Neuropathological perspectives on neuroinflammation and tau molecular imaging in frontotemporal lobar degeneration

Flortaucipir (FTP) PET imaging was developed to quantify tau burden in tauopathies such as Alzheimer’s disease (AD) and to distinguish AD from other dementias, including frontotemporal lobar degeneration (FTLD). In FTLD-tau, FTP uptake in subcortical regions is often considered off-target binding. However, tau aggregation has been associated with neuroinflammation and oxidative stress. This study investigates whether FTP uptake in FTLD-tau overlaps with neuroinflammatory and iron-related oxidative markers. We analyzed postmortem brain samples from eight individuals: two controls, one intermediate-likelihood AD (I-AD), one high-likelihood AD (H-AD), and four FTLD-tau subtypes; progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), globular glial tauopathy (GGT), and Pick’s disease (PiD). We performed fluorescence FTP analog (T726) and staining targeting neuroinflammatory markers (GFAP, IBA1, CD68), and iron via ferritin light-chain (Ferr). Samples were taken from the superior/middle frontal gyri (S/M-FG) and basal ganglia (BG), including the putamen (Pu), globus pallidus externus (GPe), and internus (GPi). FTP binding was assessed using a fluorescent analog (T726) and confocal imaging, with comparisons to premortem PET scans. We observed increased activation of GFAP+ astrocytes and microglia/macrophages in both cortical and subcortical regions, with tau deposition detected in AD and FTLD-tau cases. Distinct neuroinflammatory patterns emerged across FTLD-tau subtypes, notably in PSP and CBD. Colocalization of GFAP+, IBA1, CD68, Ferr, and T726 signals suggest that FTP uptake in FTLD-tau may reflect gliosis and neuroinflammation. These findings indicate that neuroinflammation, gliosis, and possibly oxidative stress may contribute to elevated FTP signals in FTLD-tau, offering insight into the biological underpinnings of tracer uptake beyond tau pathology.