Gorgoraptis N, Li LM, Whittington A, Zimmerman KA, Maclean LM, McLeod C, Ross E, Heslegrave A, Zetterberg H, Passchier J, Matthews PM, Gunn RN, McMillan TM, Sharp DJ. In vivo detection of cerebral tau pathology in long-term survivors of traumatic brain injury. Sci Transl Med. 2019 Sep 4;11(508) PubMed.

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  1. This study has many strengths, including the focus on long-term survivors of “civilian” TBI, a very common public health problem, and the deep phenotyping of individuals with multiple cognitive measures, MRI sequences, and genetic and fluid-based biomarkers.

    That said, significant caution is required in interpreting the biological underpinnings of flortaucipir PET signal as tau-related. The control cohort is small and there can be considerable variability in background flortaucipir signal in healthy controls (see Baker et al., 2019), such that z-scores based on such a small cohort may not be reliable or reproducible. As the authors acknowledge, there are substantial questions regarding the specificity of flortaucipir, with various sources of “off target” binding described and others still poorly understood. The anatomic patterns of binding are atypical, and don’t clearly conform in my opinion to expectations from neuropathology of CTE or acute TBI. Furthermore, though CTE and AD tangles share biochemical and micro-structural features (paired helical filaments, mix of 3R/4R tau), cryo-EM has revealed significant differences in tertiary structure that may affect PET ligand binding (Falcon et al., 2018).  Indeed autoradiography studies thus far have shown absent to low affinity of flortaucipir for CTE pathology in postmortem tissue.

    In summary, these are intriguing but very preliminary findings that need to be replicated in larger cohorts and with postmortem validation.

    References:

    Baker SL, Harrison TM, Maaß A, La Joie R, Jagust W. Effect of off-target binding on 18F-Flortaucipir variability in healthy controls across the lifespan. J Nucl Med. 2019 Mar 15; PubMed.

    Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R, Crowther RA, Ghetti B, Scheres SH, Goedert M. Structures of filaments from Pick's disease reveal a novel tau protein fold. Nature. 2018 Sep;561(7721):137-140. Epub 2018 Aug 29 PubMed.

    View all comments by Gil Rabinovici

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