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[18F]-DPA-714 PET as a specific in vivo marker of early microglial activation in a rat model of progressive dopaminergic degeneration

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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.

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Acknowledgments

The authors wish to thank the Molecular Imaging Unit and Animal Facility staff of CIC biomaGUNE for their excellent work in the radiotracer production and image acquisition. The imaging work was carried out at the Unique Scientific and Technical Infrastructure (ICTS) ReDIB.

Funding

This study was funded by the CIBERNED (INTRACIBER 2014/06). In addition, TR-C and AQ-V were funded by CIBERNED funds. TR-C held a Fundación Jesús de Gangoiti Barrera Foundation grant (Bilbao, Spain). HJ-U and AB-I holds a Predoctoral Research Fellowship from the Government of the Basque Country. LM-G holds a Predoctoral Research Fellowship from the Basque Country University (UPV/EHU).

Author information

Author notes

  1. Tatiana Rodríguez-Chinchilla and Ana Quiroga-Varela contributed equally to this work.

Authors and Affiliations

  1. Neuroscience Area, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain

    Tatiana Rodríguez-Chinchilla, Ana Quiroga-Varela, Arantzazu Belloso-Iguerategui, Leyre Merino-Galan & María Cruz Rodriguez-Oroz

  2. Network Center for Biomedical Research in Neurodegenerative Diseases, CIBERNED, Madrid, Spain

    Tatiana Rodríguez-Chinchilla, Ana Quiroga-Varela & María Cruz Rodriguez-Oroz

  3. IdiSNA (Navarra Institute for Health Research), Pamplona, Spain

    Ana Quiroga-Varela & María Cruz Rodriguez-Oroz

  4. MicroPET Research Unit, Center for Applied Medical Research, Universidad de Navarra, Pamplona, Spain

    Francisco Molinet-Dronda

  5. University of the Basque Country (UPV/EHU), Leioa, Spain

    Leyre Merino-Galan

  6. Neurodegenerative Disorders Area, Biodonostia Health Research Institute, San Sebastian, Spain

    Haritz Jimenez-Urbieta

  7. Instituto de Investigación Biomédica de Málaga, Facultad de Medicina, Universidad de Málaga, Málaga, Spain

    Belén Gago

  8. Department of Neurology, Clínica Universidad de Navarra, Universidad de Navarra, Pamplona, Spain

    María Cruz Rodriguez-Oroz

  9. Ikerbasque (Basque Foundation of Science), Bilbao, Spain

    María Cruz Rodriguez-Oroz

  10. Basque Center on Cognition, Brain and Language, San Sebastian, Spain

    María Cruz Rodriguez-Oroz

Authors
  1. Tatiana Rodríguez-Chinchilla
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  2. Ana Quiroga-Varela
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Contributions

MCR-O, AQ-V, and BG contributed to the study conception and design. Animal model and data collection were performed by TR-C and AQ-V. PET image analyses were performed by FM-D. Histological study was performed by TR-C, and AB-I and MCR-O. supervised all the study. TR-C, AQ-V and FM-D performed the statistical analysis. AQ-V and MCR-O interpreted the results of the analysis with substantial contribution from all the authors; TR-C, AQ-V, and MCR-O drafted the manuscript, to which all the authors contributed with revisions in the previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to María Cruz Rodriguez-Oroz.

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Conflict of interest

TR-C, AQ-V, FM-D, AB-I, LM-G, HJ-U, and BG have no disclosures to declare. MCR-O received honoraria for lectures, travel, and accommodation to attend scientific meetings from Abbvie, Bial, and Boston Scientific, and she received financial support for her research from national and local government funding agencies in Spain (Institute of Health Carlos III, Basque Country Local Government, and CIBERNED). None of these bodies influenced the content of the manuscript or the decision to publish in any way.

Ethical approval

All the procedures for the care and use of animals were approved by the ethics committees for animal research at Biodonostia Health Research Institute, CIC biomaGUNE (San Sebastián, Spain) and local authorities and were conducted in accordance with the guidelines of the Spanish Government (RD53/2013) and the European Union Council Directive (2010/63/EU) on animal ethics and welfare.

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Rodríguez-Chinchilla, T., Quiroga-Varela, A., Molinet-Dronda, F. et al. [18F]-DPA-714 PET as a specific in vivo marker of early microglial activation in a rat model of progressive dopaminergic degeneration. Eur J Nucl Med Mol Imaging 47, 2602–2612 (2020). https://doi.org/10.1007/s00259-020-04772-4

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