Tau Biomarkers for Long-Term Effects of Neurotrauma: Technology Versus the Null Hypothesis

The broadly accepted concept that neurotrauma causes progressive neurodegenerative proteinopathy originated in boxers of the late nineteenth and early twentieth centuries. The protracted and extensive neurotrauma in this era was unprecedented and led to an enigmatic condition known as punch drunk. As medical science struggled to understand the precise nature of the neurological deficits in punch drunk boxers, a limited number of neuropathological studies identified, among other things, neurofibrillary pathology, now understood as an accumulation of phosphorylated tau. The apparent overlap with Alzheimer's disease pathology led to the hypothesis that punch drunk syndrome was neurodegenerative in nature. A careful appraisal of the historic case material, however, argues against a neurodegenerative disease and in favor of a largely stationary condition caused by traumatic brain injury. Moreover, a number of large-scale epidemiological studies have failed to identify a causal link between neurotrauma and neurodegenerative disease, and in aggregate argue against such a link. The neurotrauma-neurodegenerative proteinopathy hypothesis continues to be pursued nevertheless with sophisticated technology, including highly sensitive biomarker analyses for various tau protein species or tau surrogates. CSF and plasma studies for phosphorylated tau and total tau have so far shown marginal differences between neurotrauma exposure and control, with unclear clinical significance. PET scan data looking at putative tau ligands have also shown differences between neurotrauma and control in cross sectional designs, again with unclear clinical significance. While studies will continue and more data will likely be assembled, it may be important to consider that the null hypothesis, that is, that neurotrauma does not lead to neurodegenerative proteinopathy, remains applicable. This may help guide the interpretation of biomarker studies and provide avenues for novel studies, including therapeutic constructs unrelated to tau.