Hypermetabolism in cerebellar 18F-FDG PET relate to microglial activation in mesial temporal lobe epilepsy

Introduction: Cerebellum is a crucial subcortical structure involved in epileptic network. Our previous study has found increased glucose metabolism in bilateral cerebellum among patients with mesial temporal lobe epilepsy (mTLE). However, the underlying pathophysiological mechanism remains unclear. This study aimed to explore the potential mechanism for abnormal cerebellar metabolism in mTLE, providing deeper insights into the pathophysiology of disease and helping search new drug targets for better management of mTLE.

Methods: Twenty-one patients with mTLE and 21 sex-and age-matched healthy controls who underwent fluorine-18-fluorodeoxyglucose positron emission tomography (¹⁸F-FDG PET) were enrolled in our study. Regional cerebral metabolic patterns were analyzed using statistical parametric mapping. Then lithium-pilocarpine mTLE rat model was subjected to ¹⁸F-FDG and ¹⁸F-DPA-714 micro-PET imaging in the acute phase (1day post status epilepticus [SE]), latent phase (14 days post SE), and chronic phase (60 days post SE), volume-of-interest-based analysis of comparing mTLE rat model to control animals was performed with the PMOD imaging processing software. Immunohistochemistry and Western blotting were conducted to investigate the expression of glucose transporters, the loss of neurons and glial cells in cerebellum. Flow cytometry and Luminex were applied to verify cerebellar microglial activation and immunizing inflammatory reaction.

Results: Compared to healthy controls, mTLE patients showed hypermetabolism in the bilateral cerebellum, occipital lobes, lingual gyrus and fusiform gyrus in addition to hypometabolism in temporal lobe. In the rat model with mTLE, increased ¹⁸F-FDG uptake of cerebellum was confirmed in chronic phase. We observed the loss of Purkinje cell without a significant decrease of Neun-expressing neurons, and the expression of glucose transporter-1 (Expressed in microglia) increased while there was no change of the glucose transporter-3 (Expressed in neurons) in the cerebellum, indicating that hypermetabolism in the cerebellum is not associated with increased glucose uptake in Purkinje cell and neurons. Compare to control animals, the immunofluorescence and Western blotting results showed that not only the number of microglia increased, but also the cell body of microglia increased and dendrites decreased in morphology in the chronic stage, there was no significant changes for astrocytes in cerebellum. Meanwhile, we further found that the M1 phenotype microglia marker CD32 was upregulated, and M2 phenotype microglia marker CD163 was downregulated accompanied with increased inflammatory factors (IL-6, IL-12, TNF-α, INF-γ, IL-12) in the cerebellum of mTLE rat model. Consistently, we verified that the cerebellumuptake of ¹⁸F-DAP-714 was significantly increased in the chronic phase mTLE rat model.

Conclusions: Patients with mTLE exhibit hypermetabolism in the bilateral cerebellum, which was also confirmed in the chronic phase of rat model with mTLE. Increased cerebellar glucose metabolism may associate with activation of M1 microglias and immunity inflammation. The study findings support the network theory for epilepsy pathogenesis and help to develop potential interventions for cerebral remote damage among patients with mTLE.

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