¹⁸F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy

Molecular biomarkers of chronic traumatic encephalopathy (CTE) are lacking. We evaluated ¹⁸F-MK-6240 tau PET as a biomarker for CTE. Two studies were done: (1) ³H-MK-6240 autoradiography and an in-vitro brain homogenate binding studies on postmortem CTE tissue, (2) an in-vivo ¹⁸F-MK-6240 tau PET study in former American football players.

Autoradiography and in-vitro binding studies were done using ³H-MK-6240 on frozen temporal and frontal cortex tissue from six autopsy cases with stage III CTE compared to Alzheimer's disease. Thirty male former National Football League (NFL) players with cognitive concerns (mean age = 58.9, SD = 7.8) completed tau (¹⁸F-MK-6240) and Aβ (¹⁸F-Florbetapir) PET. Controls included 39 Aβ-PET negative, cognitively normal males (mean age = 65.7, SD = 6.3). ¹⁸F-MK-6240 SUVr images were created using 70-90 min post-injection data with inferior cerebellar gray matter as the reference. We compared SUVr between players and controls using voxelwise and region-of-interest approaches. Correlations between ¹⁸F-MK-6240 SUVr and cognitive scores were tested.

All six CTE stage III cases had Braak NFT stage III but no neuritic plaques. Two had Thal Phase 1 for Aβ; one showed a laminar pattern of ³H-MK-6240 autoradiography binding in the superior temporal cortex and less so in the dorsolateral frontal cortex, corresponding to tau-immunoreactive lesions detected using the AT8 antibody (pSer202/pThr205 tau) in adjacent tissue sections. The other CTE cases had low frequencies of cortical tau-immunoreactive deposits and no well-defined autoradiography binding. In-vitro ³H-MK-6240 binding studies to CTE brain homogenates in the case with autoradiography signal indicated high binding affinity (K_D = 2.0 ± 0.9 nM, B_max = 97 ± 24 nM, n = 3). All NFL players had negative Aβ-PET. There was variable, low-to-intermediate intensity ¹⁸F-MK-6240 uptake across participants: 16 had no cortical signal, 7 had medial temporal lobe (MTL) uptake, 2 had frontal uptake, and 4 had MTL and frontal uptake. NFL players had higher SUVr in the entorhinal cortex (d = 0.86, p = 0.001), and the parahippocampal gyrus (d = 0.39, p = 0.08). Voxelwise regressions showed increased uptake in NFL players in two bilateral anterior MTL clusters (p < 0.05 FWE). Higher parahippocampal and frontal-temporal SUVrs correlated with worse memory (r = -0.38, r = -0.40) and semantic fluency (r = -0.38, r = -0.48), respectively.

We present evidence of ³H-MK-6240 in-vitro binding to post-mortem CTE tissue homogenates and in vivo ¹⁸F-MK-6240 PET binding in the MTL among a subset of participants. Additional studies in larger samples and PET-to-autopsy correlations are required to further elucidate the potential of ¹⁸F-MK-6240 to detect tau pathology in CTE.