Reichard, R. Ross

Abstract INTRODUCTION Globular glial tauopathy (GGT) is a rare type of frontotemporal lobar degeneration (FTLD) characterized by deposition of 4‐repeat tau. Detecting GGT with tau positron emission tomography (tau‐PET) is challenging. We aim to determine the associations between tau‐PET, autoradiography, and neuropathology methods in GGT. METHODS We identified three patients with GGT who had completed antemortem tau‐PET. Healthy control and two patients with Alzheimer's disease (AD) were also included for comparison. We analyzed gray matter (GM) and white matter (WM) from the superior/middle frontal gyrus (S/M‐FG) and the superior/middle temporal gyrus (S/M‐TG). Immunohistochemical staining was performed with antibodies against phospho‐tau (AT8, PHF‐1, RD4), glial fibrillary acidic protein (GFAP), and resting microglia (ionized calcium‐binding adaptor molecule 1; Iba1). Immunofluorescence with a fluorescent tau‐PET analog (T726) was performed. Regional tau‐PET standardized uptake value ratios (SUVRs) were calculated for comparative GM and WM regions. Autoradiographic studies with 18F‐AV1451 were also conducted. RESULTS Tau‐PET showed increased uptake in the WM regions of the S/M‐FG and S/M‐TG in GGT, and the GM regions in AD. Co‐localization was observed between T726 and PHF‐1, RD4, and GFAP in the WM in the patients with GGT, whereas co‐localization was observed with PHF‐1 predominantly in the GM in AD. Little co‐localization was observed with Iba1. In vitro 18F‐AV1451 autoradiography studies demonstrated minimal binding in GGT. Tau‐PET differentiated underlying GGT from AD based on the relative involvement of the WM and GM. CONCLUSION Histopathologic findings suggest that some flortaucipir uptake in GGT may represent underlying 4R tau, whereas autoradiographic analysis suggests that uptake is likely due to off‐target binding. Further studies with larger cohorts are needed to determine the pathological basis of flortaucipir uptake in GGT.