Abstract
PurposeTo 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.MethodsExperimental 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.ResultsSUVR 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.ConclusionsThese 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.
Highlights
Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease mainly characterized neuropathologically by inflammation, gliosis, demyelinating plaques, and axonal and/or neuronal loss [1]
SUVR and superparamagnetic iron oxide particles (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 SPIOVol was significantly increased in the caudate/putamen (p < 0.05)
Both SUVR and SPIO-Vol values were positively significantly correlated with clinical score (CS) and among them in the same regions
Summary
Multiple sclerosis (MS) is a chronic neuroinflammatory and neurodegenerative disease mainly characterized neuropathologically by inflammation, gliosis, demyelinating plaques, and axonal and/or neuronal loss [1]. Monocytederived macrophages and activated central nervous system (CNS)-resident microglia contribute to pathology of MS [2], their role in neuronal/axonal loss, the main underlying mechanism of permanent clinical disability in MS, is still controversial [1]. PET using selective radioligands for the 18-kDa translocator protein (TSPO) has demonstrated increased activated microglia in apparently normal as well as abnormal brain tissue of MS patients [4]. In the CNS, TSPO is mainly expressed by activated microglia and, to a lower extent, by astrocytes and other cell types [4, 6] including infiltrating macrophages [6] and endothelial cells [7] depending on the neuronal insult, blood-brain barrier (BBB) integrity, and temporal profile
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