In vivo imaging of CNS microglial activation/macrophage infiltration with combined [18F]DPA-714-PET and SPIO-MRI in a mouse model of relapsing remitting experimental autoimmune encephalomyelitis

  • Eur J Nucl Med Mol Imaging. 2021 Jan;48(1):40-52. doi: 10.1007/s00259-020-04842-7.
A R Coda  #  1 ,  S Anzilotti  #  2 ,  F Boscia  3 ,  A Greco  4  5 ,  M Panico  1 ,  S Gargiulo  1 ,  M Gramanzini  1 ,  A Zannetti  1 ,  S Albanese  1 ,  G Pignataro  3 ,  L Annunziato  2 ,  M Salvatore  2 ,  A Brunetti  4 ,  P De Berardinis  6 ,  Mario Quarantelli  7 ,  G Palma  1 ,  Sabina Pappatà  8
Affiliations
  • 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. [email protected].
  • 8. Institute of Biostructure and Bioimaging, National Research Council, Via T. De Amicis 95, 80145, Naples, Italy. [email protected].
  • # Contributed equally.
PMID: 32378022 DOI: 10.1007/s00259-020-04842-7
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.

Keywords
EAE; Mice; Multiple sclerosis; Neuroinflammation; SPIO-MRI; TSPO-PET.
Products