Dynamic regional divergence of SV2A expression in a mouse model of primary tauopathy: A longitudinal multi-tracer PET study.

Abstract

In tauopathies, tau accumulation and neuroinflammation are associated with progressive synaptic and network alterations that contribute to neurodegeneration. We used 8 PS19 and 12 C57Bl/6 (WT) mice undergoing consecutive [F]UCB-H PET scans between 5.7 and 11.0 months of age to longitudinally evaluate SV2A expression levels, with terminal validation via immunohistochemistry. A desynchronization index (DI) quantified deviation from a reference-derived inter-regional SV2A expression pattern from whole-brain SV2A-PET data, and principal component analysis (PCA) further summarized these regional deviation profiles. Baseline translocator protein (TSPO, [F]GE-180) and monoamine oxidase B (MAO-B, [F]F-DED) imaging for activated microglia and reactive astrogliosis were performed to detect early neuroinflammation, which was subsequently correlated with serial SV2A expression, evaluated by the area under the curve (AUC) of [F]UCB-H z-scores (PS19 vs. WT). We observed phased SV2A expression alterations in PS19 mice in the neocortex, hippocampus CA1, brainstem, thalamus, hypothalamus, and cerebellum, showing an increasing trend from 8.4 to 10.0 months of age (+8.1% ± 3.0%), followed by a rapid decline towards 11.0 months of age (-18.4% ± 4.7%), together with greater later-stage inter-regional SV2A expression pattern deviation. Tau burden tended to show a broadly negative association with SV2A expression levels across primary and exploratory regions. Associations of SV2A-PET signal variation with early microglial activation and reactive astrogliosis differed between PS19 and WT mice. In summary, these findings suggest that longitudinal [F]UCB-H PET may provide a feasible approach for tracking stage-dependent regional SV2A expression alterations and inter-regional deviation in this mouse model of primary tauopathy.