91 results found
Marques TR, Veronese M, Owen DR, et al., 2021, Specific and non-specific binding of a tracer for the translocator-specific protein in schizophrenia: an [11C]-PBR28 blocking study, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, ISSN: 1619-7070
Voysey M, Clemens SAC, Madhi SA, et al., 2021, Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials, The Lancet, Vol: 397, Pages: 881-891, ISSN: 0140-6736
BackgroundThe ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4–12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered.MethodsWe present data from three single-blind randomised controlled trials—one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)—and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked
Nutma E, Ceyzeriat K, Amor S, et al., 2021, Cellular sources of TSPO expression in healthy and diseased brain, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, ISSN: 1619-7070
Voysey M, Clemens SAC, Madhi SA, et al., 2021, Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK, The Lancet, Vol: 397, Pages: 99-111, ISSN: 0140-6736
BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pin
Kreisl WC, Kim M-J, Coughlin JM, et al., 2020, PET imaging of neuroinflammation in neurological disorders, LANCET NEUROLOGY, Vol: 19, Pages: 940-950, ISSN: 1474-4422
Nicholas R, Brooks D, Owen D, 2020, 18F-GE180, a radioligand for the TSPO protein: not ready for clinical trials in multiple sclerosis, EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING, Vol: 47, Pages: 2242-2243, ISSN: 1619-7070
Nicholas R, Brooks D, Owen D, 2020, Letter to the Editor re: Confirmation of Specific Binding of the 18-kDa Translocator Protein (TSPO) Radioligand [F-18]GE-180: a Blocking Study Using XBD173 in Multiple Sclerosis Normal Appearing White and Grey Matter In Response, MOLECULAR IMAGING AND BIOLOGY, Vol: 22, Pages: 13-14, ISSN: 1536-1632
Nutma E, Stephenson JA, Gorter RP, et al., 2019, A quantitative neuropathological assessment of translocator protein expression in multiple sclerosis, Brain, Vol: 142, Pages: 3440-3455, ISSN: 1460-2156
The 18kDa translocator protein (TSPO) is increasingly used to study brain and spinal cord inflammation in degenerative diseases of the CNS such as multiple sclerosis. The enhanced TSPO PET signal that arises during disease is widely-considered to reflect activated pathogenicmicroglia, although quantitative neuropathological data to support this interpretation has not been available. With the increasing interest in the role of chronic microglial activation in multiple sclerosis, characterising the cellular neuropathology associated with TSPO expression is of clear importance for understanding the cellular and pathological processes on which TSPO PET imaging is reporting.Here we have studied the cellular expression of TSPO and specific binding of two TSPO targeting radioligands ([3H]PK11195 and [3H]PBR28) in tissue sections from 42 multiple sclerosis cases and 12 age-matched controls. Markers of homeostatic and reactive microglia, astrocytes, and lymphocytes were used to investigate the phenotypes of cells expressing TSPO. There was an approximate 20-fold increase in cells double positive for TSPO and human leukocyte antigen -DR in active lesions and in the rim of chronic active lesion, relative to normal appearing white matter. TSPO was uniformly expressed across myeloid cells irrespective of their phenotype, rather than being preferentially associated with pro-inflammatory microglia or macrophages. TSPO+astrocytes were increased up to 7-fold compared to normal appearing white matter across all lesion sub-types and accounted for 25% of the TSPO+ cells in these lesions. To relate TSPO protein expression to ligand binding, specific binding of the TSPO ligands [3H]PK11195 and [3H]PBR28was determined in the same lesions. TSPO radioligand binding was increased up to seven times for [3H]PBR28 and up to two times for [3H]PK11195 in active lesions and the centre of chronic ac
Sridharan S, Raffel J, Nandoskar A, et al., 2019, Confirmation of specific binding of the 18 kDa translocator protein (TSPO) radioligand [18F]GE-180: a blocking study using XBD173 in multiple sclerosis normal appearing white and grey matter, Molecular Imaging and Biology, Vol: 21, Pages: 935-944, ISSN: 1536-1632
Purpose: Positron emission tomography (PET) ligands exhibit different levels of non-displaceable binding in vivo. In the case of ligands for the 18 kDa translocator protein (TSPO), the component of non-displaceable binding for the most widely used radiotracer, [11C]-(R)-PK11195, is relatively high compared to that for newer TSPO ligands. Non-displaceable binding is not often quantified in humans in vivo, partially due to a lack of available ligands that are known to be safe with which to displace binding to the target receptor. Recently, however, a technique has been developed to quantify the non-displaceable binding of TSPO tracers in vivo, by blocking the receptor with the TSPO ligand XBD173 and comparing the total volume of distribution ( ) pre and post-blockade. Here, we used an occupancy plot to quantify the non-displaceable binding ( ) of the TSPO PET tracers [18F]GE-180 and [11C]PBR28 in cohorts of people with multiple sclerosis (MS). We also compared plots of subjects carrying both high and mixed binding affinity polymorphisms of TSPO to estimate while potentially avoiding the need for receptor blockade.Procedures: Twelve people with multiple sclerosis (MS) and high (HAB) or mixed (MAB) affinity binding for TSPO underwent baseline MRI and 90-minute dynamic [18F]GE-180 PET (n=6; 3 HAB and 3 MAB) or [11C]PBR28 PET (n=6; 3 HAB, 3 MAB). Either one week later ([18F]GE-180) or the same afternoon ([11C]PBR28), participants had repeat PET following a 90mg dose of XBD173. PET images were co-registered with T1 MR volumetric images and regions of interest (ROIs) were defined using the 83-region Hammers atlas. Arterial blood sampling was used to generate plasma input functions for the two-tissue compartment model to quantify . The non-displaceable fraction of the total volume of distribution ( ) was calculated using two independent methods: the occupancy plot (by modelling the differences in signal post XBD173), and the polymorphism plot (by modelling the differences in
Fancy NN, Srivastava P, Matthews PM, et al., 2019, A bioinformatics approach to understand the regulation of TSPO gene expression in myeloid cells, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 222-222, ISSN: 1352-4585
Weinert M, Cowley SA, Alavian KN, et al., 2019, Exploring the mitochondrial TSPO protein as a possible immunometabolic modulatory target for treatment of multiple sclerosis, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 515-515, ISSN: 1352-4585
Smith AM, Khozoie C, Fancy N, et al., 2019, Single nucleus RNA sequencing of post-mortem multiple sclerosis cortical grey matter, 35th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS) / 24th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 233-233, ISSN: 1352-4585
Galloway DA, Phillips AEM, Owen DRJ, et al., 2019, Phagocytosis in the Brain: Homeostasis and Disease (vol 10, 790, 2019), FRONTIERS IN IMMUNOLOGY, Vol: 10, ISSN: 1664-3224
Field SM, Burstow NJ, Owen DR, et al., 2019, Using team-based revision to prepare medical students for the prescribing safety assessment, Advances in Medical Education and Practice, Vol: 2019, Pages: 501-506, ISSN: 1179-7258
BackgroundThe Prescribing Safety Assessment (PSA) is an online assessment of safe and effective prescribing, taken by final-year UK medical students. To prepare students for the PSA, we used a modified form of team-based learning, team-based revision (TBR), in which students consolidate previously learned prescribing knowledge and skills across a broad range of topics. We evaluated students’ response to TBR and their perceptions of team working. MethodsEight TBR sessions based on the PSA blueprint were conducted over two days by three faculty members for final year medical students. During TBR sessions, students worked in small groups answering individual multiple-choice questions, followed by group multiple-choice questions. They subsequently answered open-ended questions in their groups, with answers written on a drug chart to increase authenticity. Students completed surveys using Likert-type items to determine views on TBR and their confidence in prescribing. ResultsThe majority of respondents agreed that the sessions were useful for preparation both for the PSA (82%) and Foundation Year 1 (78%). 92% agreed that using drug-charts aided learning. Prescribing confidence increased significantly after TBR (median pre-TBR: 2, post-TBR: 5, p<0.0001). TBR significantly improved attitudes towards ‘team experience’ (p<0.001), ‘team impact on quality of learning’ (p<0.01) and ‘team impact on clinical reasoning ability’ (p <0.001). ConclusionsTeam-based revision is a resource-efficient addition to undergraduate prescribing teaching and can help with preparation for the PSA. A short course of TBR was effective in influencing students’ attitudes towards teamwork.
Sam SA, Fung CY, Wilson R, et al., 2019, Using prescribing very short answer questions to identify sources of medication errors: a prospective study in two UK medical schools, BMJ Open, Vol: 9, Pages: 1-5, ISSN: 2044-6055
Objective To assess the utility and ability of the novel prescribing very short answer (VSA) question format to identify the sources of undergraduate prescribing errors when compared with the conventional single best answer (SBA) question format and assess the acceptability of machine marking prescribing VSAs.Design A prospective study involving analysis of data generated from a pilot two-part prescribing assessment.Setting Two UK medical schools.Participants 364 final year medical students took part. Participation was voluntary. There were no other inclusion or exclusion criteria.Outcomes (1) Time taken to mark and verify VSA questions (acceptability), (2) differences between VSA and SBA scores, (3) performance in VSA and (4) SBA format across different subject areas and types of prescribing error made in the VSA format.Results 18 200 prescribing VSA questions were marked and verified in 91 min. The median percentage score for the VSA test was significantly lower than the SBA test (28% vs 64%, p<0.0001). Significantly more prescribing errors were detected in the VSA format than the SBA format across all domains, notably in prescribing insulin (96.4% vs 50.3%, p<0.0001), fluids (95.6% vs 55%, p<0.0001) and analgesia (85.7% vs 51%, p<0.0001). Of the incorrect VSA responses, 33.1% were due to the medication prescribed, 6.0% due to the dose, 1.4% due to the route and 4.8% due to the frequency.Conclusions Prescribing VSA questions represent an efficient tool for providing detailed insight into the sources of significant prescribing errors, which are not identified by SBA questions. This makes the prescribing VSA a valuable formative assessment tool to enhance students’ skills in safe prescribing and to potentially reduce prescribing errors.
Galloway DA, Phillips AEM, Owen D, et al., 2019, Phagocytosis in the brain: homeostasis and disease, Frontiers in Immunology, Vol: 10, ISSN: 1664-3224
Microglia are resident macrophages of the central nervous system and significantly contribute to overall brain function by participating in phagocytosis during development, homeostasis, and diseased states. Phagocytosis is a highly complex process that is specialized for the uptake and removal of opsonized and non-opsonized targets, such as pathogens, apoptotic cells, and cellular debris. While the role of phagocytosis in mediating classical innate and adaptive immune responses has been known for decades, it is now appreciated that phagocytosis is also critical throughout early neural development, homeostasis, and initiating repair mechanisms. As such, modulating phagocytic processes has provided unexplored avenues with the intent of developing novel therapeutics that promote repair and regeneration in the CNS. Here, we review the functional consequences that phagocytosis plays in both the healthy and diseased CNS, and summarize how phagocytosis contributes to overall pathophysiological mechanisms involved in brain injury and repair.
Sridharan S, Raffel J, Nandoskar A, et al., 2018, Confirmation of specific binding of the 18 kDa translocator protein (TSPO) radioligand [F-18]GE-180: a blocking study using XDB173 in multiple sclerosis, 34th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 421-422, ISSN: 1352-4585
Narayan N, Owen D, Mandhair H, et al., 2018, Translocator protein as an imaging marker of macrophage and stromal activation in RA pannus, Journal of Nuclear Medicine, Vol: 59, Pages: 1125-1132, ISSN: 1535-5667
Positron Emission Tomography (PET) radioligands targeted to Translocator protein (TSPO), offer a highly sensitive and specific means of imaging joint inflammation in rheumatoid arthritis (RA). Through high expression of TSPO on activated macrophages, TSPO PET has been widely reported in several studies of RA as a means of imaging synovial macrophages in vivo. However, this premise does not take into account the ubiquitous expression of TSPO. This study aimed to investigate TSPO expression in major cellular constituents of RA pannus; monocytes, macrophages, fibroblast-like synoviocytes (FLS) and CD4+ T lymphocytes, to more accurately interpret TSPO PET signal from RA synovium. Methods: 3 RA patients and 3 healthy volunteers underwent PET both knees using the TSPO radioligand 11C-PBR28. Through synovial tissue 3H-PBR28 autoradiography and immunostaining of 6 RA patients and 6 healthy volunteers, cellular expression of TSPO in synovial tissue was evaluated. TSPO mRNA expression and 3H-PBR28 radioligand binding was assessed using in vitro monocytes, macrophages, FLS and CD4+ T-lymphocytes. Results:11C-PBR28 PET signal was significantly higher in RA compared to healthy joints (average SUV 0.82± 0.12 compared to 0.03± 0.004 respectively, p<0.01). Further, 3H-PBR28 specific binding in synovial tissue was approximately 10-fold higher in RA compared to healthy controls. Immunofluorescence revealed TSPO expression on macrophages, FLS and CD4+ T cells. In vitro study demonstrated highest TSPO mRNA expression and 3H-PBR28 specific binding, in activated FLS, non-activated and activated 'M2' reparative macrophages, with least TSPO expression in activated and non-activated CD4+ T lymphocytes. Conclusion: This study is the first evaluation of cellular TSPO expression in synovium, finding highest TSPO expression and PBR28 binding on activated synovial FLS and M2 phenotype macrophages. TSPO targeted PET may therefore have unique sensitivity to detect FLS and macropha
Scott GPT, Zetterberg H, Jolly A, et al., 2017, Minocycline reduces chronic microglial activation after brain trauma but increases neurodegeneration, Brain, Vol: 141, Pages: 459-471, ISSN: 1460-2156
Survivors of a traumatic brain injury can deteriorate years later, developing brain atrophy and dementia. Traumatic brain injury triggers chronic microglial activation, but it is unclear whether this is harmful or beneficial. A successful chronic-phase treatment for traumatic brain injury might be to target microglia. In experimental models, the antibiotic minocycline inhibits microglial activation. We investigated the effect of minocycline on microglial activation and neurodegeneration using PET, MRI, and measurement of the axonal protein neurofilament light in plasma. Microglial activation was assessed using 11C-PBR28 PET. The relationships of microglial activation to measures of brain injury, and the effects of minocycline on disease progression, were assessed using structural and diffusion MRI, plasma neurofilament light, and cognitive assessment. Fifteen patients at least 6 months after a moderate-to-severe traumatic brain injury received either minocycline 100 mg orally twice daily or no drug, for 12 weeks. At baseline, 11C-PBR28 binding in patients was increased compared to controls in cerebral white matter and thalamus, and plasma neurofilament light levels were elevated. MRI measures of white matter damage were highest in areas of greater 11C-PBR28 binding. Minocycline reduced 11C-PBR28 binding (mean Δwhite matter binding = −23.30%, 95% confidence interval −40.9 to −5.64%, P = 0.018), but increased plasma neurofilament light levels. Faster rates of brain atrophy were found in patients with higher baseline neurofilament light levels. In this experimental medicine study, minocycline after traumatic brain injury reduced chronic microglial activation while increasing a marker of neurodegeneration. These findings suggest that microglial activation has a reparative effect in the chronic phase of traumatic brain injury.
Owen DRJ, Fan J, Campioli E, et al., 2017, TSPO mutations in rats and a human polymorphism impair the rate of steroid synthesis, Biochemical Journal, Vol: 474, Pages: 3985-3999, ISSN: 1470-8728
The 18 kDa translocator protein (TSPO) is a ubiquitous conserved outer mitochondrial membrane protein implicated in numerous cell and tissue functions, including steroid hormone biosynthesis, respiration, cell proliferation, and apoptosis. TSPO binds with high affinity to cholesterol and numerous compounds, is expressed at high levels in steroid-synthesizing tissues, and mediates cholesterol import into mitochondria, which is the rate-limiting step in steroid formation. In humans, the rs6971 polymorphism on the TSPO gene leads to an amino acid substitution in the fifth transmembrane loop of the protein, which is where the cholesterol-binding domain of TSPO is located, and this polymorphism has been associated with anxiety-related disorders. However, recent knockout mouse models have provided inconsistent conclusions of whether TSPO is directly involved in steroid synthesis. In this report, we show that TSPO deletion mutations in rat and its corresponding rs6971 polymorphism in humans alter adrenocorticotropic hormone-induced plasma corticosteroid concentrations. Rat tissues examined show increased cholesteryl ester accumulation, and neurosteroid formation was undetectable in homozygous rats. These results also support a role for TSPO ligands in diseases with steroid-dependent stress and anxiety elements.
Fujita M, Kobayashi M, Ikawa M, et al., 2017, Comparison of four (11)C-labeled PET ligands to quantify translocator protein 18 kDa (TSPO) in human brain: (R)-PK11195, PBR28, DPA-713, and ER176-based on recent publications that measured specific-to-non-displaceable ratios., EJNMMI Research, Vol: 7, ISSN: 2191-219X
Translocator protein (TSPO) is a biomarker for detecting neuroinflammation by PET. (11)C-(R)-PK11195 has been used to image TSPO since the 1980s. Here, we compared the utility of four (11)C-labeled ligands-(R)-PK11195, PBR28, DPA-713, and ER176-to quantify TSPO in healthy humans. For all of these ligands, BP ND (specific-to-non-displaceable ratio of distribution volumes) was measured by partially blocking specific binding with XNBD173 administration. In high-affinity binders, DPA-713 showed the highest BP ND of 7.3 followed by ER176 (4.2), PBR28 (1.2), and PK11195 (0.8). Only ER176 allows the inclusion of low-affinity binders because of little influence of radiometabolites and high BP ND. If inclusion of all three genotypes is important for study logistics, ER176 is the best of these four radioligands for studying neuroinflammation.
Narayan N, Mandhair H, Smyth E, et al., 2017, The macrophage marker translocator protein (TSPO) is down-regulated on pro-inflammatory 'M1' human macrophages., PLoS ONE, Vol: 12, ISSN: 1932-6203
The translocator protein (TSPO) is a mitochondrial membrane protein, of as yet uncertain function. Its purported high expression on activated macrophages, has lent utility to TSPO targeted molecular imaging in the form of positron emission tomography (PET), as a means to detect and quantify inflammation in vivo. However, existing literature regarding TSPO expression on human activated macrophages is lacking, mostly deriving from brain tissue studies, including studies of brain malignancy, and inflammatory diseases such as multiple sclerosis. Here, we utilized three human sources of monocyte derived macrophages (MDM), from THP-1 monocytes, healthy peripheral blood monocytes and synovial fluid monocytes from patients with rheumatoid arthritis, to undertake a detailed investigation of TSPO expression in activated macrophages. In this work, we demonstrate a consistent down-regulation of TSPO mRNA and protein in macrophages activated to a pro-inflammatory, or 'M1' phenotype. Conversely, stimulation of macrophages to an M2 phenotype with IL-4, dexamethasone or TGF-β1 did not alter TSPO expression, regardless of MDM source. The reasons for this are uncertain, but our study findings add some supporting evidence for recent investigations concluding that TSPO may be involved in negative regulation of inflammatory responses in macrophages.
Falk IN, Maric D, Lefeuvre J, et al., 2017, Characterization of TSPO expression by conventional and mutliplex immunohistochemistry in marmoset EAE, 7th Joint European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS)-Americas-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ACTRIMS), Publisher: SAGE PUBLICATIONS LTD, Pages: 765-765, ISSN: 1352-4585
Datta G, Colasanti A, Kalk N, et al., 2017, [(11)C]PBR28 or [(18)F]PBR111 detect white matter inflammatory heterogeneity in multiple sclerosis, Journal of Nuclear Medicine, Vol: 58, Pages: 1477-1482, ISSN: 1535-5667
Objective: To assess microglial activation in lesions and in normal appearing white matter of multiple sclerosis (MS) patients using positron emission tomography (PET). Methods: 34 MS patients (7 with secondary progressive MS (SPMS), 27 with relapsing remitting MS (RRMS)) and 30 healthy volunteers, genetically stratified for translocator protein (TSPO), binding status underwent PET scanning with TSPO radioligands ((11)C-PBR28 or (18)F-PBR111). Regional TSPO availability was measured as a distribution volume ratio (DVR) relative to the caudate (a pseudo-reference region). White matter lesions (WML) were classified as "active" (DVR highest in the lesion), "peripherally active" (peri-lesional DVR highest), "inactive" (DVR highest in surrounding normal appearing white matter, NAWM) or "undifferentiated" (similar DVR across lesion, peri-lesional and NAWM volumes). Results: The mean DVR in NAWM of patients was greater than that of the healthy volunteer white matter for both radioligands. Uptake for individual WML in patients was heterogeneous, but the median WML DVR and NAWM DVR for individual patients were strongly correlated (ρ = 0.94, P = 4x10-11). A higher proportion of lesions were inactive in patients with SPMS (35 %) than RRMS (23 %), but active lesions were found in all patients, including those on highly efficacious treatments. Conclusion: TSPO radioligand uptake was increased in brains of MS patients relative to healthy controls with two TSPO radiotracers. WML showed heterogeneous patterns of uptake. Active lesions were found in patients with both RRMS and SPMS. Their independent prognostic significance needs further investigation.
Owen DRJ, Narayan N, Wells L, et al., 2017, Pro-inflammatory activation of primary microglia and macrophages increases 18kDa Translocator Protein (TSPO) expression in rodents but not humans, Journal of Cerebral Blood Flow and Metabolism, Vol: 37, Pages: 2679-2690, ISSN: 1559-7016
The 18kDa Translocator Protein (TSPO) is the most commonly used tissue-specific marker of inflammation in positron emission tomography (PET) studies. It is expressed in myeloid cells such as microglia and macrophages, and in rodent myeloid cells expression increases with cellular activation. We assessed the effect of myeloid cell activation on TSPO gene expression in both primary human and rodent microglia and macrophages in vitro, and also measured TSPO radioligand binding with 3H-PBR28 in primary human macrophages. As observed previously, we found that TSPO expression increases (∼9-fold) in rodent-derived macrophages and microglia upon pro-inflammatory stimulation. However, TSPO expression does not increase with classical pro-inflammatory activation in primary human microglia (fold change 0.85 [95% CI 0.58–1.12], p = 0.47). In contrast, pro-inflammatory activation of human monocyte-derived macrophages is associated with a reduction of both TSPO gene expression (fold change 0.60 [95% CI 0.45–0.74], p = 0.02) and TSPO binding site abundance (fold change 0.61 [95% CI 0.49–0.73], p < 0.0001). These findings have important implications for understanding the biology of TSPO in activated macrophages and microglia in humans. They are also clinically relevant for the interpretation of PET studies using TSPO targeting radioligands, as they suggest changes in TSPO expression may reflect microglial and macrophage density rather than activation phenotype.
Kobayashi M, Jiang T, Telu S, et al., 2017, (11)C-DPA-713 has much greater specific binding to translocator protein 18 kDa (TSPO) in human brain than (11)C-( R)-PK11195, Journal of Cerebral Blood Flow and Metabolism, Vol: 38, Pages: 393-403, ISSN: 1559-7016
Positron emission tomography (PET) radioligands for translocator protein 18 kDa (TSPO) are widely used to measure neuroinflammation, but controversy exists whether second-generation radioligands are superior to the prototypical agent (11)C-( R)-PK11195 in human imaging. This study sought to quantitatively measure the "signal to background" ratio (assessed as binding potential ( BPND)) of (11)C-( R)-PK11195 compared to one of the most promising second-generation radioligands, (11)C-DPA-713. Healthy subjects had dynamic PET scans and arterial blood measurements of radioligand after injection of either (11)C-( R)-PK11195 (16 subjects) or (11)C-DPA-713 (22 subjects). To measure the amount of specific binding, a subset of these subjects was scanned after administration of the TSPO blocking drug XBD173 (30-90 mg PO). (11)C-DPA-713 showed a significant sensitivity to genotype in brain, whereas (11)C-( R)-PK11195 did not. Lassen occupancy plot analysis revealed that the specific binding of (11)C-DPA-713 was much greater than that of (11)C-( R)-PK11195. The BPND in high-affinity binders was about 10-fold higher for (11)C-DPA-713 (7.3) than for (11)C-( R)-PK11195 (0.75). Although the high specific binding of (11)C-DPA-713 suggests it is an ideal ligand to measure TSPO, we also found that its distribution volume increased over time, consistent with the accumulation of radiometabolites in brain.
Marques TR, Bloomfield P, Owen D, et al., 2017, PET IMAGING OF NEUROINFLAMMATION IN SCHIZOPHRENIA, 16th International Congress on Schizophrenia Research (ICOSR), Publisher: OXFORD UNIV PRESS, Pages: S64-S65, ISSN: 0586-7614
Owen DRJ, Narayan, Taylor P, 2017, Advances in positron emission tomography for the imaging of Rheumatoid Arthritis, Rheumatology, Vol: 56, Pages: 1837-1846, ISSN: 1462-0332
Imaging techniques, such as ultrasound, are well recognized as important tools to aid early diagnosis and assess response to treatment in RA. Positron Emission Tomography (PET) offers a means of imaging the inflammatory processes of RA at a cellular level, thus may be a highly sensitive method of assessing synovitis. In this review, we discuss the advantages of PET as an imaging modality for RA and summarise the existing clinical studies of PET in RA. We also highlight potentially important pre3clinical studies of PET in arthritis, discuss current limitations of PET, and ongoing developments in PET technology, likely to be of benefit for arthritis imaging.
Kalk NJ, Guo Q, Owen D, et al., 2017, Decreased hippocampal translocator protein (18 kDa) expression in alcohol dependence: a [(11)C]PBR28 PET study, Translational Psychiatry, Vol: 7, ISSN: 2158-3188
Repeated withdrawal from alcohol is clinically associated with progressive cognitive impairment. Microglial activation occurring during pre-clinical models of alcohol withdrawal is associated with learning deficits. We investigated whether there was microglial activation in recently detoxified alcohol-dependent patients (ADP), using [(11)C]PBR28 positron emission tomography (PET), selective for the 18kDa translocator protein (TSPO) highly expressed in activated microglia and astrocytes. We investigated the relationship between microglial activation and cognitive performance. Twenty healthy control (HC) subjects (45±13; M:F 14:6) and nine ADP (45±6, M:F 9:0) were evaluated. Dynamic PET data were acquired for 90 min following an injection of 331±15 MBq [(11)C]PBR28. Regional volumes of distribution (VT) for regions of interest (ROIs) identified a priori were estimated using a two-tissue compartmental model with metabolite-corrected arterial plasma input function. ADP had an ~20% lower [(11)C]PBR28 VT, in the hippocampus (F(1,24) 5.694; P=0.025), but no difference in VT in other ROIs. Hippocampal [(11)C]PBR28 VT was positively correlated with verbal memory performance in a combined group of HC and ADP (r=0.720, P<0.001), an effect seen in HC alone (r=0.738; P=0.001) but not in ADP. We did not find evidence for increased microglial activation in ADP, as seen pre-clinically. Instead, our findings suggest lower glial density or an altered activation state with lower TSPO expression. The correlation between verbal memory and [(11)C]PBR28 VT, raises the possibility that abnormalities of glial function may contribute to cognitive impairment in ADP.
Dimber R, Guo Q, Bishop C, et al., 2016, Evidence of brain inflammation in patients with Human T Lymphotropic Virus type 1 associated myelopathy (HAM): A pilot, multi-modal imaging study using [11C] PBR28 PET, MR T1w and DWI, Journal of Nuclear Medicine, Vol: 57, Pages: 1905-1912, ISSN: 1535-5667
HAM is a chronic debilitating neuroinflammatory disease with a predilection for the thoraciccord. Tissue damage is attributed to the cellular immune response to HTLV-1 infectedlymphocytes. Using a specific 18KDa Translocator Protein ligand, [11C] PBR28, T1-weightedand Diffusion Weighted magnetic resonance imaging, the brains of HTLV-1 infected patients,with and without HAM but no clinical evidence of brain involvement, were examined.Methods: Five subjects with HAM and two HTLV-1 asymptomatic carriers (AC) werestudied. All underwent clinical neurological assessment including cognitive function andobjective measures of gait, quantification of HTLV-1 proviral load in peripheral bloodmononuclear cells and HLA DR expression on circulating CD8+ lymphocytes. [11C] PBR28PET and MRI were performed on the same day. [11C]PBR28 PET total volume of distribution(VT) and distribution volume ratio (DVR) were estimated using 2-tissue compartmentmodelling. MRI data was processed using tools from the FMRIB Software Library (FSL) toestimate mean diffusivity (MD) and grey matter (GM) fraction changes. The results werecompared with data from age matched healthy volunteers.Results: Across the whole brain the VT for the subjects with HAM (5.44±0.84) wassignificantly greater than those of AC (3.44±0.80). The DVR of thalamus in patients withsevere and moderate HAM were higher compared to the healthy volunteers suggestingincreased TSPO binding (z>4.72). Subjects with more severe myelopathy and with high DRexpression on CD8+ lymphocytes had increased DVR and MD (near-significant correlationfound for the right thalamus MD: p=0.06). On the T1-weighted MRI scans, the GM fractionof the brain stem was reduced in all HTLV1-infected patients compared to controls(p<0.001), whilst the thalamus GM fraction was decreased in patients with HAM andcorrelated with the disease severity. There was no correlation between neurocognitivefunction and these markers of CNS inflammation.3Conclusio
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