Abstract
PURPOSE: Off-target binding remains a significant challenge in tau-PET neuroimaging. While off-targets including monoamine oxidase enzymes and neuromelanin-containing cells have been identified, recent studies indicated a relevant binding of novel tau tracers to melanin-containing structures. To date, little is known about the effect of melanocytes in the meninges on tracer signals in brain PET data. Thus, we aimed to identify the target structure causal for the frequently observed [(18)F]PI-2620 PET signal in the vermis and adjacent cerebellar regions. METHODS: 274 participants underwent dynamic [(18)F]PI-2620 tau-PET: 3/4R-tauopathies (n = 85), 4R-tauopathies (n = 147), tau-negative disease controls (n = 24), and healthy controls (n = 18). Standardized uptake value ratio (SUVR) and kinetic parameters including the distribution volume ratio (DVR), tracer clearance (k2) and relative perfusion (R1), were compared among the cohorts and sexes using the Automated Anatomical Labelling (AAL) atlas. Age and p-Tau levels in cerebrospinal fluid (CSF) were assessed for their relationship with vermal tau-PET signal. Furthermore, we combined autoradiographic and histochemical experiments on post-mortem brain tissue of deceased patients (n = 9). RESULTS: Male participants revealed higher mean vermal [(18)F]PI-2620 DVR (0.95 ± 0.13; vs. females 0.88 ± 0.10, p < 0.0001). Sex-related differences were most pronounced in the 3/4R-tauopathy cohort (p < 0.0001). Mean SUVR(Ver/Cbl), k2 and correlation analyses of kinetic parameters did not differ among groups. Histological assessments revealed co-localization of leptomeningeal pigmented cells with strong autoradiography signal spots within the vermal fissures. Tau-related autoradiography signals, age or p-Tau levels did not correlate significantly with tau-PET signals. Iron deposits did not cause relevant autoradiography signals in the vermis. CONCLUSION: Leptomeningeal melanocytes are the primary target structure for [(18)F]PI-2620 PET binding in anterior vermis, whereas iron and tau deposits do not contribute significantly.