Evaluation of Tau Radiotracers in Chronic Traumatic Encephalopathy

• Published in: Journal of Nuclear Medicine Vol. 64; no. 3; pp. 460 - 465
• Main Authors: Varlow, Cassis, Vasdev, Neil
• Format: Journal Article
• Language: English
• Published: United States Society of Nuclear Medicine 01.03.2023
• Subjects: Alzheimer Disease - diagnostic imaging; Alzheimer's disease; Amine oxidase (flavin-containing); Amyloid beta-Peptides; Antibodies; Autopsies; Autopsy; Autoradiography; Basic Science Investigation; Binding; Brain; Brain Injuries; Brain injury; Chronic traumatic encephalopathy; Chronic Traumatic Encephalopathy - diagnostic imaging; Displacement; Evaluation; Head injuries; Homology; Humans; Immunohistochemistry; Medical imaging; Neurodegenerative diseases; Neuroimaging; Pathology; Positron emission; Positron emission tomography; Radioactive tracers; Tau protein; tau Proteins; Traumatic brain injury; β-Amyloid; traumatic brain injury; tau; autoradiography; chronic traumatic encephalopathy; CTE; PET
• ISSN: 0161-5505; 1535-5667; 2159-662X; 1535-5667
• DOI: 10.2967/jnumed.122.264404

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. Autoradiography was used to assess the specific binding and distribution of H-flortaucipir (also known as Tauvid, AV-1451, and T807), H-MK-6240 (also known as florquinitau), H-PI-2620, H-APN-1607 (also known as PM-PBB3 and florzolotau), and H-CBD-2115 (also known as H-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 H-flortaucipir in tissue sections. H-flortaucipir demonstrated a positive signal in all CTE cases examined, with varying degrees of specific binding (68.7% ± 10.5%; = 12) defined by homologous blockade and to a lesser extent by heterologous blockade with MK-6240 (27.3% ± 13.6%; = 12). The H-flortaucipir signal was also displaced by the monoamine oxidase (MAO)-A inhibitor clorgyline (43.9% ± 4.6%; = 3), indicating off-target binding to MAO-A. H-APN-1607 was moderately displaced in homologous blocking studies and was not displaced by H-flortaucipir; however, substantial displacement was observed when blocking with the β-amyloid-targeting compound NAV-4694. H-MK-6240 and H-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. H-CBD-2115 showed moderate binding, displaced under homologous blockade, and aligned with 4R-tau immunostaining. In human CTE tissues, H-flortaucipir and H-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. H-MK-6240 and H-PI-2620 bind to CTE tau in severe- or mixed-pathology cases, and their respective F PET radiotracers warrant further evaluation in patients with severe suspected CTE.