Browsing by Author "Grégoire, MC"

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    [18F]-Flumazenil: a γ-aminobutyric acid A–specific PET radiotracer for the localisation of drug resistant temporal lobe epilepsy
    (Society of Nuclear Medicine and Molecular Imaging, 2013-07-15) Vivash, L; Grégoire, MC; Lau, EW; Ware, RE; Binns, D; Roselt, P; Bouilleret, V; Myers, DE; Cook, MJ; Hicks, RJ; O’Brien, TJ
    Studies report that 11C-flumazenil (FMZ) PET more specifically localizes the epileptogenic zone in patients with medically refractory focal epilepsy than 18F-FDG PET. However, practical aspects of 11C use limit clinical application. We report a phase I/IIa study assessing the clinical use of 18F-FMZ PET for the localization of the epileptogenic zone in patients with drug-resistant temporal lobe epilepsy (TLE). Receptor binding was quantified using kinetic modeling that did not require arterial sampling. Methods: Dynamic 18F-FMZ PET and static interictal 18F-FDG PET scans were compared in healthy controls (n = 17 for 18F-FMZ and n = 20 for 18F-FDG) and TLE patients with mesial temporal sclerosis on MR imaging (MTS, n = 12) and with normal MR imaging (NL TLE, n = 19). Masked visual assessment of images was undertaken. Parametric images of 18F-FMZ binding potential (BPND) were generated using the simplified reference tissue model. Region-of-interest analysis on coregistered MR images and statistical parametric mapping were used to quantify 18F-FMZ BPND and 18F-FDG uptake in the temporal lobe. Results: The visual assessment of static standardized uptake value images showed 18F-FMZ PET to have high specificity (16/17 [94%]) and moderate sensitivity (21/31 [68%]) for the localization of the epileptogenic zone, with a more restricted abnormality than 18F-FDG PET. However, the 18F-FMZ standardized uptake value images were falsely localizing in 3 of 31 patients (10%). Region-of-interest analysis demonstrated reductions in ipsilateral hippocampal 18F-FMZ BPND in patients with either MTS or NL TLE, compared with controls subjects. Ipsilateral hippocampal 18F-FMZ BPND was independent of both hippocampal volume and 18F-FDG uptake, whereas ipsilateral hippocampal volume was correlated with 18F-FDG uptake (r2 = 0.69, P < 0.0001). Statistical parametric mapping analysis demonstrated decreased uptake in 14 of 31 (45%) cases with 18F-FMZ PET and 18 of 29 (62%) with 18F-FDG PET. Cluster size was significantly smaller on 18F-FMZ than 18F-FDG images (37 vs. 160 voxels, P < 0.01). Conclusion: 18F-FMZ PET has potential as a clinical tool for the localization of the epileptogenic zone in the presurgical evaluation of drug-resistant TLE, providing information complementary to 18F-FDG PET, with a more restricted region of abnormality. © 2013 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
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    4D PET iterative deconvolution with spatiotemporal regularization for quantitative dynamic PET imaging
    (Elsevier, 2015-09-01) Reilhac, A; Charil, A; Wimberley, CA; Angelis, GI; Hamze, H; Callaghan, PD; Garcia, MP; Boisson, F; Ryder, W; Meikle, SR; Grégoire, MC
    Quantitative measurements in dynamic PET imaging are usually limited by the poor counting statistics particularly in short dynamic frames and by the low spatial resolution of the detection system, resulting in partial volume effects (PVEs). In this work, we present a fast and easy to implement method for the restoration of dynamic PET images that have suffered from both PVE and noise degradation. It is based on a weighted least squares iterative deconvolution approach of the dynamic PET image with spatial and temporal regularization. Using simulated dynamic [11C] Raclopride PET data with controlled biological variations in the striata between scans, we showed that the restoration method provides images which exhibit less noise and better contrast between emitting structures than the original images. In addition, the method is able to recover the true time activity curve in the striata region with an error below 3% while it was underestimated by more than 20% without correction. As a result, the method improves the accuracy and reduces the variability of the kinetic parameter estimates calculated from the corrected images. More importantly it increases the accuracy (from less than 66% to more than 95%) of measured biological variations as well as their statistical detectivity. © 2015 Elsevier Inc.
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    Analytical positron range modelling in heterogeneous media for PET Monte Carlo simulation
    (IOP Publishing Ltd, 2011-06-07) Lehnert, W; Grégoire, MC; Reilhac, A; Meikle, SR
    Monte Carlo simulation codes that model positron interactions along their tortuous path are expected to be accurate but are usually slow. A simpler and potentially faster approach is to model positron range from analytical annihilation density distributions. The aims of this paper were to efficiently implement and validate such a method, with the addition of medium heterogeneity representing a further challenge. The analytical positron range model was evaluated by comparing annihilation density distributions with those produced by the Monte Carlo simulator GATE and by quantitatively analysing the final reconstructed images of Monte Carlo simulated data. In addition, the influence of positronium formation on positron range and hence on the performance of Monte Carlo simulation was investigated. The results demonstrate that 1D annihilation density distributions for different isotope–media combinations can be fitted with Gaussian functions and hence be described by simple look-up-tables of fitting coefficients. Together with the method developed for simulating positron range in heterogeneous media, this allows for efficient modelling of positron range in Monte Carlo simulation. The level of agreement of the analytical model with GATE depends somewhat on the simulated scanner and the particular research task, but appears to be suitable for lower energy positron emitters, such as 18F or 11C. No reliable conclusion about the influence of positronium formation on positron range and simulation accuracy could be drawn. © 2011 IOP Publishing LTD
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    Assessment of neuroinflammation in transferred EAE via a translocator protein ligand
    (IntechOpen, 2012-02-03) Mattner, F; Staykova, M; Callaghan, PD; Berghofer, PJ; Ballantyne, P; Grégoire, MC; Fordham, S; Pham, TQ; Rahardjo, GL; Jackson, TW; Linares, D; Katsifis, A
    Neuroinflammation is involved in the pathogenesis and progression of neurological disorders such as Alzheimer's disease and multiple sclerosis (MS) (Doorduin et al., 2008). MS has been considered a T cell-mediated autoimmune disorder of the central nervous system (CNS), characterized by inflammatory cell infiltration and myelin destruction (Hauser et al., 1986) and focal demyelinated lesions in the white matter are the traditional hallmarks of MS. However more recent evidence suggests more widespread damage to the brain and spinal cord, to areas of white matter distant from the inflammatory lesions and demyelination of deep and cortical grey matter (McFarland & Martin, 2007). Experimental autoimmune encephalomyelitis (EAE) is an extensively used model of T-cell mediated CNS inflammation; modelling disease processes involved in MS. EAE can be induced in several species by immunization with myelin antigens or via adoptive transfer of myelin-reactive T cells. The models of EAE in rodents [actively induced and transferred] provide information about different phases [inflammation, demyelination and remyelination] and types [monophasic, chronic-relapsing and chronic-progressive] of the human disease multiple sclerosis and a vast amount of clinical and histopathologic data has been accumulated through the decades. A key aim of current investigations is developing the ability to recognise the early symptoms of the disease and to follow its course and response to treatment. Molecular imaging is a rapidly evolving field of research that involves the evaluation of biochemical and physiological processes utilising specific, radioactive, fluorescent and magnetic resonance imaging probes. However, it is positron emission tomography (PET) and single photon emission computer tomography (SPECT) which, due to their exquisite sensitivity involving specifically designed radiolabelled molecules, that is leading the way in molecular imaging and has greatly enabled the non-invasive “visualisation” of many diseases in both animal models and humans. Furthermore, PET and SPECT molecular imaging are providing invaluable imaging data based on a biochemical-molecular biology interaction rather than from the traditional anatomical view. Increasingly, PET and SPECT radiotracers have been exploited to study or identify molecular biomarkers of disease, monitor disease progression, determining the effects of a drug on a particular pathology and assess the pharmacokinetic behaviour of pharmaceuticals in vivo. Significantly, these new imaging systems provide investigators with an unprecedented ability to examine and measure in vivo biological and pharmacological processes over time in the same animals thus reducing experimental variability, time and costs. Molecular imaging based on the radiotracer principle allows chemical processes ranging from cellular events, to cellular communication and interaction in their environment, to the organisation and function of complete tissue and organs to be studied in real time without perturbation. One of the key benefits of molecular imaging is a technique that allows longitudinal studies vital for monitoring intra-individual progression in disease, or regression with supplementary pharmacotherapies. This is key in animal models of diseases such as MS, where there is significant intra-individual variability in the disease course and severity. Recent investigations have proposed the translocator protein (TSPO; 18 kDa), also known as the peripheral benzodiazepine receptor (PBR), as a molecular target for imaging neuroinflammation (Chen & Guilarte, 2008; Doorduin et al., 2008; Papadopoulos et al., 2006). TSPO (18 kDa) is a multimeric protein consisting of five transmembrane helices, which, in association with a 32 kDa subunit that functions as a voltage dependent anion channel and a 30 kDa subunit that functions as an adenine nucleotide carrier forms part of a hetero-oligomeric complex (McEnery et al., 1992) responsible for cholesterol, heme and calcium transport in specific tissue. TSPO is primarily located on the outer mitochondrial membrane and is predominantly expressed in visceral organs (kidney, heart) and the steroid hormone producing cells of the adrenal cortex, testis and ovaries. In the central nervous system (CNS), TSPO is sparsely expressed under normal physiological conditions, however its expression is significantly upregulated following CNS injury (Chen et al., 2004; Papadopoulos et al., 1997; Venneti et al., 2006; Venneti, et al., 2008). Several studies have identified activated glial cells as the cells responsible for TSPO upregulation in inflamed brain tissue, both in humans and in experimental models (Mattner et al., 2011; Myers et al., 1991a; Stephenson et al., 1995; Vowinckel et al., 1997) and the TSPO ligand [11C]-PK11195 was one of the first PET ligands used for imaging activated microglia in various neurodegenerative diseases (Venneti et al., 2006). Although [11C]-(R)-PK11195 is widely used for imaging of microglia, its considerable high plasma protein binding, high levels of nonspecific binding, relatively poor blood–brain barrier permeability and short half-life, limits its use in brain imaging (Chauveau et al., 2008). Recently, alternative PET radioligands for TSPO including the phenoxyarylacetamide derivative [11C]-DAA1106 and its analogues (Gulyas et al., 2009; Takano et al., 2010; Venneti et al., 2008), the imidazopyridines (PBR111) and its analogues (Boutin et al., 2007a; Fookes et al., 2008) and the pyrazolo[1,5-a]pyrimidine derivatives [18F]-DPA-714 and [11C]-DPA-713 (Boutin et al., 2007b; James et al., 2008) have been investigated. In addition to imaging with PET, recent advances in new generation of hybrid SPECT imaging systems enabling increased resolution and morphological documentation with associated computed tomography have been made for use clinically and preclinically. These advances have created a need and an opportunity for SPECT tracers; particularly those incorporating the longer lived radiotracer iodine-123 (t ½ = 13.2 h), to facilitate extended longitudinal imaging studies. In this study the recently developed high-affinity TSPO, SPECT ligand, 6-chloro-2-(4′-iodophenyl)-3-(N,N-diethyl)-imidazo[1,2-a]pyridine-3-acetamide or CLINDE , was used to explore the expression of activated glia in a model of transferred EAE (tEAE). [123I]-CLINDE has demonstrated its potency and specificity for TSPO binding, its ability to penetrate the blood-brain barrier and suitable pharmacokinetics for SPECT imaging studies (Mattner et al., 2008). It has also been shown that [123I]-CLINDE was able to detect in vivo inflammatory processes characterized by increased density of TSPO in several animal models (Arlicot et al., 2008; Arlicot et al., 2010; Mattner et al., 2005; Mattner et al., 2011; Song et al., 2010), thus representing a promising SPECT radiotracer for imaging neuroinflammation. The present study aimed to investigate the effectiveness of [123I]-CLINDE to detect and quantify the activated glia and consequently correlate the intensity of TSPO upregulation with the severity of disease in a model of tEAE. © 2022 IntechOpen (Open Access).
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    Astrocytic TSPO upregulation appears before microglial TSPO in Alzheimer’s disease
    (IOS Press, 2020-06-30) Tournier, BB; Tsartsalis, S; Ceyzériat, K; Fraser, BH; Grégoire, MC; Kövari, E; Millet, P
    Background: In vivo PET/SPECT imaging of neuroinflammation is primarily based on the estimation of the 18 kDa-rranslocator-protein (TSPO). However, TSPO is expressed by different cell types which complicates the interpretation. Objective: The present study evaluates the cellular origin of TSPO alterations in Alzheimer’s disease (AD). Methods: The TSPO cell origin was evaluated by combining radioactive imaging approaches using the TSPO radiotracer [125I]CLINDE and fluorescence-activated cell sorting, in a rat model of AD (TgF344-AD) and in AD subjects. Results: In the hippocampus of TgF344-AD rats, TSPO overexpression not only concerns glial cells but the increase is visible at 12 and 24 months in astrocytes and only at 24 months in microglia. In the temporal cortex of AD subjects, TSPO upregulation involved only glial cells. However, the mechanism of this upregulation appears different with an increase in the number of TSPO binding sites per cell without cell proliferation in the rat, and a microglial cell population expansion with a constant number of binding sites per cell in human AD. Conclusion: These data indicate an earlier astrocyte intervention than microglia and that TSPO in AD probably is an exclusive marker of glial activity without interference from other TSPO-expressing cells. This observation indicates that the interpretation of TSPO imaging depends on the stage of the pathology, and highlights the particular role of astrocytes. © 2020 IOS Press and the authors. Open Access CC BY-NC 4.0
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    Can structural or functional changes following traumatic brain injury in the rat predict epileptic outcome?
    (John Wiley and Sons Inc., 2013-07-01) Shultz, SR; Cardamone, L; Liu, YR; Hogan, RE; Maccotta, L; Wright, DK; Zheng, P; Koe, A; Grégoire, MC; Williams, JP; Hicks, RJ; Jones, NC; Myers, DE; O'Brien, TJ; Bouilleret, V
    Posttraumatic epilepsy (PTE) occurs in a proportion of traumatic brain injury (TBI) cases, significantly compounding the disability, and risk of injury and death for sufferers. To date, predictive biomarkers for PTE have not been identified. This study used the lateral fluid percussion injury (LFPI) rat model of TBI to investigate whether structural, functional, and behavioral changes post‐TBI relate to the later development of PTE. © 2013 International League Against Epilepsy
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    Central nervous system expression and PET imaging of the translocator protein in relapsing–remitting experimental autoimmune encephalomyelitis
    (Society of Nuclear Medicine and Molecular Imaging, 2013-01-15) Mattner, F; Staykova, M; Berghofer, PJ; Wong, HJ; Fordham, S; Callaghan, PD; Jackson, T; Pham, TQ; Grégoire, MC; Zahra, D; Rahardjo, GL; Linares, D; Katsifis, A
    Glial neuroinflammation is associated with the development and progression of multiple sclerosis. PET imaging offers a unique opportunity to evaluate neuroinflammatory processes longitudinally in a noninvasive and clinically translational manner. (18)F-PBR111 is a newly developed PET radiopharmaceutical with high affinity and selectivity for the translocator protein (TSPO), expressed on activated glia. This study aimed to investigate neuroinflammation at different phases of relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) in the brains of SJL/J mice by postmortem histologic analysis and in vivo by PET imaging with (18)F-PBR111. METHODS: RR EAE was induced by immunization with PLP(139-151) peptide in complete Freund's adjuvant. Naive female SJL/J mice and mice immunized with saline-complete Freund's adjuvant were used as controls. The biodistribution of (18)F-PBR111 was measured in 13 areas of the central nervous system and compared with PET imaging results during different phases of RR EAE. The extents of TSPO expression and glial activation were assessed with immunohistochemistry, immunofluorescence, and a real-time polymerase chain reaction. RESULTS: There was significant TSPO expression in all of the central nervous system areas studied at the peak of the first clinical episode and, importantly, at the preclinical stage. In contrast, only a few TSPO-positive cells were observed at the second episode. At the third episode, there was again an increase in TSPO expression. TSPO expression was associated with microglial cells or macrophages without obvious astrocyte labeling. The dynamics of (18)F-PBR111 uptake in the brain, as measured by in vivo PET imaging and biodistribution, followed the pattern of TSPO expression during RR EAE. CONCLUSION: PET imaging with the TSPO ligand (18)F-PBR111 clearly reflected the dynamics of microglial activation in the SJL/J mouse model of RR EAE. The results are the first to highlight the discrepancy between the clinical symptoms of EAE and TSPO expression in the brain, as measured by PET imaging at the peaks of various EAE episodes. The results suggest a significant role for PET imaging investigations of neuroinflammation in multiple sclerosis and allow for in vivo follow-up of antiinflammatory treatment strategies. © 2013 Society of Nuclear Medicine and Molecular Imaging, Inc.
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    Cerebral monoamine oxidase a inhibition in tobacco smokers confirmed with PET and [c-11]befloxatone
    (Lippincott, Williams & Wilkins, 2009-02) Leroy, C; Bragulat, V; Berlin, I; Grégoire, MC; Bottlaender, MA; Roumenov, D; Dollé, F; Bourgeois, S; Penttilae, J; Artiges, E; Martinot, JL; Trichard, C
    The inhibition of cerebral monoamine oxidases (MAOs) by cigarette smoke components could participate to the tobacco addiction. However, the actual extent of this inhibition in vivo in smokers is still poorly known. We investigated cerebral MAO-A availability in 7 tobacco-dependent subjects and 6 healthy nonsmokers, using positron emission tomography (PET) and the MAO-A selective radioligand [11C]befloxatone. In comparison to nonsmokers, smokers showed a significant overall reduction of [11C]befloxatone binding potential (BP) in cortical areas (average reduction, -60%) and a similar trend in caudate and thalamus (-40%). Our findings confirm a widespread inhibition of cerebral MAO-A in smokers. This mechanism may contribute to tobacco addiction and for a possible mood-modulating effect of tobacco. © 2009, Lippincott, Williams & Wilkins
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    Characterisation of partial volume effect and region-based correction in small animal positron emission tomography (PET) of the rat brain
    (Elsevier Inc, 2012-05-01) Lehnert, W; Grégoire, MC; Reilhac, A; Meikle, SR
    Accurate quantification of PET imaging data is required for a useful interpretation of the measured radioactive tracer concentrations. The partial volume effect (PVE) describes signal dilution and mixing due to spatial resolution and sampling limitations, which introduces bias in quantitative results. In the present study we investigated the magnitude of PVE for volumes of interest (VOIs) in the rat brain and the effect of positron range. In simulated 11C-raclopride studies we examined the influence of PVE on time activity curves in striatal and cerebellar VOIs and binding potential estimation. The performance of partial volume correction (PVC) was studied using the region-based geometric transfer matrix (GTM) method including the question of whether a spatially variant point spread function (PSF) is necessary for PVC of a rat brain close to the centre of the field of view. Furthermore, we determined the effect of spillover from activity outside the brain. The results confirmed that PVE is significant in rat brain PET and showed that positron range is an important factor that needs to be included in the PSF. There was considerable bias in time activity curves for the simulated 11C-raclopride studies and significant underestimation of binding potential even for very small centred VOIs. Good activity recovery was achieved with the GTM PVC using a spatially invariant simulated PSF when no activity was present outside the brain. PVC using a simple Gaussian fit point spread function was not sufficiently accurate. Spillover from regions outside the brain had a significant impact on measured activity concentrations and reduced the accuracy of PVC with the GTM method using rat brain regions alone, except for the smallest VOI size but at the cost of increased noise. Voxel-based partial volume correction methods which inherently compensate for spillover from outside the brain might be a more suitable choice. © 2012 Elsevier Inc.
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    Characterisation of peripheral benzodiazepine receptors changes in early phase of epileptogenesis in the rat with PET and [18F]PBR111
    (Society of Nuclear Medicine, 2009-05) Grégoire, MC; Dedeurwaerdere, S; Callaghan, PD; Loc'h, C; Pham, TQ; Katsifis, A
    The current project aims at investigating the role of microglial activation in epileptogenesis by estimating PBR changes in the rat brain with a new and highly specific PBR ligand, [18F]PBR111, during the early phase, i.e. one week after status epilepticus induced by kainic acid (KA). Methods Four controls and 6 KA rats were scanned for 180 minutes with our small animal PET/CT under a triple-injection protocol. The results presented here cover only the first 60 minutes after injection of 0.06nmoles of [18F]PBR111. Arterial blood samples were withdrawn and metabolite corrected plasma time-activity curves were derived. Each CT and PET data were co-registered to an age and strain matched rat brain atlas containing 25 Regions-Of-Interest (ROIs). The Volume of Distribution (Vd) were calculated for each region. Whole-brain-normalised Vd (nVd) were also calculated to assess local variations. Results Compared to controls, KA-treated rats show a 2 to 3-fold increase of the Vd in all brain areas except the midbrain. No significant asymmetry was detected (< 9%), so the ROIs were grouped. Normalized Vd values (Table 1) show that Amygdala, Striata, Thalamus and Hippocampus are predominantly involved. No significant changes were detected in the midbrain and all cortical areas. Estimates of receptors densitiy (Bmax) and apparent affinity (KdVr) will be calculated from the full kinetics (three phases) and reported later. Conclusions This in vivo imaging study has identified significant microglial activation during early epileptogenesis in several brain regions which are known to play a key role in chronic epilepsy.
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    Comparison of cannabinoid CB1 receptor binding in adolescent and adult rats: a positron emission tomography study using [18F]MK-947
    (Hindawi Publishing Corporation, 2011-01-01) Verdurand, M; Nguyen, VH; Stark, D; Zahra, D; Grégoire, MC; Greguric, I; Zavitsanou, K
    Despite the important role of cannabinoid CB1 receptors (CB1R) in brain development, little is known about their status during adolescence, a critical period for both the development of psychosis and for initiation to substance abuse. In the present study, we assessed the ontogeny of CB1R in adolescent and adult rats in vivo using positron emission tomography with [18F]MK-9470. Analysis of covariance (ANCOVA) to control for body weight that would potentially influence [18F]MK-9470 values between the two groups revealed a main effect of age ( 𝐹 ( 1 , 1 0 9 ) = 5 . 0 , 𝑃 = 0 . 0 2 ) on [18F]MK-9470 absolute binding (calculated as percentage of injected dose) with adult estimated marginal means being higher compared to adolescents amongst 11 brain regions. This finding was confirmed using in vitro autoradiography with [3H]CP55,940 ( 𝐹 ( 1 0 , 9 9 ) = 1 4 0 . 1 , 𝑃 < 0 . 0 0 0 1 ). This ontogenetic pattern, suggesting increase of CB1R during the transition from adolescence to adulthood, is the opposite of most other neuroreceptor systems undergoing pruning during this period. Copyright © 2011 Mathieu Verdurand et al.
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    Comparison of in vivo binding properties of the 18-kDa translocator protein (TSPO) ligands [18F]PBR102 and [18F]PBR111 in a model of excitotoxin-induced neuroinflammation
    (Springer Link, 2015-01) Callaghan, PD; Wimberley, CA; Rahardjo, GL; Berghofer, PJ; Pham, TQ; Jackson, TW; Zahra, D; Bourdier, T; Wyatt, N; Greguric, I; Howell, NR; Siegele, R; Pastuovic, Z; Mattner, F; Loc'h, C; Grégoire, MC; Katsifis, A
    The in vivo binding parameters of the novel imidazopyridine TSPO ligand [18F]PBR102 were assessed and compared with those of [18F]PBR111 in a rodent model of neuroinflammation. The validity of the key assumptions of the simplified reference tissue model (SRTM) for estimation of binding potential (BP) was determined, with validation against a two-tissue compartment model (2TC). Methods Acute neuroinflammation was assessed 7 days after unilateral stereotaxic administration of (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA) in anaesthetized adult Wistar rats. Anaesthetized rats were implanted with a femoral arterial cannula then injected with a low mass of [18F]PBR102 or [18F]PBR111 and dynamic images were acquired over 60 min using an INVEON PET/CT camera. Another population of rats underwent the same PET protocol after pretreatment with a presaturating mass of the same unlabelled tracer (1 mg/kg) to assess the validity of the reference region for SRTM analysis. Arterial blood was sampled during imaging, allowing pharmacokinetic determination of radiotracer concentrations. Plasma activity concentration–time curves were corrected for unchanged tracer based on metabolic characterization experiments in a separate cohort of Wistar rats. The stability of neuroinflammation in both imaging cohorts was assessed by [125I] CLINDE TSPO quantitative autoradiography, OX42/GFAP immunohistochemistry, Fluoro-Jade C histology, and elemental mapping using microparticle-induced x-ray emission spectroscopy. The BP of each ligand were assessed in the two cohorts of lesioned animals using both SRTM and a 2TC with arterial parent compound concentration, coupled with the results from the presaturation cohort for comparison and validation of the SRTM. Results The BPs of [18F]PBR102 [18F]PBR111 were equivalent, with improved signal-to-noise ratio and sensitivity compared with [11C]PK11195. The presaturation study showed differences in the volume of distribution between the ipsilateral striatum and the striatum contralateral to the injury (0.7) indicating that an assumption of the SRTM was not met. The modelling indicated that the BPs were consistent for both ligands. Between the SRTM and 2TC model, the BPs were highly correlated, but there was a bias in BP. Conclusion [18F]PBR102 and [18F]PBR111 have equivalent binding properties in vivo, displaying significantly greater BPs with lower signal-to-noise ratio than [11C]PK11195. While an assumption of the SRTM was not met, this modelling approach was validated against 2TC modelling for both ligands, facilitating future use in longitudinal PET imaging of neuroinflammation.© 2014, Springer Nature
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    A data driven method for estimation of Bavail and appKD using a single injection protocol with [11C]raclopride in the mouse
    (Elsevier Inc., 2014-10-01) Wimberley, CA; Fischer, K; Reilhac, A; Pichler, BJ; Grégoire, MC
    Purpose The partial saturation approach (PSA) is a simple, single injection experimental protocol that will estimate both Bavail and appKD without the use of blood sampling. This makes it ideal for use in longitudinal studies of neurodegenerative diseases in the rodent. The aim of this study was to increase the range and applicability of the PSA by developing a data driven strategy for determining reliable regional estimates of receptor density (Bavail) and in vivo affinity (1/appKD), and validate the strategy using a simulation model. Methods The data driven method uses a time window guided by the dynamic equilibrium state of the system as opposed to using a static time window. To test the method, simulations of partial saturation experiments were generated and validated against experimental data. The experimental conditions simulated included a range of receptor occupancy levels and three different Bavail and appKD values to mimic diseases states. Also the effect of using a reference region and typical PET noise on the stability and accuracy of the estimates was investigated. Results The investigations showed that the parameter estimates in a simulated healthy mouse, using the data driven method were within 10±30% of the simulated input for the range of occupancy levels simulated. Throughout all experimental conditions simulated, the accuracy and robustness of the estimates using the data driven method were much improved upon the typical method of using a static time window, especially at low receptor occupancy levels. Introducing a reference region caused a bias of approximately 10% over the range of occupancy levels. Conclusions Based on extensive simulated experimental conditions, it was shown the data driven method provides accurate and precise estimates of Bavail and appKD for a broader range of conditions compared to the original method. © 2014 Elsevier Inc.
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    Decrease of nicotinic receptors in the nigrostriatal system in Parkinson's disease
    (Nature Publishing Group, 2009-09) Kas, A; Bottlaender, MA; Gallezot, JD; Vidailhet, M; Villafane, G; Grégoire, MC; Coulon, CM; Valette, H; Dollé, F; Ribeiro, MJ; Hantraye, P; Remy, P
    Smoking is associated with a lower incidence of Parkinson's disease (PD), which might be related to a neuroprotective action of nicotine. Postmortem studies have shown a decrease of cerebral nicotinic acetylcholine receptors (nAChRs) in PD. In this study, we evaluated the decrease of nAChRs in PD in vivo using positron emission tomography (PET), and we explored the relationship between nAChRs density and PD severity using both clinical scores and the measurement of striatal dopaminergic function. Thirteen nondemented patients with PD underwent two PET scans, one with 6-[18F]fluoro-3,4-dihydroxy-L-phenylalanine (6-[18F]fluoro-L-DOPA) to measure the dopaminergic function and another with 2-[18F]fluoro-3-[2(S)-2-azetidinylmethoxy]pyridine (2-[18F]fluoro-A-85380), a radiotracer with high affinity for the nAChRs. Distribution volumes (DVs) of 2-[18F]fluoro-A-85380 measured in the PD group were compared with those obtained from six nonsmoking healthy controls, with regions-of-interest and voxel-based approaches. Both analyses showed a significant (P <0.05) decrease of 2-[18F]fluoro-A-85380 DV in the striatum (−10%) and substantia nigra (−14.9%) in PD patients. Despite the wide range of PD stages, no correlation was found between DV and the clinical and PET markers of PD severity. © 2009, Nature Publishing Group.
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    Development of [18F]-Flumazenil-PET for localisation of the epileptogenic zone in patients with medically refractory focal epilepsy
    (Springer, 2010-10-11) Vivash, L; Grégoire, MC; Dedeurwaerdere, S; Bouilleret, V; Roselt, P; Lau, EW; Ware, RE; Binns, D; Katsifis, A; Hicks, RJ; Myers, DE; O'Brien, TJ
    Introduction: Studies of GABAA/central benzodiazepine receptor (GABAA/cBZR) distribution in the CNS using [11C]-flumazenil-PET (FMZ-PET) have enabled localisation of the epileptogenic zone (EZ) in patients with medically refractory epilepsy. [11C]-FMZ-PET images show a more restricted region of abnormality with increased sensitivity when compared with FDG-PET. However, use of [11C]-FMZ in routine clinical practice has been hindered by practical limitations of [11C]. The aim of the current study is to develop an [18F]-radiolabelled FMZ tracer with high specificity and improved imaging quality for EZ localisation in routine clinical practice. Methods: Preclinical studies: Presaturation, displacementand uptake PET scans were performed to define the kinetics of [18F]-FMZ binding in non-epileptic rats (n=8). Bmax (receptor density) and KD (binding affinity) were then quantified in the brains of epileptic (n=9; kainic acid-induced model of temporal lobe epilepsy) vs. non-epileptic control animals (n=10). Clinical study: 4 patient groups have been studied; healthy controls (n=20), patients with well-localised TLE from MRI scans (n=10), patients with lateralised TLE(n=7), and patients with other focal epilepsies (n=4). Each participant underwent a single 60 minute dynamic [18F]-FMZ-PET scan. Patients also underwent an FDG-PET scan. Blinded visual assessment of images to locate the EZ was performed. Parametric images of binding potential (BP) were generated. Datasets were processed using ROI analysis and SPM to assess differences in BP between patients and controls and localisation of the EZ in patients. Results:[18F]-FMZ was shown to be a suitable PET radiotracer for imaging GABAA/cBZR in vivo, with reversible and competitive binding and low non-specific binding. [18F]-FMZ-PET reliably detected decreased Bmax in the hippocampi of epilepticrats (left 16.3, right 15.9) compared with controls (left 20.9, right 19.8, p=0.022, p=0.049), with no change in KD (left 8.24 vs 8.46, p=0.82, right 7.43vs 8.07 p=0.56). There were no changes in whole brain Bmax or KD. To date the visual assessment of the clinical data has shown [18F]-FMZ-PET to have high sensitivity (100%) and positive predictive value (100%) for the EZ in patients, with a more restricted localisation of the EZ compared to FDG-PET. Quantitative analysis is ongoing. Conclusions: The pre-clinical studies have demonstrated that [18F]-FMZ-PET is a reliable radiotracer for quantification of CNSGABAA/cBZR expression in vivo. Preliminary analysis in our current clinical study indicates that [18F]-FMZ-PET also has excellent imaging characteristics in humans, and shows promise as a new clinical tool for localising the EZ in TLE patients. © 2020 Springer Nature Switzerland AG
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    Evaluation of [I-123]-CLINDE as a potent SPECT radiotracer to assess the degree of astroglia activation in cuprizone-induced neuroinflammation
    (Springer, 2011-08-01) Mattner, F; Bandin, DL; Staykova, M; Berghofer, PJ; Grégoire, MC; Ballantyne, P; Quinlivan, M; Fordham, S; Pham, TQ; Willenborg, DO; Katsifis, A
    The purpose of this study was to assess the feasibility and sensitivity of the high-affinity translocator protein (TSPO) ligand [123I]-CLINDE in imaging TSPO changes in vivo and characterise and compare astroglial and TSPO changes in the cuprizone model of demyelination and remyelination in C57BL/6 mice. Methods C57BL/6 mice were fed with cuprizone for 4 weeks to induce demyelination followed by 2–4 weeks of standard diet (remyelination). Groups of mice were followed by in vivo single photon emission computed tomography (SPECT)/CT imaging using [123I]-CLINDE and uptake correlated with biodistribution, autoradiography, immunohistochemistry, immunofluorescence and real-time polymerase chain reaction (RT-PCR). Results The uptake of [123I]-CLINDE in the brain as measured by SPECT imaging over the course of treatment reflects the extent of the physiological response, with significant increases observed during demyelination followed by a decrease in uptake during remyelination. This was confirmed by autoradiography and biodistribution studies. A positive correlation between TSPO expression and astrogliosis was found and both activated astrocytes and microglial cells expressed TSPO. [123I]-CLINDE uptake reflects astrogliosis in brain structures such as corpus callosum, caudate putamen, medium septum and olfactory tubercle as confirmed by both in vitro and in vivo results. Conclusion The dynamics in the cuprizone-induced astroglial and TSPO changes, observed by SPECT imaging, were confirmed by immunofluorescence, RT-PCR and autoradiography. The highly specific TSPO radioiodinated ligand CLINDE can be used as an in vivo marker for early detection and monitoring of a variety of neuropathological conditions using noninvasive brain imaging techniques. © 2011, Springer.
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    Evaluation of the PBR ligand [123I]CLINDE in an animal model of experimental autoimmune encephalomyelitis
    (Australasian Quaternary Association, 2008-05-01) Mattner, F; Linares, D; Staykova, M; Grégoire, MC; Pham, TQ; Bourdier, T; Quinlivan, M; Callaghan, PD; Willenborg, DO; Katsifis, A
    Objectives: The aim of this study was to evaluate the Peripheral Benzodiazepine Receptor (PBR) radioligand [123I]CLINDE in the rat inflammatory disease model of Experimental Autoimmune Encephalomyelitis (EAE). Methods: EAE was induced with blast cells collected from spleen and lymph nodes of Lewis rats induced with myelin basic protein and complete Freund's adjuvant. Biodistribution with [123I]CLINDE was undertaken on EAE rats exhibiting different disease severity and compared to controls.The relationship between inflammatory lesions and tracer uptake was investigated using ex vivo autoradiography and immunohistochemistry. Results: Disease severity was confirmed by histopathology in spinal cord. Results indicate enhanced uptake of [123I]CLINDE in all animals induced with EAE compared to controls. This uptake reflected the ascending nature of the inflammatory lesions ie. uptake in the lumbar spinal cord > thoracic cord > cervical cord > medulla > cerebellum. Uptake of [123I]CLINDE in the lumbar and thoracic cord correlated with disease severity. A 2 and 3 fold enhancement in PBR expression was observed in the brain and spinal cord of animals with a clinical score of 3 compared to controls. Regional [123I]CLINDE uptake closely correlated with localisation of PBR, shown using autoradiography and immunohistochemisty. Conclusions: These results demonstrate the ability of [123I]CLINDE to measure in vivo changes of PBR density according to area of involvement and the severity of disease suggesting it as a potential SPECT tracer for the study of inflammation and multiple sclerosis. © 2022 Journal of Nuclear Medicine
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    Feasibility of imaging the ontogeny of CB1 receptors in adolescent and adult rats in vivo with [18F]MK 9470 and PET: a pilot study
    (Royal Australian and New Zealand College of Psychiatrists (RANZCP), 2010-09-23) Verdurand, M; Nguyen, VH; Stark, D; Zahra, D; Grégoire, MC; Greguric, I; Zavitsanou, K
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    Fluorescence-activated cell sorting to reveal the cell origin of radioligand binding
    (SAGE, 2019-06-19) Tournier, BB; Tsartsalis, S; Ceyzériat, K; Medina, Z; Fraser, BH; Grégoire, MC; Kövari, E; Millet, P
    Many studies have explored the role of TSPO (18 kDa translocator protein) as a marker of neuroinflammation using single-photon emission computed tomography (SPECT) or positron emission tomography (PET). In vivo imaging does not allow to determine the cells in which TSPO is altered. We propose a methodology based on fluorescence-activated cell sorting to sort different cell types of radioligand-treated tissues. We compared left/right hippocampus of rats in response to a unilateral injection of lipopolysaccharide (LPS), ciliary neurotrophic factor (CNTF) or saline. We finally applied this methodology in human samples (Alzheimer's disease patients and controls). Our data show that the pattern of TSPO overexpression differs across animal models of acute neuroinflammation. LPS induces a microglial expansion and an increase in microglial TSPO binding. CNTF is associated with an increase in TSPO binding in microglia and astrocytes in association with an increase in the number of microglial binding sites per cell. In humans, we show that the increase in CLINDE binding in Alzheimer's disease concerns microglia and astrocytes in the presence of a microglial expansion. Thus, the cellular basis of TSPO overexpression is condition dependent, and alterations in TSPO binding found in PET/SPECT imaging studies cannot be attributed to particular cell types indiscriminately. © 2021 International Society for Cerebral Blood Flow and Metabolism
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    Fluorine-18 radiolabelling and in vitro / in vivo metabolism of [18F]D4-PBR111
    (John Wiley & Sons, Inc, 2019-05-26) Wyatt, NA; Safavi-Naeini, M; Wotherspoon, ATL; Arthur, A; Nguyen, AP; Parmar, A; Hamze, H; Day, CM; Zahra, D; Matesic, L; Davis, E; Rahardjo, GL; Yepuri, NR; Shepherd, R; Murphy, RB; Pham, TQ; Nguyen, VH; Callaghan, PD; Holden, PJ; Grégoire, MC; Darwish, TA; Fraser, BH
    Objectives The purinergic receptor P2X ligand-gated ion channel type 7 (P2X7R) is an adenosine triphosphate (ATP)-gated ion-channel, and P2X7R is a key player in inflammation. P2X7R is an emerging therapeutic target in central nervous system (CNS) diseases including Alzheimer's disease (AD) and Parkinson's disease (PD), because P2X7R also plays a pivotal role in neuroinflammation. P2X7R represents a potential molecular imaging target for neuroinflammation via biomedical imaging technique positron emission tomography (PET), and several radioligands targeting P2X7R have been developed and evaluated in animals. In our previous work, we have developed and characterized [11C]GSK1482160 as a P2X7R radioligand for neuroinflammation,2 clinical evaluation of [11C]GSK1482160 in healthy controls and patients is currently underway, and the estimation of radiation dosimetry for [11C]GSK1482160 in normal human subjects has been reported.3 Since the half-life (t1/2) of radionuclide carbon-11 is only 20.4 min, it is attractive for us to develop derivatives of [11C]GSK1482160, which can be labeled with the radionuclide fluorine-18 (t1/2, 109.7 min), and a fluorine-18 ligand would be ideal for widespread use.4 To this end, a series of [18F]fluoroalkyl including [18F]fluoromethyl (FM), [18F]fluoroethyl (FE), and [18F]fluoropropyl (FP) derivatives of GSK1482160 have been prepared and examined as new potential P2X7R radioligands. © 2019 The Authors