Abstracts

Rationale: The controversy surrounding the significance of phosphorylated tau (PT) in neurological diseases is one of the hottest topics in current neuroscience research. A potential etiologic link between PT and chronic traumatic encephalopathy (CTE) has garnered attention with the discovery of PT in brain specimens of deceased NFL players as well as in victims of blast-induced or closed head injury. Many of these studies concluded that a history of repetitive traumatic brain injury (rTBI) is necessary for deposition of PT and subsequent neurodegeneration. However, PT and other broad neurodegenerative changes have also been implicated in poorly controlled seizures. Given that rTBI is a risk factor for delayed posttraumatic seizures, we wished to quantify PT in temporal lobe epilepsy (TLE) and CTE to unveil similar patterns of expression. Methods: 6 post mortem CTE (50-99 years; mean 73.3 years, 25 % females) and age matched control temporal lobe samples were compared to 12 surgically resected TLE brain specimens (4 months-58 years; mean 27.6 years, 60 % females). No history of TBI was present in TLE or control and all CTE samples were derived from patients with a documented history of rTBI. ELISA, western blots and immuncoytcohemistry were used to determine expression of total tau, PT Ser202, PT Ser202/Ser205 and PT Ser359. Results: TLE and CTE brains displayed increased levels of PT compared to control. There was a similar distribution of PT in both TLE and CTE. Specifically, cortical neurons and perivascular regions around penetrating pial vessels were immunopositive for PT while white matter tracts displayed robust expression of extracellular PT organized in bundles parallel to venules. Significant differences in staining intensities were found between CTE and control brain (P<0.01) but not between CTE and TLE (P=0.08). Perivascular staining for PT was spatially distinct from extravasated IgGs, suggesting that blood brain barrier leakage was not the source of PT. Furthermore, PT levels depended on the phosphorylation site measured, and ratios of PT Ser202 measured by western blot did not correlate with PT Ser359 measured by ELISA Conclusions: These results demonstrate a lack of specificity of PT expression for CTE versus TLE. Qualitative and quantitative assessment of PT in CTE versus TLE revealed similar patterns of expression suggesting a potential shared pathologic mechanism in which PT may play a pathogenic role or may serve as a marker of another pathway dysfunction such as impaired clearance from the brain. Our results signify that PT deposition may not be specific to rTBI since TLE recapitulated similar expression patterns as CTE. Thus further investigation is warranted to determine the role of PT in the pathogenesis of TLE and CTE. Acknowledgements: Supported by R01NS078307, R01NS43284, R41MH093302, R21NS077236, R42MH093302, UH3TR000491 and R21HD057256 (DJ), the American Heart Association [13SDG13950015] and Brain Behavior Research Foundation (CG). Select samples and antibodies were provided by Dr. Ann McKee and Dr. Peter Davies respectively.