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

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 [ 18 F]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 PLP 139–151 . 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 [ 18 F]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. [ 18 F]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 [ 18 F]DPA-714-PET and SPIO-MRI appear suitable modalities for preclinical study of neuroinflammation in MS mice models.

TSPO imaging in animal models of brain diseases

“…The in vivo PET data were confirmed by IHC, demonstrating that TSPO expression was limited to microglial cells while astrocytes were TSPO negative. Additionally, Nack et al [190] reported that TSPO + cells were microglia following cuprizone treatment and that supplementing Cuprizone with MOG 35-55 peptide immunization drove the recruitment of TSPO + monocytes in the lesion contributing to the overall PET signal on top of resident activated microglia; these results are in agreement with a more recent study with [ 18 F]DPA714 [194]. Interestingly, Zinnhardt et al [193] showed using [ 18 F]DPA714 that during demyelination TSPO + cells consisted only of microglia, while during remyelination, astrocytes also became TSPO + .…”

“…Various studies investigated the neuroinflammatory profile of different models of MS (EAE or WM lesion) using [ 18 F]PBR111 [188], [ 18 F]VC701 [189], [ 18 F]GE-180 [190][191][192] or [ 18 F]DPA-714 [193,194] PET tracers. Overall, TSPO imaging studies in MS models consistently reported a moderate to large increase in TSPO tracer uptake in the affected brain regions.…”

Imaging the Neuroimmune Dynamics Across Space and Time

“…Ultimately, correlative [18F]DPA-714-PET and MRI-USPIOs together with confocal imaging allowed to investigate microglia/macrophage properties in an experimental autoimmune encephalomyelitis mouse model of multiple sclerosis. This work showed that microglia/macrophages upregulate TSPO and IBA1 in the demyelinating regions during acute phases, suggesting their dysfunction as a contributing factor to the inflammation seen in multiple sclerosis (Coda et al, 2020).…”

Radiation Pneumonitis in Thoracic Cancer Patients: Multi-Center Voxel-Based Analysis

“…In principle, VBA techniques can be formally applied, in a similar way, to both functional imaging and dosimetric datasets; however, there is a substantial difference between the two fields that warrants caution during result interpretation. Indeed, in functional imaging, VBA can identify the metabolic patterns that depend only on the investigated pathophysiology, at least as long as the chosen image contrast, which is usually given by the contrast medium in nuclear medicine and by the pulse sequence in MRI, allows for an effective representation of the underlying functional mechanisms [33,34]. In radiation oncology, on the contrary, VBA can identify those dose patterns that not only depend on the regional radiosensitivity, but are also within the reach of the intrinsic heterogeneity of the dose distributions included in the analyzed dataset.…”