Tatiana Rodríguez-Chinchilla1,2, Ana Quiroga-Varela1,2,3, Francisco Molinet-Dronda4, Arantzazu Belloso-Iguerategui1, Leyre Merino-Galan1,5, Haritz Jimenez-Urbieta6, Belén Gago7, María Cruz Rodriguez-Oroz8,9,10,11,12,13. 1. Neuroscience Area, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain. 2. Network Center for Biomedical Research in Neurodegenerative Diseases, CIBERNED, Madrid, Spain. 3. IdiSNA (Navarra Institute for Health Research), Pamplona, Spain. 4. MicroPET Research Unit, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain. 5. University of the Basque Country (UPV/EHU), Leioa, Spain. 6. Neurodegenerative Disorders Area, Biodonostia Health Research Institute, San Sebastian, Spain. 7. Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Universidad de Málaga, Málaga, Spain. 8. Neuroscience Area, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain. mcroroz@unav.es. 9. Network Center for Biomedical Research in Neurodegenerative Diseases, CIBERNED, Madrid, Spain. mcroroz@unav.es. 10. IdiSNA (Navarra Institute for Health Research), Pamplona, Spain. mcroroz@unav.es. 11. Department of Neurology, Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain. mcroroz@unav.es. 12. Ikerbasque (Basque Foundation of Science), Bilbao, Spain. mcroroz@unav.es. 13. Basque Center on Cognition, Brain and Language, San Sebastian, Spain. mcroroz@unav.es.
Abstract
PURPOSE: To study the feasibility of the in vivo [18F]-DPA-714 TSPO positron emission tomography (PET) to detect glial activation in a rat model of progressive parkinsonism induced by viral-mediated overexpression of A53T mutated human α-synuclein (hα-syn) in the substantia nigra pars compacta (SNpc). METHODS: We conducted a cross-sectional study in a model of progressive parkinsonism. Bilateral intranigral injections with 2/9 adeno-associated viral vectors encoding either hα-syn (AAV-hα-syn) or green fluorescent protein (AAV-GFP) were performed in rats (n = 60). In vivo [18F]-DPA-714 PET imaging was performed at different time points after inoculation (p.i.) of the viral vector (24 and 72 h and 1, 2, 3, and 16 weeks). Images were analyzed to compute values of binding potential (BP) in the SNpc and striatum using a volume of interest (VOI) analysis. Immunohistochemistry of markers of dopaminergic degeneration (tyrosine hydroxylase (TH)), microglia (Iba-1), and astrocytes (GFAP) was carried out. Binding potential (BP) of [18F]-DPA-714 PET in the in vivo PET study was correlated with post-mortem histological markers. RESULTS: In the SNpc of AAV-hα-syn rats, there was higher in vivo [18F]-DPA-714 BP (p < 0.05) and increased number of post-mortem Iba-1+ cells (p < 0.05) from second week p.i. onwards, which were highly correlated (p < 0.05) between each other. These findings antedated the nigral reduction of TH+ cells that occurs since third week p.i. (p < 0.01). In addition, the [18F]-DPA-714 BP was inversely correlated (p < 0.05) with the TH+ cells. In contrast, GFAP+ cells only increased at 16 weeks p.i. and did not correlate with the in vivo results. In the striatum, no changes in the number of Iba-1+ and GFAP+ cells were observed, but an increment in the [18F]-DPA-714 BP was found at 16 weeks p.i. CONCLUSIONS: Our study showed that in vivo PET study with [18F]-DPA-714 is a selective and reliable biomarker of microglial activation and could be used to study preclinical stages of Parkinson's disease (PD) and to monitor the progression of the disease.
PURPOSE: To study the feasibility of the in vivo [18F]-DPA-714 TSPO positron emission tomography (PET) to detect glial activation in a rat model of progressive parkinsonism induced by viral-mediated overexpression of A53T mutated human α-synuclein (hα-syn) in the substantia nigra pars compacta (SNpc). METHODS: We conducted a cross-sectional study in a model of progressive parkinsonism. Bilateral intranigral injections with 2/9 adeno-associated viral vectors encoding either hα-syn (AAV-hα-syn) or green fluorescent protein (AAV-GFP) were performed in rats (n = 60). In vivo [18F]-DPA-714 PET imaging was performed at different time points after inoculation (p.i.) of the viral vector (24 and 72 h and 1, 2, 3, and 16 weeks). Images were analyzed to compute values of binding potential (BP) in the SNpc and striatum using a volume of interest (VOI) analysis. Immunohistochemistry of markers of dopaminergic degeneration (tyrosine hydroxylase (TH)), microglia (Iba-1), and astrocytes (GFAP) was carried out. Binding potential (BP) of [18F]-DPA-714 PET in the in vivo PET study was correlated with post-mortem histological markers. RESULTS: In the SNpc of AAV-hα-syn rats, there was higher in vivo [18F]-DPA-714 BP (p < 0.05) and increased number of post-mortem Iba-1+ cells (p < 0.05) from second week p.i. onwards, which were highly correlated (p < 0.05) between each other. These findings antedated the nigral reduction of TH+ cells that occurs since third week p.i. (p < 0.01). In addition, the [18F]-DPA-714 BP was inversely correlated (p < 0.05) with the TH+ cells. In contrast, GFAP+ cells only increased at 16 weeks p.i. and did not correlate with the in vivo results. In the striatum, no changes in the number of Iba-1+ and GFAP+ cells were observed, but an increment in the [18F]-DPA-714 BP was found at 16 weeks p.i. CONCLUSIONS: Our study showed that in vivo PET study with [18F]-DPA-714 is a selective and reliable biomarker of microglial activation and could be used to study preclinical stages of Parkinson's disease (PD) and to monitor the progression of the disease.
Authors: A L Bartels; A T M Willemsen; J Doorduin; E F J de Vries; R A Dierckx; K L Leenders Journal: Parkinsonism Relat Disord Date: 2009-05-31 Impact factor: 4.891
Authors: Alexander Gerhard; Nicola Pavese; Gary Hotton; Federico Turkheimer; Meltem Es; Alexander Hammers; Karla Eggert; Wolfgang Oertel; Richard B Banati; David J Brooks Journal: Neurobiol Dis Date: 2005-09-21 Impact factor: 5.996
Authors: Fillipe Mendes De Araújo; Annyta Fernandes Frota; Lívia Bacelar de Jesus; Ticiane Caribe Macedo; Lorena Cuenca-Bermejo; Consuelo Sanchez-Rodrigo; Kariny Maria Silva Ferreira; Juciele Valéria Ribeiro de Oliveira; Maria de Fatima Dias Costa; Juan Segura-Aguilar; Silvia Lima Costa; Maria Trinidad Herrero; Victor Diógenes Amaral Silva Journal: Cell Mol Neurobiol Date: 2022-01-06 Impact factor: 5.046
Authors: Omkar L Patkar; Abdalla Z Mohamed; Ashwin Narayanan; Karine Mardon; Gary Cowin; Rajiv Bhalla; Damion H R Stimson; Michael Kassiou; Kate Beecher; Arnauld Belmer; Ignatius Alvarez Cooper; Michael Morgan; David A Hume; Katharine M Irvine; Selena E Bartlett; Fatima Nasrallah; Paul Cumming Journal: Sci Rep Date: 2021-05-27 Impact factor: 4.379
Authors: Kathrine Stokholm; Majken Borup Thomsen; Jenny-Ann Phan; Line K Møller; Cecilie Bay-Richter; Søren H Christiansen; David P D Woldbye; Marina Romero-Ramos; Anne M Landau Journal: Biomedicines Date: 2021-12-10