Publications by authors named "Fabien Chauveau"

36 Publications

Neuroprotection by remote ischemic conditioning in the setting of acute ischemic stroke: a preclinical two-centre study.

Sci Rep 2020 10 9;10(1):16874. Epub 2020 Oct 9.

The Hatter Cardiovascular Institute, University College London, 67 Chenies Mews, London, WC1E 6HX, UK.

Reperfusion is the only existing strategy for patients with acute ischemic stroke, however it causes further brain damage itself. A feasible therapy targeting reperfusion injury is remote ischemic conditioning (RIC). This was a two-centre, randomized, blinded international study, using translational imaging endpoints, aimed to examine the neuroprotective effects of RIC in ischemic stroke model. 80 male rats underwent 90-min middle cerebral artery occlusion. RIC consisted of 4 × 5 min cycles of left hind limb ischemia. The primary endpoint was infarct size measured on T2-weighted MRI at 24 h, expressed as percentage of the area-at-risk. Secondary endpoints were: hemispheric space-modifying edema, infarct growth between per-occlusion and 24 h MRI, neurofunctional outcome measured by neuroscores. 47 rats were included in the analysis after applying pre-defined inclusion criteria. RIC significantly reduced infarct size (median, interquartile range: 19% [8%; 32%] vs control: 40% [17%; 59%], p = 0.028). This effect was still significant after adjustment for apparent diffusion coefficient lesion size in multivariate analysis. RIC also improved neuroscores (6 [3; 8] vs control: 9 [7; 11], p = 0.032). Other secondary endpoints were not statistically different between groups. We conclude that RIC in the setting of acute ischemic stroke in rats is safe, reduces infarct size and improves functional recovery.
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http://dx.doi.org/10.1038/s41598-020-74046-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547701PMC
October 2020

Change in Expression of 5-HT6 Receptor at Different Stages of Alzheimer's Disease: A Postmortem Study with the PET Radiopharmaceutical [18F]2FNQ1P.

J Alzheimers Dis 2020 ;75(4):1329-1338

Lyon Neuroscience Research Center (CRNL), Université de Lyon, CNRS, INSERM, Lyon, France.

Background: The 5-HT6 receptor is one of the most recently identified serotonin receptors in the central nervous system. Because of its role in memory and cognitive process, this receptor might be implicated in Alzheimer's disease (AD) and associated disorders.

Objective: The aim of this study was to investigate the binding of [18F]2FNQ1P, a new specific radiotracer of 5-HT6 receptors, and to quantify 5-HT6 receptor density in caudate nucleus in a population of patients with different AD stages.

Methods: Patients were classified according to the "ABC" NIA-AA classification. In vitro binding assays were performed in postmortem brain tissue from the healthy control (HC; n = 8) and severe AD ("High"; n = 8) groups. In vitro quantitative autoradiography was performed in human brain tissue (caudate nucleus) from patients with different stages of AD: HC (n = 15), "Low" (n = 18), "Int" (n = 20), and "High" (n = 15).

Results: In vitro binding assays did not show significant differences for the KD and Bmax parameters between "High" and HC groups. In vitro quantitative autoradiography showed a significant difference between the "High" and HC groups (p = 0.0025). We also showed a progressive diminution in [18F]2FNQ1P specific binding, which parallels 5-HT6 receptors expression, according to increasing AD stage. Significant differences were observed between the HC group and all AD stages combined ("Low", "Intermediate", and "High") (p = 0.011).

Conclusion: This study confirms the interest of investigating the role of 5-HT6 receptors in AD and related disorders. [18F]2FNQ1P demonstrated specific binding to 5-HT6 receptors.
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http://dx.doi.org/10.3233/JAD-191278DOI Listing
January 2020

The apparent mechanical effect of isolated amyloid-β and α-synuclein aggregates revealed by multi-frequency MRE.

NMR Biomed 2020 01 6;33(1):e4174. Epub 2019 Nov 6.

Université de Lyon, INSA-Lyon, Université Claude Bernard Lyon 1, UJM-Saint Etienne, CNRS, Inserm, CREATIS UMR 5220, U1206, Lyon, France.

Several biological processes are involved in dementia, and fibrillar aggregation of misshaped endogenous proteins appears to be an early hallmark of neurodegenerative disease. A recently developed means of studying neurodegenerative diseases is magnetic resonance elastography (MRE), an imaging technique investigating the mechanical properties of tissues. Although mechanical changes associated with these diseases have been detected, the specific signal of fibrils has not yet been isolated in clinical or preclinical studies. The current study aims to exploit the fractal-like properties of fibrils to separate them from nonaggregated proteins using a multi-frequency MRE power law exponent in a phantom study. Two types of fibril, α-synuclein (α-Syn) and amyloid-β (Aβ), and a nonaggregated protein, bovine serum albumin, used as control, were incorporated in a dedicated nondispersive agarose phantom. Elastography was performed at multiple frequencies between 400 and 1200 Hz. After 3D-direct inversion, storage modulus (G'), phase angle (ϕ), wave speed and the power law exponent (y) were computed. No significant changes in G' and ϕ were detected. Both α-Syn and Aβ inclusions showed significantly higher y values than control inclusions (P = 0.005) but did not differ between each other. The current phantom study highlighted a specific biomechanical effect of α-Syn and Aβ aggregates, which was better captured with the power law exponent derived from multi-frequency MRE than with single frequency-derived parameters.
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http://dx.doi.org/10.1002/nbm.4174DOI Listing
January 2020

MRI coupled with clinically-applicable iron oxide nanoparticles reveals choroid plexus involvement in a murine model of neuroinflammation.

Sci Rep 2019 07 11;9(1):10046. Epub 2019 Jul 11.

Univ Lyon, CarMeN laboratory, Inserm U1060, INRA U1397, INSA Lyon, Université Claude Bernard Lyon 1, Lyon, France.

Choroid plexus (ChPs) are involved in the early inflammatory response that occurs in many brain disorders. However, the activation of immune cells within the ChPs in response to neuroinflammation is still largely unexplored in-vivo. There is therefore a crucial need for developing imaging tool that would allow the non-invasive monitoring of ChP involvement in these diseases. Magnetic resonance imaging (MRI) coupled with superparamagnetic particles of iron oxide (SPIO) is a minimally invasive technique allowing to track phagocytic cells in inflammatory diseases. Our aim was to investigate the potential of ultrasmall SPIO (USPIO)-enhanced MRI to monitor ChP involvement in-vivo in a mouse model of neuroinflammation obtained by intraperitoneal administration of lipopolysaccharide. Using high resolution MRI, we identified marked USPIO-related signal drops in the ChPs of animals with neuroinflammation compared to controls. We confirmed these results quantitatively using a 4-points grading system. Ex-vivo analysis confirmed USPIO accumulation within the ChP stroma and their uptake by immune cells. We validated the translational potential of our approach using the clinically-applicable USPIO Ferumoxytol. MR imaging of USPIO accumulation within the ChPs may serve as an imaging biomarker to study ChP involvement in neuroinflammatory disorders that could be applied in a straightforward way in clinical practice.
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http://dx.doi.org/10.1038/s41598-019-46566-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6624288PMC
July 2019

Evaluation of Myelin Radiotracers in the Lysolecithin Rat Model of Focal Demyelination: Beware of Pitfalls!

Contrast Media Mol Imaging 2019 29;2019:9294586. Epub 2019 May 29.

University of Lyon, Lyon Neuroscience Research Center (CRNL), Lyon, France.

The observation that amyloid radiotracers developed for Alzheimer's disease bind to cerebral white matter paved the road to nuclear imaging of myelin in multiple sclerosis. The lysolecithin (lysophosphatidylcholine (LPC)) rat model of demyelination proved useful in evaluating and comparing candidate radiotracers to target myelin. Focal demyelination following stereotaxic LPC injection is larger than lesions observed in experimental autoimmune encephalitis models and is followed by spontaneous progressive remyelination. Moreover, the contralateral hemisphere may serve as an internal control in a given animal. However, demyelination can be accompanied by concurrent focal necrosis and/or adjacent ventricle dilation. The influence of these side effects on imaging findings has never been carefully assessed. The present study describes an optimization of the LPC model and highlights the use of MRI for controlling the variability and pitfalls of the model. The prototypical amyloid radiotracer [C]PIB was used to show that PET does not provide sufficient sensitivity to reliably track myelin changes and may be sensitive to LPC side effects instead of demyelination as such. autoradiography with a fluorine radiotracer should be preferred, to adequately evaluate and compare radiotracers for the assessment of myelin content.
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http://dx.doi.org/10.1155/2019/9294586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594279PMC
July 2020

Clinical Imaging of Choroid Plexus in Health and in Brain Disorders: A Mini-Review.

Front Mol Neurosci 2019 12;12:34. Epub 2019 Feb 12.

Univ-Lyon, CarMeN Laboratory, Inserm U1060, INRA U1397, Université Claude Bernard Lyon 1, INSA Lyon, Charles Mérieux Medical School, Oullins, France.

The choroid plexuses (ChPs) perform indispensable functions for the development, maintenance and functioning of the brain. Although they have gained considerable interest in the last years, their involvement in brain disorders is still largely unknown, notably because their deep location inside the brain hampers non-invasive investigations. Imaging tools have become instrumental to the diagnosis and pathophysiological study of neurological and neuropsychiatric diseases. This review summarizes the knowledge that has been gathered from the clinical imaging of ChPs in health and brain disorders not related to ChP pathologies. Results are discussed in the light of pre-clinical imaging studies. As seen in this review, to date, most clinical imaging studies of ChPs have used disease-free human subjects to demonstrate the value of different imaging biomarkers (ChP size, perfusion/permeability, glucose metabolism, inflammation), sometimes combined with the study of normal aging. Although very few studies have actually tested the value of ChP imaging biomarkers in patients with brain disorders, these pioneer studies identified ChP changes that are promising data for a better understanding and follow-up of diseases such as schizophrenia, epilepsy and Alzheimer's disease. Imaging of immune cell trafficking at the ChPs has remained limited to pre-clinical studies so far but has the potential to be translated in patients for example using MRI coupled with the injection of iron oxide nanoparticles. Future investigations should aim at confirming and extending these findings and at developing translational molecular imaging tools for bridging the gap between basic molecular and cellular neuroscience and clinical research.
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http://dx.doi.org/10.3389/fnmol.2019.00034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379459PMC
February 2019

Magnetic Resonance Elastography of Rodent Brain.

Front Neurol 2018 27;9:1010. Epub 2018 Nov 27.

Univ. Lyon, INSA-Lyon, Université Claude Bernard Lyon 1, UJM-Saint Etienne, CNRS, Inserm, CREATIS UMR 5220, U1206, Lyon, France.

Magnetic resonance elastography (MRE) is a non-invasive imaging technique, using the propagation of mechanical waves as a probe to palpate biological tissues. It consists in three main steps: production of shear waves within the tissue; encoding subsequent tissue displacement in magnetic resonance images; and extraction of mechanical parameters based on dedicated reconstruction methods. These three steps require an acoustic-frequency mechanical actuator, magnetic resonance imaging acquisition, and a post-processing tool for which no turnkey technology is available. The aim of the present review is to outline the state of the art of reported set-ups to investigate rodent brain mechanical properties. The impact of experimental conditions in dimensioning the set-up (wavelength and amplitude of the propagated wave, spatial resolution, and signal-to-noise ratio of the acquisition) on the accuracy and precision of the extracted parameters is discussed, as well as the influence of different imaging sequences, scanners, electromagnetic coils, and reconstruction algorithms. Finally, the performance of MRE in demonstrating viscoelastic differences between structures constituting the physiological rodent brain, and the changes in brain parameters under pathological conditions, are summarized. The recently established link between biomechanical properties of the brain as obtained on MRE and structural factors assessed by histology is also studied. This review intends to give an accessible outline on how to conduct an elastography experiment, and on the potential of the technique in providing valuable information for neuroscientists.
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http://dx.doi.org/10.3389/fneur.2018.01010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6277573PMC
November 2018

In Silico, in Vitro, and in Vivo Evaluation of New Candidates for α-Synuclein PET Imaging.

Mol Pharm 2018 08 25;15(8):3153-3166. Epub 2018 Jul 25.

Université de Lyon, Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028 , Lyon 69361 , France.

Accumulation of α-synuclein (α-syn) is a neuropathological hallmark of synucleinopathies. To date, no selective α-syn positron emission tomography (PET) radiotracer has been identified. Our objective was to develop the first original, selective, and specific α-syn PET radiotracer. Chemical design inspired from three structural families that demonstrated interesting α-syn binding characteristics was used as a starting point. Bioinformatics modeling of α-syn fibrils was then employed to select the best molecular candidates before their syntheses. An in vitro binding assay was performed to evaluate the affinity of the compounds. Radiotracer specificity and selectivity were assessed by in vitro autoradiography and in vivo PET studies in animal (rodents) models. Finally, gold standard in vitro autoradiography with patients' postmortem tissues was performed to confirm/infirm the α-syn binding characteristics. Two compounds exhibited a good brain availability and bound to α-syn and Aβ fibrils in a rat model. In contrast, no signal was observed in a mouse model of synucleinopathy. Experiments in human tissues confirmed these negative results.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00229DOI Listing
August 2018

Amyloid-Beta Radiotracer [F]BF-227 Does Not Bind to Cytoplasmic Glial Inclusions of Postmortem Multiple System Atrophy Brain Tissue.

Contrast Media Mol Imaging 2018 6;2018:9165458. Epub 2018 Feb 6.

Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028, Université Claude Bernard Lyon 1, Université de Lyon, Lyon, France.

The accumulation of aggregated alpha-synuclein (-syn) in multiple brain regions is a neuropathological hallmark of synucleinopathies. Multiple system atrophy (MSA) is a synucleinopathy characterized by the predominant cerebral accumulation of aggregated -syn as cytoplasmic glial inclusions (CGI). A premortem diagnosis tool would improve early diagnosis and help monitoring disease progression and therapeutic efficacy. One Positron Emission Tomography (PET) study suggested [C]BF-227 as a promising radiotracer for monitoring intracellular -syn deposition in MSA patients. We sought to confirm the binding of this radiotracer to -syn using state-of-the-art autoradiography. Medulla sections were obtained from 9 MSA patients and 9 controls (London Neurodegenerative Diseases Brain Bank). [F]BF-227, chemically identical to [C]BF-227, was used at nanomolar concentrations to perform autoradiography assays. Autoradiograms were superimposed on fluorescent staining from the conformational anti--syn antibody 5G4 and quantified after immunofluorescence-driven definition of regions of interest. Autoradiography showed no specific signals in MSA patients in comparison to controls despite widespread pathology detected by immunofluorescence. Autoradiography does not support a significant binding of [F]BF-227 to CGI at concentrations typically achieved in PET experiments.
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http://dx.doi.org/10.1155/2018/9165458DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5818909PMC
July 2019

Effect of Cyclosporine on Lesion Growth and Infarct Size within the White and Gray Matter.

Front Neurol 2017 27;8:151. Epub 2017 Apr 27.

Department of Stroke Medicine, Université Lyon 1, Lyon, France.

Background: In a recent trial, cyclosporine A (CsA) failed to reduce infarct size in acute stroke patients treated with intravenous thrombolysis. White matter (WM) and gray matter (GM) may have distinct vulnerability to ischemia and response to therapy. Using final infarct size and lesion growth as endpoints, our objectives were to (1) investigate any tissue-specific effect of CsA and (2) compare WM and GM response to thrombolysis.

Materials And Methods: We analyzed 84 patients from the randomized and placebo-controlled CsA-Stroke trial, who underwent MRI both on admission and at 1 month. Lesion growth was defined voxel-wise as infarcted tissue at 1 month with no visible lesion on baseline diffusion-weighted imaging. After automatic segmentation of GM/WM, final infarct size and lesion growth were compared within the GM and WM.

Results: Occlusion level was distal (>M1) in 51% of cases. No significant difference in GM/WM proportions was observed within final infarcts between treatment groups ( = 0.21). Infarct size within the GM or WM was similar between the CsA and control groups [GM: 9.2 (2.4; 22.8) with CsA vs 8.9 (3.7; 28.4) mL with placebo,  = 0.74; WM: 9.9 (4.7; 25.4) with CsA vs 14.1 (5.6; 34.1) mL with placebo,  = 0.26]. There was no significant effect of CsA on lesion growth in either the GM or WM. Pooling all patients, a trend for increased relative lesion growth in WM compared to GM was observed [49.0% (14.7; 185.7) vs 43.1% (15.4; 117.1), respectively;  = 0.12].

Conclusion: No differential effect of CsA was observed between WM and GM. Pooling all patients, a trend toward greater lesion growth in WM was observed.
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http://dx.doi.org/10.3389/fneur.2017.00151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406390PMC
April 2017

Exercise Does Not Protect against Peripheral and Central Effects of a High Cholesterol Diet Given in Old ApoE Mice.

Front Physiol 2016 6;7:453. Epub 2016 Oct 6.

Univ Lyon, CarMeN Laboratory, Institut National de la Santé et de la Recherche Médicale U1060, INRA U1397, Université Lyon 1, INSA Lyon, F-69600 Oullins, France.

Advanced atherosclerosis increases inflammation and stroke risk in the cerebral vasculature. Exercise is known to improve cardio-metabolic profiles when associated with a caloric restriction, but it remains debated whether it is still beneficial without the dietary control. The aim of this study was to determine both the peripheral and central effects of exercise training combined with a cholesterol-rich diet given in old ApoE mice. : Forty-five-weeks old obese ApoE mice fed with a high cholesterol diet were divided into Exercise-trained (EX; running wheel free access) and Sedentary (SED) groups. Insulin tolerance and brain imaging were performed before and after the twelve-weeks training. Tissue insulin resistance, oxidative stress, and inflammation markers in plasma, aorta, and brain were then assessed. : In EX ApoE mice, no beneficial effect of exercise was observed on weight, abdominal fat, metabolic parameters, oxidative stress, or inflammation compared to SED. Despite the regular exercise training in ApoE EX mice (mean of 12.5 km/week during 12 weeks), brain inflammation imaging score was significantly associated with increased blood brain barrier (BBB) leakage evaluated by imaging follow-up ( = 0.87; = 0.049) with a faster evolution compared to SED ApoEmice. : We conclude that in a context of high cardio-metabolic risk, exercise does not provide any protective effect in old ApoE animals under high cholesterol diet given . Peripheral (insulin sensitivity and oxidative/inflammatory status) but also central features (BBB preservation and protection against inflammation) did not show any benefits of exercise. Indeed, there was a fast induction of irreversible brain damage that was more pronounced in exercise-trained ApoE mice.
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http://dx.doi.org/10.3389/fphys.2016.00453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5052582PMC
October 2016

Magnetic resonance imaging biomarkers of exercise-induced improvement of oxidative stress and inflammation in the brain of old high-fat-fed ApoE mice.

J Physiol 2016 12;594(23):6969-6985

Cardiovascular, Metabolism, Diabetes and Nutrition (CarMeN INSERM U-1060), Faculty of Medicine Hospital Lyon Sud, University of Lyon, University Lyon 1, Oullins, France.

Key Points: Vascular brain lesions and atherosclerosis are two similar conditions that are characterized by increased inflammation and oxidative stress. Non-invasive imaging in a murine model of atherosclerosis showed vascular brain damage and peripheral inflammation. In this study, exercise training reduced magnetic resonance imaging-detected abnormalities, insulin resistance and markers of oxidative stress and inflammation in old ApoE mice. Our results demonstrate the protective effect of exercise on neurovascular damage in the ageing brain of ApoE mice.

Abstract: Vascular brain lesions, present in advanced atherosclerosis, share pathological hallmarks with peripheral vascular lesions, such as increased inflammation and oxidative stress. Physical activity reduces these peripheral risk factors, but its cerebrovascular effect is less documented, especially by non-invasive imaging. Through a combination of in vivo and post-mortem techniques, we aimed to characterize vascular brain damage in old ApoE mice fed a high-cholesterol (HC) diet with dietary controlled intake. We then sought to determine the beneficial effects of exercise training on oxidative stress and inflammation in the brain as a treatment option in an ageing atherosclerosis mouse model. Using in vivo magnetic resonance imaging (MRI) and biological markers of oxidative stress and inflammation, we evaluated the occurrence of vascular abnormalities in the brain of HC-diet fed ApoE mice >70 weeks old, its association with local and systemic oxidative stress and inflammation, and whether both can be modulated by exercise. Exercise training significantly reduced both MRI-detected abnormalities (present in 71% of untrained vs. 14% of trained mice) and oxidative stress (lipid peroxidation, 9.1 ± 1.4 vs. 5.2 ± 0.9 μmol mg ; P < 0.01) and inflammation (interleukin-1β, 226.8 ± 27.1 vs. 182.5 ± 21.5 pg mg ; P < 0.05) in the brain, and the mortality rate. Exercise also decreased peripheral insulin resistance, oxidative stress and inflammation, but significant associations were seen only within brain markers. Highly localized vascular brain damage is a frequent finding in this ageing atherosclerosis model, and exercise is able to reduce this outcome and improve lifespan. In vivo MRI evaluated both the neurovascular damage and the protective effect of exercise.
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http://dx.doi.org/10.1113/JP271903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5134731PMC
December 2016

Multi-site laser Doppler flowmetry for assessing collateral flow in experimental ischemic stroke: Validation of outcome prediction with acute MRI.

J Cereb Blood Flow Metab 2017 Jun 1;37(6):2159-2170. Epub 2016 Jan 1.

6 Université de Lyon, Lyon Neuroscience Research Center, BioRaN team; CNRS UMR5292; Inserm U1028; Université Lyon 1, Lyon, France.

High variability in infarct size is common in experimental stroke models and affects statistical power and validity of neuroprotection trials. The aim of this study was to explore cerebral collateral flow as a stratification factor for the prediction of ischemic outcome. Transient intraluminal occlusion of the middle cerebral artery was induced for 90 min in 18 Wistar rats. Cerebral collateral flow was assessed intra-procedurally using multi-site laser Doppler flowmetry monitoring in both the lateral middle cerebral artery territory and the borderzone territory between middle cerebral artery and anterior cerebral artery. Multi-modal magnetic resonance imaging was used to assess acute ischemic lesion (diffusion-weighted imaging, DWI), acute perfusion deficit (time-to-peak, TTP), and final ischemic lesion at 24 h. Infarct volumes and typology at 24 h (large hemispheric versus basal ganglia infarcts) were predicted by both intra-ischemic collateral perfusion and acute DWI lesion volume. Collateral flow assessed by multi-site laser Doppler flowmetry correlated with the corresponding acute perfusion deficit using TTP maps. Multi-site laser Doppler flowmetry monitoring was able to predict ischemic outcome and perfusion deficit in good agreement with acute MRI. Our results support the additional value of cerebral collateral flow monitoring for outcome prediction in experimental ischemic stroke, especially when acute MRI facilities are not available.
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http://dx.doi.org/10.1177/0271678X16661567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5464709PMC
June 2017

Improved Neuroprotection Provided by Drug Combination in Neurons Exposed to Cell-Derived Soluble Amyloid-β Peptide.

J Alzheimers Dis 2016 05;52(3):975-87

Université de Lorraine, ENSAIA, UR AFPA, EA 3998, USC INRA 0340, Nancy, France.

Oligomeric amyloid-β (Aβ) peptide contributes to impaired synaptic connections and neurodegenerative processes, and as such, represents a primary therapeutic target for Alzheimer's disease (AD)-modifying approaches. However, the lack of efficacy of drugs that inhibit production of Aβ demonstrates the need for a better characterization of its toxic effects, both on synaptic and neuronal function. Here, we used conditioned medium obtained from recombinant HEK-AβPP cells expressing the human amyloid-β protein precursor (Aβ-CM), to investigate Aβ-induced neurotoxic and synaptotoxic effects. Characterization of Aβ-CM revealed that it contained picomolar amounts of cell-secreted Aβ in its soluble form. Incubation of primary cortical neurons with Aβ-CM led to significant decreases in synaptic protein levels as compared to controls. This effect was no longer observed in neurons incubated with conditioned medium obtained from HEK-AβPP cells grown in presence of the γ-secretase inhibitor, Semagacestat or LY450139 (LY-CM). However, neurotoxic and pro-apoptotic effects of Aβ-CM were only partially prevented using LY-CM, which could be explained by other deleterious compounds related to chronic oxidative stress that were released by HEK-AβPP cells. Indeed, full neuroprotection was observed in cells exposed to LY-CM by additional treatment with the antioxidant resveratrol, or with the pluripotent n-3 polyunsaturated fatty acid docosahexaenoic acid. Inhibition of Aβ production appeared necessary but insufficient to prevent neurodegenerative effects associated with AD due to other neurotoxic compounds that could exert additional deleterious effects on neuronal function and survival. Therefore, association of various types of protective agents needs to be considered when developing strategies for AD treatment.
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http://dx.doi.org/10.3233/JAD-151110DOI Listing
May 2016

Spatiotemporal characterization of brain infarction by sequential multimodal MR imaging following transient focal ischemia in a Rat model of intra-arterial middle cerebral artery occlusion.

Eur Radiol 2016 Dec 17;26(12):4505-4514. Epub 2016 Mar 17.

FHU IRIS, Department of Interventional Neuroradiology, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 59 Bd Pinel, 69677, Bron, France.

Objectives: To assess spatiotemporal brain infarction evolution by sequential multimodal magnetic resonance (MR) imaging in an endovascular model of acute stroke in rats.

Materials And Methods: A microwire was selectively placed in the middle cerebral artery (MCA) in 16 consecutives rats during 90 minutes occlusion. Longitudinal 7-T MR imaging, including angiography, diffusion, and perfusion was performed during ischemia, immediately after reperfusion, 3 h and 24 h after subsequent reperfusion.

Results: MCA occlusion was complete in 75 % and partial in 18.7 %. Hypoperfusion (mean ± SD) was observed in all animals during ischemia (-59 ± 18 % of contralateral hemisphere, area 31 ± 5 mm). Infarction volume (mean ± SD) was 90 ± 64 mm during ischemia and 57 ± 67 mm at 24 h. Brain infarction was fronto-parietal cortical in five animals (31 %), striatal in four animals (25 %), and cortico-striatal in seven animals (44 %) at 24 h. All rats survived at 24 h.

Conclusion: This model is suitable to neuroprotection studies because of possible acute and close characterization of spatiotemporal evolution of brain infarction by MR imaging techniques, and evidence of ischemic penumbra, the target of neuroprotection agents. However, optimization of the brain infarct reproducibility needs further technical and neurointerventional tools improvements.

Key Points: • Nitinol microwire is MRI compatible allowing spatiotemporal characterization of brain infarction in rats. • Microwire selective placement in middle cerebral artery allows complete artery occlusion in 75 %. • A diffusion/perfusion mismatch during arterial occlusion is observed in 77 % of rats.
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http://dx.doi.org/10.1007/s00330-016-4290-xDOI Listing
December 2016

Differential effects of amyloid-beta 1-40 and 1-42 fibrils on 5-HT1A serotonin receptors in rat brain.

Neurobiol Aging 2016 Apr 19;40:11-21. Epub 2015 Dec 19.

Université de Lyon; Lyon Neuroscience Research Center, CNRS UMR5292; INSERM U1028, Université Claude Bernard Lyon 1, Lyon, France; CERMEP-Imaging Platform, Lyon, France; Hospices Civils de Lyon, Lyon, France. Electronic address:

Evidence accumulates suggesting a complex interplay between neurodegenerative processes and serotonergic neurotransmission. We have previously reported an overexpression of serotonin 5-HT1A receptors (5-HT(1A)R) after intrahippocampal injections of amyloid-beta 1-40 (Aβ40) fibrils in rats. This serotonergic reactivity paralleled results from clinical positron emission tomography studies with [(18)F]MPPF revealing an overexpression of 5-HT(1A)R in the hippocampus of patients with mild cognitive impairment. Because Aβ40 and Aβ42 isoforms are found in amyloid plaques, we tested in this study the hypothesis of a peptide- and region-specific 5-HT(1A)R reactivity by injecting them, separately, into the hippocampus or striatum of rats. [(18)F]MPPF in vitro autoradiography revealed that Aβ40 fibrils, but not Aβ42, were triggering an overexpression of 5-HT(1A)R in the hippocampus and striatum of rat brains after 7 days. Immunohistochemical approaches targeting neuronal precursor cells, mature neurons, and astrocytes showed that Aβ42 fibrils caused more pathophysiological damages than Aβ40 fibrils. The mechanisms of Aβ40 fibrils-induced 5-HT(1A)R expression remains unknown, but hypotheses including neurogenesis, glial expression, and axonal sprouting are discussed.
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http://dx.doi.org/10.1016/j.neurobiolaging.2015.12.008DOI Listing
April 2016

Cyclosporine in acute ischemic stroke.

Neurology 2015 Jun 6;84(22):2216-23. Epub 2015 May 6.

From the Departments of Neurology (N.N., L.M., L.D., T.H.C., T.R., S.R., E.O.) and Neuroradiology (Y. Berthezène, F.C.), Hôpital Neurologique Pierre Wertheimer, Creatis CNRS UMR 5220, INSERM U1044, Université Lyon 1, INSA Lyon; Dijon Stroke Registry (Y. Béjot, A.J., M.G., F.R.) (EA 4184, Inserm, Invs), University Hospital of Dijon, Regional Council and University of Burgondy, CHU le Bocage, Dijon; Department of Neurology (F.P.), Centre Hospitalier de Fleyriat, Bourg en Bresse; Departments of Neurology (C.L., G.T., E.B., V.D., V.G., J.-L.M.) and Neuroradiology (C.O.), CH Sainte-Anne, University Paris-Descartes, INSERM U894, DHU NeuroVasc Sorbonne Paris Cité; Department of Neurology (P.A.), Hôpital Bichat-Claude Bernard, Paris; Department of Neurology (S.C.), Hôpital Nord-Ouest, Plateau d'Ouilly, Villefranche sur Saône; Department of Neurology (M.S.-A., B.G., H.D.), Hôpital Nord-Laënnec, Saint-Herblain; Department of Neurology (H.H.), Hôpital Henri Mondor, Créteil; Department of Neurology (I.S.), Groupe Hospitalier Pellegrin, Place Amélie Raba-Léon, Bordeaux; Unité Neurosciences (M.-H.M.), Hôpital Saint Roch, Nice; Hôpital Louis Pradel (N.M., M.O.), Service d'Explorations Fonctionelles Cardiovasculaires, Centre d'Investigation Clinique & UMR1060 (CarMeN), Université Claude Bernard Lyon 1, France.

Objectives: We examined whether IV administration of cyclosporine in combination with thrombolysis might reduce cerebral infarct size.

Methods: Patients aged 18 to 85 years, presenting with an anterior-circulation stroke and eligible for thrombolytic therapy, were enrolled in this multicenter, single-blinded, controlled trial. Fifteen minutes after randomization, patients received either an IV bolus injection of 2.0 mg/kg cyclosporine (Sandimmune, Novartis) or placebo. The primary endpoint was infarct volume on MRI at 30 days. Secondary endpoints included infarct volume according to the site (proximal/distal) of arterial occlusion and recanalization after thrombolysis.

Results: From October 2009 to July 2013, 127 patients were enrolled. The primary endpoint was assessed in 110 of 127 patients. The reduction of infarct volume in the cyclosporine compared with the control group was overall not significant (21.8 mL [interquartile range, IQR 5.1, 69.2 mL] vs 28.8 mL [IQR 7.7, 95.0 mL], respectively; p = 0.18). However, in patients with proximal occlusion and effective recanalization, infarct volume was significantly reduced in the cyclosporine compared with the control group (14.9 mL [IQR 1.3, 23.2 mL] vs 48.3 mL [IQR 34.5, 118.2 mL], respectively; p = 0.009).

Conclusions: Cyclosporine was generally not effective in reducing infarct size. However, a smaller infarct size was observed in patients with proximal cerebral artery occlusion and efficient recanalization.

Classification Of Evidence: This study provides Class I evidence that in patients with an acute anterior-circulation stroke, thrombolysis plus IV cyclosporine does not significantly decrease 30-day MRI infarct volume compared with thrombolysis alone.
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http://dx.doi.org/10.1212/WNL.0000000000001639DOI Listing
June 2015

Cerebral collateral flow defines topography and evolution of molecular penumbra in experimental ischemic stroke.

Neurobiol Dis 2015 Feb 5;74:305-13. Epub 2014 Dec 5.

Laboratory of Experimental Stroke Research, Department of Surgery and Translational Medicine, University of Milano Bicocca, Monza, Italy; Milan Center for Neuroscience (NeuroMi), Milano, Italy.

Intracranial collaterals are dynamically recruited after arterial occlusion and are emerging as a strong determinant of tissue outcome in both human and experimental ischemic stroke. The relationship between collateral flow and ischemic penumbra remains largely unexplored in pre-clinical studies. The aim of the present study was to investigate the pattern of collateral flow with regard to penumbral tissue after transient middle cerebral artery (MCA) occlusion in rats. MCA was transiently occluded (90min) by intraluminal filament in adult male Wistar rats (n=25). Intracranial collateral flow was studied in terms of perfusion deficit and biosignal fluctuation analyses using multi-site laser Doppler monitoring. Molecular penumbra was defined by topographical mapping and quantitative signal analysis of Heat Shock Protein 70kDa (HSP70) immunohistochemistry. Functional deficit and infarct volume were assessed 24h after ischemia induction. The results show that functional performance of intracranial collaterals during MCA occlusion inversely correlated with HSP70 immunoreactive areas in both the cortex and the striatum, as well as with infarct size and functional deficit. Intracranial collateral flow was associated with reduced areas of both molecular penumbra and ischemic core and increased areas of intact tissue in rats subjected to MCA occlusion followed by reperfusion. Our findings prompt the development of collateral therapeutics to provide tissue-saving strategies in the hyper-acute phase of ischemic stroke prior to recanalization therapy.
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http://dx.doi.org/10.1016/j.nbd.2014.11.019DOI Listing
February 2015

Effects of a TAFI-inhibitor combined with a suboptimal dose of rtPA in a murine thromboembolic model of stroke.

Cerebrovasc Dis 2014 13;38(4):268-75. Epub 2014 Nov 13.

CREATIS, CNRS UMR5220, INSERM U1044, INSA de Lyon, Université de Lyon, Lyon 1, France.

Background: Since thrombolysis is the only approved intervention for ischemic stroke, improving its efficacy and safety is a therapeutic aim of considerable interest. The activated form of thrombin activatable fibrinolysis inhibitor (TAFI) has antifibrinolytic effects, and inhibition of TAFI might thus favor recanalization. The present study compared efficacy between TAFI inhibition alone and TAFI inhibition in combination with rtPA at a suboptimal dose, in a murine model of thromboembolic stroke.

Methods: Focal ischemia was induced in mice by thrombin injection in the middle cerebral artery. Animals were placed within the magnet immediately after surgery for baseline MRI (H0). MRI examination comprised diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), and T2-weighted imaging (T2-WI). Animals were randomly assigned to 1 of 5 treatment groups: saline, rtPA 5 mg/kg (tPA(5): suboptimal or low dose), rtPA 10 mg/kg (tPA(10): standard dose), TAFI-I 100 mg/kg (TAFI-I), and rtPA 5 mg/kg + TAFI-I 100 mg/kg (tPA(5) + TAFI-I). Treatments were administered inside the magnet, via a catheter placed in the tail vein, using a power injector, as 10% bolus and 90% infusion over a period of 20 min. MRI examination was repeated at 3 h (H3) and 24 h (H24) after surgery. Therapeutic benefit was evaluated by: (1) improvement of reperfusion and (2) reduction in final lesion size. Microhemorrhages were assessed as black spots on T2-WI at H24. Animals were sacrificed after the last MR examination. The surgeon and all investigators were blinded to treatment allocation.

Results: A total of 104 mice were operated on. Forty four of these were excluded from the study and 27 from the analysis, according to a priori defined criteria (no lesion or no mismatch), leading to the following distribution: saline (n = 6), tPA(5) (n = 8), tPA(10) (n = 7), TAFI-I (n = 7), and TAFI-I + tPA(5) (n = 5). Standard-dose rtPA treatment (tPA(10)) significantly improved lesion regression between H0 and H24 compared to saline (-57 ± 18% vs. -36 ± 21%, p = 0.03), which treatment with rtPA(5) or TAFI-I alone did not. On the other hand, combined treatment with tPA(5) + TAFI-I showed only a trend toward lesion regression (-49 ± 26%), similarly to treatment with tPA(10), but not significantly different from saline (p = 0.46). Nine animals showed microhemorrhage on T2-WI at H24. These animals were evenly distributed between groups.

Conclusions: The present study showed that the combination of TAFI-I with a suboptimal dose of rtPA is not as effective as the standard dose of rtPA, while TAFI inhibition alone is not effective at all. The thromboembolic model is of particular interest in assessing rtPA association to improve thrombolysis, especially when coupled with longitudinal MRI assessment.
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http://dx.doi.org/10.1159/000366266DOI Listing
August 2015

Binding of the PET radiotracer [¹⁸F]BF227 does not reflect the presence of alpha-synuclein aggregates in transgenic mice.

Curr Alzheimer Res 2014 ;11(10):955-60

CERMEP-Imaging Platform, 59 boulevard Pinel, Lyon, F-69003, France.

Alpha-synuclein (α-syn) aggregation is a neuropathological hallmark of many neurodegenerative diseases, collectively termed synucleinopathies. There is currently no pre-mortem diagnosis tool for these diseases. Although some compounds have been described as potential ligands for α-syn aggregates, no specific PET radiotracer of aggregated α-syn is currently available. Recently, [(18)F]BF227 has been proposed as an α-syn PET radiotracer in the absence of other specific candidates. We proposed here, for the first time, to use this radiotracer in an accelerated mouse model of synucleinopathy presenting α-syn depositions in brainstem and thalamus. Our in vivo and in vitro studies showed that [(18)F]BF227 does not bind to α-syn aggregates. These results highlight the fact that [(18)F]BF227 PET has no suitable characteristics for monitoring this experimental synucleinopathy, justifying the need to develop alternative α-syn PET radiotracers.
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http://dx.doi.org/10.2174/1567205011666141107154201DOI Listing
August 2015

In vitro and in vivo models of cerebral ischemia show discrepancy in therapeutic effects of M2 macrophages.

PLoS One 2013 25;8(6):e67063. Epub 2013 Jun 25.

CNRS, UMR 5220; INSERM, U1044; INSA de Lyon, France.

THE INFLAMMATORY RESPONSE FOLLOWING ISCHEMIC STROKE IS DOMINATED BY INNATE IMMUNE CELLS: resident microglia and blood-derived macrophages. The ambivalent role of these cells in stroke outcome might be explained in part by the acquisition of distinct functional phenotypes: classically (M1) and alternatively activated (M2) macrophages. To shed light on the crosstalk between hypoxic neurons and macrophages, an in vitro model was set up in which bone marrow-derived macrophages were co-cultured with hippocampal slices subjected to oxygen and glucose deprivation. The results showed that macrophages provided potent protection against neuron cell loss through a paracrine mechanism, and that they expressed M2-type alternative polarization. These findings raised the possibility of using bone marrow-derived M2 macrophages in cellular therapy for stroke. Therefore, 2 million M2 macrophages (or vehicle) were intravenously administered during the subacute stage of ischemia (D4) in a model of transient middle cerebral artery occlusion. Functional neuroscores and magnetic resonance imaging endpoints (infarct volumes, blood-brain barrier integrity, phagocytic activity assessed by iron oxide uptake) were longitudinally monitored for 2 weeks. This cell-based treatment did not significantly improve any outcome measure compared with vehicle, suggesting that this strategy is not relevant to stroke therapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0067063PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3692438PMC
February 2014

Spontaneous reperfusion after in situ thromboembolic stroke in mice.

PLoS One 2012 16;7(11):e50083. Epub 2012 Nov 16.

Université de Lyon, CREATIS, CNRS UMR5220, INSERM U1044, INSA-Lyon, Université Lyon 1, Hospices Civils de Lyon, Lyon, France.

Injection of thrombin into the middle cerebral artery (MCA) of mice has been proposed as a new model of thromboembolic stroke. The present study used sequential multiparametric Magnetic Resonance Imaging (MRI), including Magnetic Resonance Angiography (MRA), Diffusion-Weighted Imaging (DWI) and Perfusion-Weighted Imaging (PWI), to document MCA occlusion, PWI-DWI mismatch, and lesion development. In the first experiment, complete MCA occlusion and reproducible hypoperfusion were obtained in 85% of animals during the first hour after stroke onset. In the second experiment, 80% of animals showed partial to complete reperfusion during a three-hour follow-up. Spontaneous reperfusion thus contributed to the variability in ischemic volume in this model. The study confirmed the value of the model for evaluating new thrombolytic treatments, but calls for extended MRI follow-up at the acute stage in therapeutic studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0050083PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500336PMC
April 2013

Pre- and post-treatment with cyclosporine A in a rat model of transient focal cerebral ischaemia with multimodal MRI screening.

Int J Stroke 2013 Dec 7;8(8):669-74. Epub 2012 Aug 7.

Université de Lyon, CREATIS; CNRS UMR5220, INSERM U1044, INSA-Lyon; Université Lyon 1, Hospices Civils de Lyon, France.

Background: Irreversible damage may occur at reperfusion after sustained cerebral ischaemia.

Aims: We investigated the value of cyclosporine A for reducing the infarct size in a model of transient middle cerebral artery occlusion.

Methods: Twenty-seven Sprague-Dawley rats sustained a middle cerebral artery occlusion of one-hour. Acute multimodal Magnetic Resonance Imaging (MRI) was used during occlusion to confirm the success of surgery and measure baseline lesion size. Animals were randomly treated by: (i) intracarotid cyclosporine A (10 mg/kg) 20 mins before middle cerebral artery occlusion (pretreatment group); (ii) intracarotid cyclosporine A (10 mg/kg) immediately after reperfusion (post-treatment group); and (iii) intracarotid saline immediately after reperfusion.

Results: Histopathological measurements on day 1 showed a significant reduction of infarct size in the pretreatment group compared to the post-treatment (percentage values of ipsilateral hemispheres: 16 ± 5% vs. 29 ± 11%, P = 0·004) and saline groups (16 ± 5% vs. 42 ± 12%, P = 0·015). No significant difference was observed between the post-treatment and saline groups (P = 0·065). Behavioural examinations on day 1 showed no significant difference between groups. Immunohistochemistry showed a statistically significant reduction of microglial cell count in the pretreatment group compared to either saline or cyclosporine A post-treatment groups.

Conclusions: We conclude that intracarotid cyclosporine A is effective in reducing infarct size when given prior to ischaemia, but not when administered at reperfusion.
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http://dx.doi.org/10.1111/j.1747-4949.2012.00849.xDOI Listing
December 2013

Monitoring therapeutic effects in experimental stroke by serial USPIO-enhanced MRI.

Eur Radiol 2013 Jan 26;23(1):37-47. Epub 2012 Jul 26.

UMR CNRS 5520 CREATIS, Hopital Louis Pradel, Université de Lyon, Lyon 1, 28 avenue du Doyen LEPINE, 69677, Bron, France.

Objectives: This study sought to evaluate whether the therapeutic effects of an anti-inflammatory drug such as minocycline could be monitored by serial ultrasmall superparamagnetic particles of iron oxide (USPIO)-enhanced MRI in experimental stroke.

Methods: Mice received a three-dose minocycline treatment (n = 12) or vehicle (n = 12) after permanent middle cerebral artery occlusion. USPIOs were administered 5 h post-surgery. MRI was performed before, 24 h and 48 h post-USPIO administration. MRI endpoints were the extent of signal abnormalities on R2 maps (=1/T2) and quantitative R2 changes over time (∆R2). Post-mortem brains were prepared either for immunohistology (n = 16) or for iron dosage (n = 8).

Results: As expected, treatment with minocycline significantly reduced infarct size, blood-brain barrier permeability and F4/80 immunostaining for microglia/macrophages. Areas of R2 maps > 35 ms(-1) also appeared significantly decreased in minocycline-treated mice (ANOVA for repeated measures, P = 0.017). There was a fair correlation between these areas and the amount of iron in the brain (R(2) = 0.69, P = 0.010), but no significant difference in ∆R2 was found between the two groups.

Conclusions: This study showed that the extent of signal abnormalities on R2 maps can be used as a surrogate marker to detect minocycline effects in a murine experimental model of stroke.
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http://dx.doi.org/10.1007/s00330-012-2567-2DOI Listing
January 2013

MRI assessment of the intra-carotid route for macrophage delivery after transient cerebral ischemia.

NMR Biomed 2013 Feb 25;26(2):115-23. Epub 2012 Jun 25.

Université de Lyon, Lyon 1, UMR CNRS 5220, INSERM U1044, INSA de Lyon, Creatis, Bron, France.

The broad aim underlying the present research was to investigate the distribution and homing of bone marrow-derived macrophages in a rodent model of transient middle cerebral artery occlusion using MRI and ultrasmall superparamagnetic iron oxide (USPIO) to magnetically label bone marrow-derived macrophages. The specific aim was to assess the intra-carotid infusion route for bone marrow-derived macrophage delivery at reperfusion. Fifteen Sprague-Dawley rats sustained 1 h of middle cerebral artery occlusion. USPIO-labeled bone marrow-derived macrophages were slowly injected for 5 min immediately after reperfusion in ischemic animals (n=7), 1 h after the end of surgery in sham animals (n=5) and very shortly after anesthesia in healthy animals (n=3). Multiparametric MRI was performed at day 0, just after cell administration, and repeated at day 1. Immunohistological analysis included Prussian blue for iron detection and rat endothelial cell antigen-1 for endothelium visualization. Intra-carotid cell delivery brought a large number of cells to the ipsilateral hemisphere of the brain, as seen on both MRI and immunohistology. However, it was associated with high mortality (50%). The study of sham animals demonstrated that intra-carotid cell delivery could induce ischemic lesions and may thus favor additional brain damage. The present study highlights severe drawbacks to the intra-carotid delivery of macrophages at the time of reperfusion in this rodent model of transient cerebral ischemia. Multiparametric MRI appears to be a method of choice to monitor longitudinally the effects of cell infusion, allowing the assessment of both cell fate with the help of magnetic labeling and of potential tissue damage.
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http://dx.doi.org/10.1002/nbm.2826DOI Listing
February 2013

Does acute behavioral testing reflect successful ischemia in rats with transient middle cerebral artery occlusion?

Int J Stroke 2012 Aug 8;7(6):465-72. Epub 2011 Dec 8.

Université de Lyon, CREATIS, CNRS UMR5220, Inserm U1044, INSA-Lyon, Université Lyon 1, France.

Background: Models of intraluminal middle cerebral artery occlusion present an intrinsic variability in infarct size. Behavioral evaluation is frequently performed during arterial occlusion to confirm success of surgery.

Aims And/or Hypothesis: We compared the value of behavioral testing and multimodal magnetic resonance imaging performed during arterial occlusion for identifying successfully operated animals.

Methods: Rats were tested with behavioral assessment (using three scoring scales and the adhesive removal test) and multimodal magnetic resonance imaging (including magnetic resonance angiography, diffusion-weighted and perfusion-weighted imaging), both performed during the two-hours of middle cerebral artery occlusion using the intraluminal suture model. Behavioral assessment was repeated 24 h after reperfusion, followed by sacrifice.

Results: Acute apparent diffusion coefficient lesion volume was correlated with both 2,3,5-triphenyl tetrazolium chloride infarct size (r = 0·75, P = 0·02) and behavioral status (r = 0·66, P = 0·05) on day one. Conversely, no correlation was found between acute behavioral examination and day one outcomes (2,3,5-triphenyl tetrazolium chloride infarct volume, r = 0·40, P = 0·28; behavioral examination, r = 0·39, P = 0·30). Day zero apparent diffusion coefficient volumes (P = 0·04), but not behavioral assessment (P = 0·60), discriminated animals with day one corticostriatal infarcts from these with subcortical infarcts.

Conclusions: Acute behavioral testing performed during arterial occlusion fails to identify successfully operated animals. Acute diffusion magnetic resonance imaging may be more appropriate to assess and reduce infarct size variability in this model.
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http://dx.doi.org/10.1111/j.1747-4949.2011.00710.xDOI Listing
August 2012

Brain-targeting form of docosahexaenoic acid for experimental stroke treatment: MRI evaluation and anti-oxidant impact.

Curr Neurovasc Res 2011 May;8(2):95-102

Université de Lyon, Lyon 1, Lyon F-69003, France.

Epidemiologic studies report cardiovascular protection conferred by omega-3 fatty acids, in particular docosahexaenoic acid (DHA). However, few experimental studies have addressed its potential in acute stroke treatment. The present study used multimodal MRI to assess in vivo the neuroprotection conferred by DHA and by a brain-targeting form of DHA-containing lysophosphatidylcholine (AceDoPC) in experimental stroke. Rats underwent intraluminal middle cerebral artery occlusion (MCAO) and were treated at reperfusion by intravenous injection of i) saline, ii) plasma from donor rats, iii) DHA or iv) AceDoPC, both solubilized in plasma. Twenty-four hours after reperfusion, animals underwent behavioral tests and were sacrificed. Multiparametric MRI (MRA, DWI, PWI, T2-WI) was performed at H0, during occlusion, and at H24, before sacrifice. Brain tissue was used for assay of F(2)-isoprostanes as lipid peroxidation markers. Initial lesion size and PWI/DWI mismatch were comparable in the four groups. Between H0 and H24, lesion size increased in the saline group (mean ± s.d.: +18% ± 20%), was stable in the plasma group (-3% ± 29%), and decreased in the DHA (-17% ± 15%, P=0.001 compared to saline) and AceDoPC (-34% ± 27%, P=0.001 compared to saline) groups. Neuroscores in the AceDoPC group tended to be lower than in the other groups (P=0.07). Treatments (pooled DHA and AceDoPC groups) significantly decreased lipid peroxidation as compared to controls (pooled saline and vehicle) (P=0.03). MRI-based assessment demonstrated the neuroprotective effect of DHA in the MCAO model. Results further highlighted the therapeutic potential of engineered brain-targeting forms of omega-3 fatty acids for acute stroke treatment.
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http://dx.doi.org/10.2174/156720211795495349DOI Listing
May 2011

In vivo imaging of neuroinflammation in the rodent brain with [11C]SSR180575, a novel indoleacetamide radioligand of the translocator protein (18 kDa).

Eur J Nucl Med Mol Imaging 2011 Mar 9;38(3):509-14. Epub 2010 Oct 9.

Service Hospitalier Frédéric Joliot, CEA, DSV, I²BM, Orsay, France.

Purpose: Neuroinflammation is involved in neurological disorders through the activation of microglial cells. Imaging of neuroinflammation with radioligands for the translocator protein (18 kDa) (TSPO) could prove to be an attractive biomarker for disease diagnosis and therapeutic evaluation. The indoleacetamide-derived 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide, SSR180575, is a selective high-affinity TSPO ligand in human and rodents with neuroprotective effects.

Methods: Here we report the radiolabelling of SSR180575 with (11)C and in vitro and in vivo imaging in an acute model of neuroinflammation in rats.

Results: The image contrast and the binding of [(11)C]SSR180575 are higher than that obtained with the isoquinoline-based TSPO radioligand, [(11)C]PK11195. Competition studies demonstrate that [(11)C]SSR180575 has high specific binding for the TSPO.

Conclusion: [(11)C]SSR180575 is the first PET radioligand for the TSPO based on an indoleacetamide scaffold designed for imaging neuroinflammation in animal models and in the clinic.
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http://dx.doi.org/10.1007/s00259-010-1628-5DOI Listing
March 2011

Quantification of iron-labeled cells with positive contrast in mouse brains.

Mol Imaging Biol 2011 Aug 24;13(4):672-8. Epub 2010 Aug 24.

Université de Lyon, Lyon 1, Lyon, France.

Purpose: To quantify small amounts of iron-labeled cells in mouse brains with magnetic resonance imaging (MRI).

Procedures: Iron-labeled cells (from 500 to 7,500) were stereotaxically transplanted into the brain of living mice that were subsequently imaged with MRI at 4.7 T. We compared four quantitative methods: (1) T2 relaxometry, (2) T2* relaxometry, (3) the volume of the cloverleaf hypointense artifact generated on T2*-weighted images, and (4) the volume of the cloverleaf hyperintense artifact generated on positive contrast images.

Results: The methods based on relaxometry, whether T2 or T2*, did not correlate with the number of injected cells. By contrast, those based on measurement of cloverleaf artifact volume, whether using negative or positive enhancement, showed a significant linear relationship for the given range of cells (R [0.92-0.95], p < 0.05).

Conclusions: T2* artifact volume imaging (negative or positive) appears promising for the quantification of magnetically labeled cells following focal injection in the brain.
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http://dx.doi.org/10.1007/s11307-010-0402-1DOI Listing
August 2011

In vivo MRI assessment of permanent middle cerebral artery occlusion by electrocoagulation: pitfalls of procedure.

Exp Transl Stroke Med 2010 Feb 4;2(1). Epub 2010 Feb 4.

Cerebrovascular Unit, Hôpital Neurologique Pierre Wertheimer, Lyon, France.

Permanent middle cerebral artery (MCA) occlusion (pMCAO) by electrocoagulation is a commonly used model but with potential traumatic lesions. Early MRI monitoring may assess pMCAO for non-specific brain damage. The surgical steps of pMCAO were evaluated for traumatic cerebral injury in 22 Swiss mice using diffusion and T2-weighted MRI (7T) performed within 1 h and 24 h after surgery. Temporal muscle cauterization without MCA occlusion produced an early T2 hyperintensity mimicking an infarct. No lesion was visible after temporal muscle incision or craniotomy. Early MRI monitoring is useful to identify non-specific brain injury that could hamper neuroprotective drugs assessment.
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http://dx.doi.org/10.1186/2040-7378-2-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827391PMC
February 2010