculature.\nThe comparison of lesions with and without contrast enhancement suggests that BBB disruption is playing a major role in tissue uptake of [18F]-GE180 in ischaemic lesions. Although some proportion of increased uptake will probably indicate increased binding to TSPO receptors, this was also observed in LABs, which suggested that there is a large amount of non-specific uptake in ischaemic lesions with contrast enhancement. Thus, clinical interpretation of findings would need to take into account the effects of the polymorphism and BBB damage, which cannot be quantified accurately. Furthermore, assessment of BBB damage requires MR scanning with gadolinium, which, for safety reasons, could not be applied in two of our patients.\nAnother challenge to the interpretation of clinical studies are recent in vitro findings27 suggesting that, in contrast to findings in rodents, TSPO gene expression does not depend on microglia activation in humans.\nGiven the significant impact of rs6971 genotype and BBB disruption on the signal, LABs and patients not receiving contrast-enhanced MRI scans need to be excluded, which results in a substantial increase in the size of the required sample. Furthermore, the statistical analysis would have taken the presence of contrast enhancement into account as a major confounder. Considering these factors, the number of participants planned for phase 2 (n\u2009=\u200940), which was aiming at correlation with clinical outcome, would not have provided adequate power.\nA limitation of the current study was the time window to assess TSPO binding with [18F]-GE180 (15\u201330 minutes post injection). Most other studies report a time window of 60 to 90 minutes as the optimal interval. Kinetic studies13,28 showed a relatively high contribution of intravascular blood activity to total observed activity, even after 60 minutes. However, with late static scans, correction for intravascular activity is not possible and we therefore chose scanning for 30 minutes immediately after injection. Analysis of kinetic data from multiple studies (compiled in Sridharan29) showed relatively little change in lesion-to-background ratios after 15 minutes. In addition, the close correlation between [18F]-GE180 and [11C]-(R)-PK11195 that was observed in our study supports the validity of using an early time window. Nevertheless, we cannot exclude that late scanning could have provided increased lesion-to-background ratios.", "pairs": [], "interleaved": []}
+{"file": "ukeme0701_NBK553477/s7.nxml", "text": "This pilot study demonstrates that neuroinflammation in ischaemic stroke can be imaged by the TSPO PET radioligands [18F]-GE180 and [11C]-(R)-PK11195. Uptake in lesions, relative to contralateral tissue, is similar and highly correlated with both radiotracers. As expected, [18F]-GE180 intravascular activity is high during the entire scanning time, so correction for intravascular activity was necessary and could be performed successfully. Genotype and BBB damage have significant effects on [18F]-GE180 uptake. High uptake of [18F]-GE180 in lesions with BBB damage, even in LABs, suggests the presence of non-specific binding, whereas uptake in normal brain tissue is very low. Further studies are warranted to fully understand the influence of BBB damage on PET microglia imaging.\nThe very low uptake of [18F]-GE180 in normal brain tissue and the substantial confounding effect of BBB damage had not been known when designing the present study. Thus, according to our own judgement and the opinion of the Independent Data Monitoring Committee, phase 2 could not be conducted as envisaged and the study has been closed after completion of phase 1.", "pairs": [], "interleaved": []}