A R Coda1, S Anzilotti2, F Boscia3, A Greco4,5, M Panico1, S Gargiulo1, M Gramanzini1, A Zannetti1, S Albanese1, G Pignataro3, L Annunziato2, M Salvatore2, A Brunetti4, P De Berardinis6, Mario Quarantelli7, G Palma1, Sabina Pappatà8. 1. Institute of Biostructure and Bioimaging, National Research Council, Via T. De Amicis 95, 80145, Naples, Italy. 2. IRCCS SDN, Via E. Gianturco 113, 80143, Naples, Italy. 3. Division of Pharmacology, Department of Neuroscience, Reproductive and Odontostomatological Sciences, School of Medicine, University "Federico II", Via S. Pansini 5, 80131, Naples, Italy. 4. Department of Advanced Biomedical Sciences, University "Federico II", Via S. Pansini 5, 80131, Naples, Italy. 5. Ceinge Biotecnologie Avanzate s. c. a. r. l., Via G. Salvatore 486, 80145, Naples, Italy. 6. Institute of Biochemistry and Cell Biology, National Research Council, Via P. Castellino 111, 80131, Naples, Italy. 7. Institute of Biostructure and Bioimaging, National Research Council, Via T. De Amicis 95, 80145, Naples, Italy. quarante@unina.it. 8. Institute of Biostructure and Bioimaging, National Research Council, Via T. De Amicis 95, 80145, Naples, Italy. sabina.pappata@ibb.cnr.it.
Abstract
PURPOSE: To evaluate the feasibility and sensitivity of multimodality PET/CT and MRI imaging for non-invasive characterization of brain microglial/macrophage activation occurring during the acute phase in a mouse model of relapsing remitting multiple sclerosis (RR-MS) using [18F]DPA-714, a selective radioligand for the 18-kDa translocator protein (TSPO), superparamagnetic iron oxide particles (SPIO), and ex vivo immunohistochemistry. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice by immunization with PLP139-151. Seven symptomatic EAE mice and five controls underwent both PET/CT and MRI studies between 11 and 14 days post-immunization. SPIO was injected i.v. in the same animals immediately after [18F]DPA-714 and MRI acquisition was performed after 24 h. Regional brain volumes were defined according to a mouse brain atlas on co-registered PET and SPIO-MRI images. [18F]DPA-714 standardized uptake value (SUV) ratios (SUVR), with unaffected neocortex as reference, and SPIO fractional volumes (SPIO-Vol) were generated. Both SUVR and SPIO-Vol values were correlated with the clinical score (CS) and among them. Five EAE and four control mice underwent immunohistochemical analysis with the aim of identifying activated microglia/macrophage and TSPO expressions. RESULTS: SUVR and SPIO-Vol values were significantly increased in EAE compared with controls in the hippocampus (p < 0.01; p < 0.02, respectively), thalamus (p < 0.02; p < 0.05, respectively), and cerebellum and brainstem (p < 0.02), while only SPIO-Vol was significantly increased in the caudate/putamen (p < 0.05). Both SUVR and SPIO-Vol values were positively significantly correlated with CS and among them in the same regions. TSPO/Iba1 and F4/80/Prussian blue staining immunohistochemistry suggests that increased activated microglia/macrophages underlay TSPO expression and SPIO uptake in symptomatic EAE mice. CONCLUSIONS: These preliminary results suggest that both activated microglia and infiltrated macrophages are present in vulnerable brain regions during the acute phase of PLP-EAE and contribute to disease severity. Both [18F]DPA-714-PET and SPIO-MRI appear suitable modalities for preclinical study of neuroinflammation in MS mice models.
PURPOSE: To evaluate the feasibility and sensitivity of multimodality PET/CT and MRI imaging for non-invasive characterization of brain microglial/macrophage activation occurring during the acute phase in a mouse model of relapsing remitting multiple sclerosis (RR-MS) using [18F]DPA-714, a selective radioligand for the 18-kDa translocator protein (TSPO), superparamagnetic iron oxide particles (SPIO), and ex vivo immunohistochemistry. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced in female SJL/J mice by immunization with PLP139-151. Seven symptomatic EAE mice and five controls underwent both PET/CT and MRI studies between 11 and 14 days post-immunization. SPIO was injected i.v. in the same animals immediately after [18F]DPA-714 and MRI acquisition was performed after 24 h. Regional brain volumes were defined according to a mouse brain atlas on co-registered PET and SPIO-MRI images. [18F]DPA-714 standardized uptake value (SUV) ratios (SUVR), with unaffected neocortex as reference, and SPIO fractional volumes (SPIO-Vol) were generated. Both SUVR and SPIO-Vol values were correlated with the clinical score (CS) and among them. Five EAE and four control mice underwent immunohistochemical analysis with the aim of identifying activated microglia/macrophage and TSPO expressions. RESULTS: SUVR and SPIO-Vol values were significantly increased in EAE compared with controls in the hippocampus (p < 0.01; p < 0.02, respectively), thalamus (p < 0.02; p < 0.05, respectively), and cerebellum and brainstem (p < 0.02), while only SPIO-Vol was significantly increased in the caudate/putamen (p < 0.05). Both SUVR and SPIO-Vol values were positively significantly correlated with CS and among them in the same regions. TSPO/Iba1 and F4/80/Prussian blue staining immunohistochemistry suggests that increased activated microglia/macrophages underlay TSPO expression and SPIO uptake in symptomatic EAE mice. CONCLUSIONS: These preliminary results suggest that both activated microglia and infiltrated macrophages are present in vulnerable brain regions during the acute phase of PLP-EAE and contribute to disease severity. Both [18F]DPA-714-PET and SPIO-MRI appear suitable modalities for preclinical study of neuroinflammation in MS mice models.
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