Chronic Traumatic Encephalopathy (CTE): The Football Disease. A Look into the Potential Diagnostics and Therapy for Focal Tau Hyperphosphorylation in Cortical Tissue.
Matthew G. Mitchell
Introduction. Known for decades as “dementia pugilistica” or “punch-drunk syndrome” affecting boxers, Chronic Traumatic Encephalopathy (CTE) has been identified as a subset of traumatic brain injury resulting from exposure to repetitive force also prevalent in American football players and veterans.1 CTE clinically presents as progressively worsening mood swings, irritability, depression, and suicidal ideation.2 Pathologically, CTE is defined as aggregations of hyperphosphorylated tau found focally in regions of cortical tissue exposed to repetitive trauma. Currently, CTE cannot be definitively diagnosed until autopsy, and there are no current treatment options for CTE. Promising diagnostic and treatment studies include imaging biomarker techniques4,5 and antibody therapy are underway.3,6 This abstract focuses on the efficacy of antibody therapy for CTE in mouse models. Methods. Hyperphosphorylated tau aggregation was induced in mouse models via closed repetitive traumatic brain injury (rTBI) for five days. Mice were then directly administered an Adenovirus-associated vector (AAV) encoding a monoclonal antibody against phosphorylated tau (pTau) to the hippocampus. After 6 weeks of repeated stereotaxic antibody administration, the mice were sacrificed. Brain tissue was examined via fluorescence confocal microscopy and Western blot for presence of pTau.3 Results. Of the four anti-pTau antibody vectors tested, one was found produce a sufficient quantity of antibody to significantly decrease pTau aggregates across the CNS in mice exposed to rTBI.3 Conclusions. There are no current therapeutics for treatment of CTE. Results of this study show promise potential in antibody-clearing treatment for CTE and other tauopathies (Alzheimer’s disease, Frontotemporal dementia). Administration of anti-pTau antibody can be scaled to doses safe for humans, but there are the challenges of circumventing the blood brain barrier. This data warrants clinical trials of intrathecal anti-pTau vaccinations.3
- Falcon B, Zivanov J, Zhang W, et al. Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules. Nature. 2019;568(7752):420-423. doi:10.1038/s41586-019-1026-5
- Mckee AC, Abdolmohammadi B, Stein TD. The neuropathology of chronic traumatic encephalopathy. Handb Clin Neurol. 2018;158:297-307. doi: 10.1016/B978-0-444-63954-7.00028-8. PMID: 30482357.
- Sacramento CB, Sondhi D, Rosenberg JB, et al. Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy. Hum Gene Ther. 2020;31(1-2):57-69. doi:10.1089/hum.2019.174
- Mantyh WG, Spina S, Lee A, et al. Tau Positron Emission Tomographic Findings in a Former US Football Player With Pathologically Confirmed Chronic Traumatic Encephalopathy. JAMA Neurol. 2020;77(4):517-521. doi:10.1001/jamaneurol.2019.4509
- Veksler R, Vazana U, Serlin Y, et al. Slow blood-to-brain transport underlies enduring barrier dysfunction in American football players. Brain. 2020;143(6):1826-1842. doi:10.1093/brain/awaa140
- Lu KP, Kondo A, Albayram O, Herbert MK, Liu H, Zhou XZ. Potential of the Antibody Against cis–Phosphorylated Tau in the Early Diagnosis, Treatment, and Prevention of Alzheimer Disease and Brain Injury. JAMA Neurol.2016;73(11):1356–1362. doi:10.1001/jamaneurol.2016.2027