Differential Vulnerability of Hippocampal Subfields in Primary Age-Related Tauopathy and Chronic Traumatic Encephalopathy
Kurt Farrell, Megan A. Iida, Jonathan D. Cherry, Alicia Casella, Thor D. Stein, Kevin F. Bieniek, Jamie M. Walker, Timothy E. Richardson, Charles L. White, Victor E. Alvarez, Bertrand R. Huber, Dennis W. Dickson, Ricardo Insausti, Kristen Dams-O’Connor, The Part Working Group, Jean‐Paul Vonsattel, Andy F Teich, Marla Gearing, Jonathan D. Glass, Juan C. Troncoso, Matthew P. Frosch, Bradley T. Hyman, Melissa E. Murray, Johannes Attems, Margaret E. Flanagan, Qinwen Mao, M-Marsel Mesulam, Sandra Weıntraub, Randy Woltjer, Thao Pham, Julia Kofler, Julie A. Schneider, Lei Yu, Dushyant P. Purohit, Vahram Haroutunian, Patrick R. Hof, Sam Gandy, Mary Sano, Thomas G. Beach, Wayne W. Poon, Claudia H. Kawas, María M. Corrada, Robert A. Rissman, Jeff Metcalf, Sara Shuldberg, Bahar Salehi, Peter T. Nelson, John Q. Trojanowski, Edward B. Lee, David A. Wolk, Corey T. McMillan, C. Dirk Keene, Caitlin S. Latimer, Thomas J. Montine, Gábor G. Kovács, Mirjam I. Lutz, Peter Fischer, Richard J. Perrin, Nigel J. Cairns, Ann C. McKee, John F. Crary
Abstract
Chronic traumatic encephalopathy (CTE) is a tauopathy associated with repetitive mild head impacts characterized by perivascular hyperphosphorylated tau (p-tau) in neurofibrillary tangles (NFTs) and neurites in the depths of the neocortical sulci. In moderate to advanced CTE, NFTs accumulate in the hippocampus, potentially overlapping neuroanatomically with primary age-related tauopathy (PART), an age-related tauopathy characterized by Alzheimer disease-like tau pathology in the hippocampus devoid of amyloid plaques. We measured p-tau burden using positive-pixel counts on immunohistochemically stained and neuroanatomically segmented hippocampal tissue. Subjects with CTE had a higher total p-tau burden than PART subjects in all sectors (p = 0.005). Within groups, PART had significantly higher total p-tau burden in CA1/subiculum compared to CA3 (p = 0.02) and CA4 (p = 0.01) and total p-tau burden in CA2 trended higher than CA4 (p = 0.06). In CTE, total p-tau burden in CA1/subiculum was significantly higher than in the dentate gyrus; and CA2 also trended higher than dentate gyrus (p = 0.01, p = 0.06). When controlling for p-tau burden across the entire hippocampus, CA3 and CA4 had significantly higher p-tau burden in CTE than PART (p < 0.0001). These data demonstrate differences in hippocampal p-tau burden and regional distribution in CTE compared to PART that might be helpful in differential diagnosis and reveal insights into disease pathogenesis.