. Tau Positron-Emission Tomography in Former National Football League Players. N Engl J Med. 2019 Apr 10; PubMed.

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  1. Developing in vivo biomarkers of CTE is absolutely critical for efforts to understand basic questions about disease prevalence, mechanisms, susceptibility and resilience factors, and ultimately for drug development. This paper by Stern and colleagues represents a significant advance by providing proof of concept that detecting tau pathology in CTE may be possible using PET imaging.

    However, the overall degree of flortaucipir binding was modest, solidly in the range of controls in some at-risk former NFL players, and even in the “high binders” their SUVR values were lower than we typically see in symptomatic patients with AD. It is not clear whether the overall modest binding is due to absent or low tau burden in the players, or to a lack of sensitivity of this tracer to detect the tau lesions in CTE. We know from the recent cryo-EM study (Falcon et al. 2019) and other work that tau lesions in CTE are microstructurally distinct from neurofibrillary tangles in AD, and this certainly may affect the affinity of a PET tracer to bind to the aggregates.

    Another concern in interpreting the data is the lack of specificity of flortaucipir, which we know binds with low affinity to targets other than tau. It will be interesting to see how second-generation tau tracers, such as MK6240, perform in this population. Overall, this is an encouraging first step, but I agree with the authors that tau PET is not yet ready for “prime time” as a diagnostic agent in CTE.

    References:

    . Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature. 2019 Apr;568(7752):420-423. Epub 2019 Mar 20 PubMed.

    View all comments by Gil Rabinovici
  2. This is a welcome and carefully written paper. It is the first good evidence that tau imaging can detect a signal in chronic traumatic encephalopathy, but the authors make very clear that this is a long way off from being a useful diagnostic test for individuals suspected of having the disease. The areas of tau tracer uptake in the group with clinically suspected CTE in the dorsal prefrontal and medial temporal cortex match well with the areas of highest tau density in stage 3 or greater stages of CTE as described at postmortem by McKee et al., 2013.

    The results are therefore encouraging and justify support for independent replication studies. Postmortem confirmation is needed to assess if the large overlap with controls and lack of correlation with cognition or other clinical features is due to absence of CTE in some of the symptomatic patients. This is highly likely given the nonspecific nature of the mood, cognition and behavioural features used for clinical diagnosis of CTE. Alternatively, a better tracer with higher affinity for tau and lower nonspecific background may be needed before tau PET can be used to assist the diagnosis of this condition.  

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    References:

    . The spectrum of disease in chronic traumatic encephalopathy. Brain. 2013 Jan;136(Pt 1):43-64. PubMed.

    View all comments by Christopher Rowe
  3. This is a very interesting and important study. For the first time, it is convincingly shown (at the group level) that former National Fotboll League players, with cognitive and behavioral symptoms, have increased tau PET ligand retention in several cortical brain areas, know to be affected by tau pathology in postmortem CTE case series.

    These data are of particular interest, since they support that the acute damage to brain cell structures (e.g., neuronal axons, glial cells, or capillaries) induced by repeated concussions initiates pathophysiological processes driving tau aggregation in the cerebral cortex. While no associations were found with neuropsychological test scores, flortaucipir SUVRs correlated with total years of participation in football, supporting a relation with repeated head impacts.

    It will be interesting to learn whether regional cortical tau deposition also is associated with biomarker evidence of neurodegeneration in the same areas (evaluated by volumetric MRI), or by increases in fluid biomarkers reflecting neurodegeneration, such as plasma levels of tau or neurofilament light (NFL) protein, especially in longitudinal studies employing such measures.

    View all comments by Kaj Blennow

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