Longitudinal P2X7R and myelin PET reveal distinct neuroinflammatory and white matter signatures compared with TSPO PET and DTI-MRI in the TgF344-AD rat model

Emerging evidence links glial activation, particularly microglia, to Alzheimer's disease (AD) progression. While TSPO PET (positron emission tomography) imaging detects neuroinflammation, its limitations drive interest in alternative targets like the P2X7 receptor. Myelin loss, potentially tied to chronic inflammation, is increasingly recognized as a key hallmark in AD, though the timing and relationship between neuroinflammation and demyelination remain poorly understood. We conducted a longitudinal PET study from 4 to 22 months of age in TgF344-AD rats and wild-type controls to assess neuroinflammation with [¹⁸F]JNJ-64413739 (P2X7R) and [¹⁸F]DPA-714 (TSPO) only at 22 months, alongside myelin content using [¹⁸F]Florbetaben. Diffusion tensor imaging (DTI) was used to study variations on myelin structure in old AD and WT rats. In vitro studies, including autoradiography, immunofluorescence and staining were used to support the in vivo results. [¹⁸F]JNJ-64413739 PET showed increased P2X7 receptor expression in AD and control animals over time, while [¹⁸F]DPA-714 PET showed significant differences between groups at 22 months. [¹⁸F]Florbetaben PET showed different uptake in white matter rich areas between groups with observed demyelination in AD rats at 20 months in the brain stem, supported by diffusional MRI findings. In our study, P2X7R overexpression was attributed to aging rather than genotype effects, and no link was found to the observed demyelination in AD rats. Conversely, increased TSPO neuroinflammation in TgF344-AD rats correlated with myelin loss and the reported cognitive decline in this model. Our results support the use of the TgF344-AD model to study early AD pathology, focusing on neuroinflammation and white matter integrity.