Evaluation of Tau Radiotracers in Chronic Traumatic Encephalopathy

Abstract

Chronic traumatic encephalopathy (CTE) is a neurologic disorder associated with head injuries, diagnosed by the perivascular accumulation of hyperphosphorylated tau protein (phospho-tau) identified at autopsy. Tau PET radiopharmaceuticals developed for imaging Alzheimer disease are under evaluation for brain injuries. The goal of this study was to conduct a head-to-head in vitro evaluation of 5 tau PET radiotracers in subjects pathologically diagnosed with CTE. Methods: Autoradiography was used to assess the specific binding and distribution of ³H-flortaucipir (also known as Tauvid, AV-1451, and T807), ³H-MK-6240 (also known as florquinitau), ³H-PI-2620, ³H-APN-1607 (also known as PM-PBB3 and florzolotau), and ³H-CBD-2115 (also known as ³H-OXD-2115) in fresh-frozen human postmortem CTE brain tissue (stages I-IV). Immunohistochemistry was performed for phospho-tau with AT8, 3R tau with RD3, 4R tau with RD4 and amyloid-β with 6F/3D antibodies. Tau target density (maximum specific binding) was quantified by saturation analysis with ³H-flortaucipir in tissue sections. Results: ³H-flortaucipir demonstrated a positive signal in all CTE cases examined, with varying degrees of specific binding (68.7% ± 10.5%; n = 12) defined by homologous blockade and to a lesser extent by heterologous blockade with MK-6240 (27.3% ± 13.6%; n = 12). The ³H-flortaucipir signal was also displaced by the monoamine oxidase (MAO)-A inhibitor clorgyline (43.9% ± 4.6%; n = 3), indicating off-target binding to MAO-A. ³H-APN-1607 was moderately displaced in homologous blocking studies and was not displaced by ³H-flortaucipir; however, substantial displacement was observed when blocking with the β-amyloid-targeting compound NAV-4694. ³H-MK-6240 and ³H-PI-2620 had negligible binding in all but 2 CTE IV cases, and binding may be attributed to pathology severity or mixed Alzheimer disease/CTE pathology. ³H-CBD-2115 showed moderate binding, displaced under homologous blockade, and aligned with 4R-tau immunostaining. Conclusion: In human CTE tissues, ³H-flortaucipir and ³H-APN-1607 revealed off-target binding to MAO-A and amyloid-β, respectively, and should be considered if these radiotracers are used in PET imaging studies of patients with brain injuries. ³H-MK-6240 and ³H-PI-2620 bind to CTE tau in severe- or mixed-pathology cases, and their respective ¹⁸F PET radiotracers warrant further evaluation in patients with severe suspected CTE.

Keywords: CTE; PET; autoradiography; chronic traumatic encephalopathy; tau; traumatic brain injury.