Background <p>Anti-IgLON5 disease is a rare autoimmune neurological disorder with prominent Tau protein deposits in the brainstem and hypothalamus. The aim of this study was to visualize the in vivo distribution patterns of Tau protein in patients with anti-IgLON5 disease using the second-generation Tau PET tracer, Florzolotau (18F) PET imaging.</p> Methods <p>Patients diagnosed with anti-IgLON5 disease were enrolled consecutively. Age- and sex-matched healthy controls (HCs) were also enrolled. The uptake of Florzolotau (18F) and ¹⁸F-FDG was assessed using both visual and semi-quantitative analysis techniques.</p> Results <p>A total of 10 patients with anti-IgLON5 disease and 40 HCs were included in the study. All ten patients with anti-IgLON5 disease underwent Florzolotau (18F) PET scans, and five of them underwent ¹⁸F-FDG PET scans. Twenty HCs underwent Florzolotau (18F) PET scans, and the remaining 20 HCs underwent ¹⁸F-FDG PET scans. In patients with anti-IgLON5 disease, significant uptake of Florzolotau (18F) was observed predominantly in the midbrain, pons, cerebellum, caudate, and putamen. This uptake pattern was notably absent in the control group. Moreover, semi-quantitative analysis techniques demonstrated widespread hypometabolism in the cerebral cortex in patients with anti-IgLON5 disease.</p> Conclusions <p>This study indicates distinct Tau protein deposition patterns in patients with anti-IgLON5 disease, potentially serving as imaging biomarkers.</p>