Publications
109 results found
Calsolaro V, Matthews PM, Donat CK, et al., 2021, Astrocyte reactivity with late onset cognitive impairment assessed in-vivo using 11C-BU99008 PET and its relationship with amyloid load, Molecular Psychiatry, Vol: 26, Pages: 5848-5855, 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.
Palmer EOC, Ward G, Mota B, et al., 2021, ALCOHOL HANGOVER INDUCES INCREASED NEUROINFLAMMATORY RESPONSE IN A RODENT MODEL, Publisher: WILEY, Pages: 202A-203A, ISSN: 0145-6008
Borissova A, Ferguson B, Wall MB, et al., 2021, Acute effects of MDMA on trust, cooperative behaviour and empathy: A double-blind, placebo-controlled experiment, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 35, Pages: 547-555, ISSN: 0269-8811
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- Citations: 12
Mirzaei N, Mota B, Birch A, et al., 2021, Imidazoline ligand BU224 reverses cognitive deficits, reduces microgliosis and enhances synaptic connectivity in a mouse model of Alzheimer’s disease, British Journal of Pharmacology, Vol: 178, Pages: 654-671, ISSN: 0007-1188
Background and PurposeActivation of type‐2 Imidazoline receptors has been shown to exhibit neuroprotective properties including anti‐apoptotic and anti‐inflammatory effects, suggesting a potential therapeutic value in Alzheimer's disease (AD). Here, we explored the effects of the Imidazoline‐2 ligand BU224 in a model of amyloidosis.Experimental approach6‐month‐old female transgenic 5XFAD and wild‐type (WT) mice were treated intraperitoneally with 5 mg.kg‐1 BU224 or vehicle twice a day for 10 days. Behavioural tests were performed for cognitive functions and neuropathological changes were investigated by immunohistochemistry, Western blot, ELISA and qPCR. Effects of BU224 on APP processing, spine density and calcium imaging were analysed in brain organotypic cultures and N2a cells.Key ResultsBU224 treatment attenuated spatial and perirhinal cortex‐dependent recognition memory deficits in 5XFAD mice. Fear conditioning testing revealed that BU224 also improved both associative learning and hippocampal‐ and amygdala‐dependent memory in transgenic but not in WT mice. In the brain, BU224 reduced levels of the microglial marker Iba1 and pro‐inflammatory cytokines IL‐1β and TNFα, and increased the expression of astrocytic marker GFAP in 5XFAD mice. These beneficial effects were not associated with changes in amyloid pathology, neuronal apoptosis, mitochondrial density, oxidative stress or autophagy markers. Interestingly, ex vivo and in vitro studies suggested that BU224 treatment increased the size of dendritic spines and induced a 3‐fold reduction in Aβ‐induced functional changes in NMDA receptors.Conclusions and implicationsOur data indicate that sub‐chronic treatment with BU224 improves memory and reduces inflammation in transgenic AD mice, at stages when animals display severe pathology.
Wilson H, Dervenoulas G, Pagano G, et al., 2019, Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an <i>in vivo</i> <SUP>11</SUP>C-BU99008 PET study, BRAIN, Vol: 142, Pages: 3116-3128, ISSN: 0006-8950
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- Citations: 52
Wilson H, Niccolini F, Dervenoulas G, et 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
Wilson H, Dervenoulas G, Pagano G, et 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
Roussakis A-A, Mohamed MA, Myers J, et al., 2019, Astrogliosis in Parkinson's disease dementia: a preliminary report with brain, 5th Congress of the European-Academy-of-Neurology (EAN)
Wilson H, Dervenoulas G, Pagano G, et al., 2019, Evaluation of Imidazoline 2 binding sites reflecting astroglia pathology in Parkinson's disease: an in vivo [11C] BU99008 PET study, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 1005-1005, ISSN: 1351-5101
Wilson H, Niccolini F, Dervenoulas G, et al., 2019, Evaluation of imidazoline 2 binding sites reflecting astroglia pathology in Huntington's disease: an in vivo [11C] BU99008 PET study, 5th Congress of the European-Academy-of-Neurology (EAN), Publisher: WILEY, Pages: 317-318, ISSN: 1351-5101
Palmer E, Tyacke R, Sastre M, et al., 2019, Alcohol hangover: underlying biochemical, inflammatory and neurochemical mechanisms, Alcohol and Alcoholism, Vol: 54, Pages: 196-203, ISSN: 0735-0414
AIM: To review current alcohol hangover research in animals and humans and evaluate key evidence for contributing biological factors. METHOD: Narrative review with alcohol hangover defined as the state the day after a single episode of heavy drinking, when the alcohol concentration in the blood approaches zero. RESULTS: Many of the human studies of hangover are not well controlled, with subjects consuming different concentrations of alcohol over variable time periods and evaluation not blinded. Also, studies have measured different symptoms and use varying methods of measurement. Animal studies show variations with respect to the route of administration (intragastric or intraperitoneal), the behavioural tests utilised and discrepancy in the timepoint used for hangover onset. Human studies have the advantage over animal models of being able to assess subjective hangover severity and its correlation with specific behaviours and/or biochemical markers. However, animal models provide valuable insight into the neural mechanisms of hangover. Despite such limitations, several hangover models have identified pathological changes which correlate with the hangover state. We review studies examining the contribution of alcohol's metabolites, neurotransmitter changes with particular reference to glutamate, neuroinflammation and ingested congeners to hangover severity. CONCLUSION: Alcohol metabolites, neurotransmitter alterations, inflammatory factors and mitochondrial dysfunction are the most likely factors in hangover pathology. Future research should aim to investigate the relationship between these factors and their causal role.
Tyacke R, Myers J, Venkataraman A, et al., 2018, Evaluation of 11C-BU99008, a positron emission tomography ligand for the Imidazoline2 binding site in human brain, Journal of Nuclear Medicine, Vol: 59, Pages: 1597-1602, ISSN: 1535-5667
The imidazoline2 binding sites (I2BS), are thought to be expressed in glia, and implicated in the regulation of glial fibrillary acidic protein. A positron emission tomography (PET) ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C BU99008 has previously been identified as a putative PET radioligand. Here we present the first in vivo characterisation of this PET radioligand in humans and assess its test-retest reproducibility. Methods: 14 healthy male volunteers underwent dynamic PET imaging with 11C BU99008 and arterial sampling. Six subjects were used to assess test-retest and eight were used in the pharmacological evaluation, undergoing a second, or third heterologous competition scan with the mixed I2BS/α2 adrenoceptor drug, idazoxan (n=8; 20, 40, 60 and 80 mg) and the mixed irreversible monoamine oxidase (MAO) A/B inhibitor, isocarboxazid (n=4; 50 mg), respectively. Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure VT (regional total distribution volume). All image processing and kinetic analysis was performed in MIAKAT™ (www.miakat.org). Results: Brain uptake of 11C BU99008 was good with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment was preferred. VT estimates were high in the striatum (105±21 mL cm 3), medium in cingulate cortex (62±10 mL cm 3) and low in the cerebellum (41±7 mL cm 3). Test-retest reliability was found to be reasonable. The uptake was dose-dependently reduced by pre-treatment with idazoxan throughout the brain, with an average block across all regions of ~60% (VT≅30 mL cm 3) at the highest dose (80 mg). The median effective dose (ED50) for idazoxan was calculated as 28 mg. Uptake was not blocked by pre-treatme
Venkataraman A, Keat N, Myers J, et al., 2018, First evaluation of PET-based human biodistribution and radiation dosimetry of 11C-BU99008, a tracer for imaging the imidazoline2 binding site, EJNMMI Research, Vol: 8, ISSN: 2191-219X
BackgroundWe measured whole body distribution of 11C-BU99008, a new PET biomarker for non-invasive identification of the imidazoline2 binding site. The purpose of this phase I study was to evaluate the biodistribution and radiation dosimetry of 11C-BU99008 in healthy human subjects.MethodsA single bolus injection of 11C-BU99008 (296 ± 10.5 MBq) was administered to four healthy subjects who underwent whole-body PET/CT over 120 min from the cranial vertex to the mid-thigh. Volumes of interest were drawn around visually identifiable source organs to generate time-activity curves (TAC). Residence times were determined from time-activity curves. Absorbed doses to individual organs and the whole body effective dose were calculated using OLINDA/EXM 1.1 for each subject.ResultsThe highest measured activity concentration was in the kidney and spleen. The longest residence time was in the muscle at 0.100 ± 0.023 h, followed by the liver at 0.067 ± 0.015 h and lungs at 0.052 ± 0.010 h. The highest mean organ absorbed dose was within the heart wall (0.028 ± 0.002 mGy/MBq), followed by the kidneys (0.026 ± 0.005 mGy/MBq). The critical organ was the heart wall. The total mean effective dose averaged over subjects was estimated to be 0.0056 ± 0.0004 mSv/MBq for an injection of 11C-BU99008.ConclusionsThe biodistribution of 11C-BU99008 has been shown here for the first time in humans. Our dosimetry data showed the total mean effective dose over all subjects was 0.0056 ± 0.0004 mSv/MBq, which would result in a total effective dose of 1.96 mSv for a typical injection of 350 MBq of 11C-BU99008. The effective dose is not appreciably different from those obtained with other 11C tracers.
Calsolaro V, Mayers J, Fan Z, et al., 2018, Evaluation of novel astrocyte marker [11C]BU99008 PET in Alzheimer’s disease: a Dementia Platform U.K. experimental medicine study, Alzheimer's and Dementia, Vol: 14, Pages: P842-P843, ISSN: 1552-5260
Fan Z, Calsolaro V, Mayers J, et al., 2018, Relationship between astrocyte activation using [11C]BU99008 PET, glucose metabolism and amyloid in Alzheimer’s disease: a Dementia Platform UK experimental medicine study, Alzheimer's and Dementia, Vol: 14, Pages: P1640-P1640, ISSN: 1552-5260
Edison P, Mayers J, Calsolaro V, et al., 2017, Dementia Platform U.K. Experimental medicine: human in vivo astroglial activation in early Alzheimer’s disease, Alzheimer's and Dementia, Vol: 13, Pages: P1073-P1074, ISSN: 1552-5260
Tang SP, Mirzaei N, Coello C, et al., 2016, EVALUATION OF [11C]PBR28 PET IMAGING TO DETECT CHANGES IN MICROGLIAL ACTIVATION IN MOUSE MODELS OF ALZHEIMER'S DISEASE, 27th International Symposium on Cerebral Blood Flow, Metabolism and Function / 12th International Conference on Quantification of Brain Function with PET, Publisher: SAGE PUBLICATIONS INC, Pages: 654-655, ISSN: 0271-678X
Mirzaei N, Tang SP, Ashworth S, et al., 2016, In vivo imaging of microglial activation by positron emission tomography with [11 C]PBR28 in the 5XFAD model of Alzheimer's disease, GLIA, ISSN: 0894-1491
Microglial activation has been linked with deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulated in reactive microglia. Accurate visualization and quantification of microglial density by PET imaging using the TSPO tracer [11C]-R-PK11195 has been challenging due to the limitations of the ligand. In this study, it was aimed to evaluate the new TSPO tracer [11C]PBR28 as a marker for microglial activation in the 5XFAD transgenic mouse model of AD. Dynamic PET scans were acquired following intravenous administration of [11C]PBR28 in 6-month-old 5XFAD mice and in wild-type controls. Autoradiography with [3H]PBR28 was carried out in the same brains to further confirm the distribution of the radioligand. In addition, immunohistochemistry was performed on adjacent brain sections of the same mice to evaluate the co-localization of TSPO with microglia. PET imaging revealed that brain uptake of [11C]PBR28 in 5XFAD mice was increased compared with control mice. Moreover, binding of [3H]PBR28, measured by autoradiography, was enriched in cortical and hippocampal brain regions, coinciding with the positive staining of the microglial marker Iba-1 and amyloid deposits in the same areas. Furthermore, double-staining using antibodies against TSPO demonstrated co-localization of TSPO with microglia and not with astrocytes in 5XFAD mice and human post-mortem AD brains. The data provided support of the suitability of [11C]PBR28 as a tool for in vivo monitoring of microglial activation and assessment of treatment response in future studies using animal models of AD
Mirzaei N, Tang S, Ashworth S, et al., 2016, In vivo Imaging of microglial activation by positron emission tomography with [11C]PBR28 in the 5XFAD model of Alzheimer’s disease, GLIA, ISSN: 0894-1491
Microglial activation has been linked with deficits in neuronal function and synaptic plasticity inAlzheimer’s disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulatedin reactive microglia. Accurate visualization and quantification of microglial density by PET imagingusing the TSPO tracer [11C]-R-PK11195 has been challenging due to the limitations of the ligand. Inthis study, we aimed to evaluate the new TSPO tracer [11C]PBR28 as a marker for microglialactivation in the 5XFAD transgenic mouse model of AD. Dynamic PET scans were acquired followingintravenous administration of [11C]PBR28 in 6 month old 5XFAD mice and in wild-type controls.Autoradiography with [3H]PBR28 was carried out in the same brains to further confirm thedistribution of the radioligand. In addition, immunohistochemistry was performed on adjacent brainsections of the same mice to evaluate the co-localization of TSPO with microglia. PET imagingrevealed that brain uptake of [11C]PBR28 in 5XFAD mice was increased compared with control mice.Moreover, binding of [3H]PBR28, measured by autoradiography, was enriched in cortical andhippocampal brain regions, coinciding with the positive staining of the microglial marker Iba-1 andamyloid deposits in the same areas. Furthermore, double-staining using antibodies against TSPOdemonstrated co-localization of TSPO with microglia and not with astrocytes in 5XFAD mice andhuman post-mortem AD brains. Our data provide support of the suitability of [11C]PBR28 as a tool forin vivo monitoring of microglial activation and assessment of treatment response in future studiesusing animal models of AD.
Carhart-Harris RL, Murphy K, Leech R, et al., 2015, The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level-Dependent Resting State Functional Connectivity, Biological Psychiatry, Vol: 78, Pages: 554-562, ISSN: 1873-2402
BackgroundThe compound 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine releaser that produces an acute euphoria in most individuals.MethodsIn a double-blind, placebo-controlled, balanced-order study, MDMA was orally administered to 25 physically and mentally healthy individuals. Arterial spin labeling and seed-based resting state functional connectivity (RSFC) were used to produce spatial maps displaying changes in cerebral blood flow (CBF) and RSFC after MDMA administration. Participants underwent two arterial spin labeling and two blood oxygen level–dependent scans in a 90-minute scan session; MDMA and placebo study days were separated by 1 week.ResultsMarked increases in positive mood were produced by MDMA. Decreased CBF only was observed after MDMA, and this was localized to the right medial temporal lobe (MTL), thalamus, inferior visual cortex, and the somatosensory cortex. Decreased CBF in the right amygdala and hippocampus correlated with ratings of the intensity of global subjective effects of MDMA. The RSFC results complemented the CBF results, with decreases in RSFC between midline cortical regions, the medial prefrontal cortex, and MTL regions, and increases between the amygdala and hippocampus. There were trend-level correlations between these effects and ratings of intense and positive subjective effects.ConclusionsThe MTLs appear to be specifically implicated in the mechanism of action of MDMA, but further work is required to elucidate how the drug’s characteristic subjective effects arise from its modulation of spontaneous brain activity.
Tyacke RJ, Nutt DJ, 2015, Optimising PET approaches to measuring 5-HT release in human brain, SYNAPSE, Vol: 69, Pages: 505-511, ISSN: 0887-4476
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- Citations: 14
Quelch D, De Santis V, Strege A, et al., 2015, Influence of Agonist Induced Internalization on [<SUP>3</SUP>H]Ro15-4513 Binding-An Application to Imaging Fluctuations in Endogenous GABA With Positron Emission Tomography, SYNAPSE, Vol: 69, Pages: 60-65, ISSN: 0887-4476
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- Citations: 8
Ghazaleh HA, Tyacke RJ, Hudson AL, 2015, Borne Identity: Leading Endogenous Suspects at Imidazoline Binding Sites, Journal of Neurology and Neuroscience, Vol: 06
Quelch DR, Withey SL, Nutt DJ, et al., 2014, The influence of different cellular environments on PET radioligand binding: An application to D<sub>2/3</sub>-dopamine receptor imaging, NEUROPHARMACOLOGY, Vol: 85, Pages: 305-313, ISSN: 0028-3908
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- Citations: 12
Quelch DR, Katsouri L, Nutt DJ, et al., 2014, Imaging endogenous opioid peptide release with [<SUP>11</SUP>C]carfentanil and [<SUP>3</SUP>H]diprenorphine: influence of agonist-induced internalization, JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, Vol: 34, Pages: 1604-1612, ISSN: 0271-678X
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- Citations: 24
Bosker FJ, Doorduin J, Jongsma ME, et al., 2014, Pharmacological interventions that have the potential to alter neurotransmitter levels in the human brain, PET and SPECT in Psychiatry, Pages: 45-63, ISBN: 9783642403835
Monitoring of neuronal activity in vivo is one of the greatest challenges in neuropsychiatry. Theoretically, levels of intra and extra synaptic neurotransmitters can be estimated through competition with suitable PET ligands at their receptors. When validating candidate receptor PET ligands for competition studies it is essential to manipulate neurotransmitter levels in vivo using interventions with drugs that have negligible affinity for the receptors aimed at and are allowed to be used in humans. Neurochemical evidence for pharmacological interventions mostly originates from microdialysis studies in animals. First we will give a brief historical and methodological overview of the microdialysis technique. We will focus on serotonin and present microdialysis data of various pharmacological interventions in rats that have the potential to alter serotonin levels in humans. Our primary aim is to broaden the arsenal of pharmacological tools for PET competition studies, in particular because the type of neuronal manipulation might be a critical factor. Microdialysis of glutamate is briefly discussed, merely to illustrate some of the shortcomings of the technique.
Kalk NJ, Owen DR, Tyacke RJ, et al., 2013, Are Prescribed Benzodiazepines Likely to Affect the Availability of the 18 kDa Translocator Protein (TSPO) in PET Studies?, SYNAPSE, Vol: 67, Pages: 909-912, ISSN: 0887-4476
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- Citations: 16
Kealey S, Turner EM, Husbands SM, et al., 2013, Imaging Imidazoline-I<sub>2</sub> Binding Sites in Porcine Brain Using <SUP>11</SUP>C-BU99008, JOURNAL OF NUCLEAR MEDICINE, Vol: 54, Pages: 139-144, ISSN: 0161-5505
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- Citations: 29
Quelch DR, Parker CA, Nutt DJ, et al., 2012, Influence of different cellular environments on [3H]DASB radioligand binding, SYNAPSE, Vol: 66, Pages: 1035-1039, ISSN: 0887-4476
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- Citations: 16
Quelch D, Parker C, Nutt D, et al., 2012, The effects of different cellular environments on opioid receptor binding, 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM), Publisher: NATURE PUBLISHING GROUP, Pages: S53-S54, ISSN: 0271-678X
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