TDP-43 Neuropathologic Associations in the Nun Study and the Honolulu-Asia Aging Study

Article type: Research Article

Authors: Flanagan, Margaret E.^{a; *} | Cholerton, Brenna^b | Latimer, Caitlin S.^c | Hemmy, Laura S.^{d; e} | Edland, Steven D.^f | Montine, Kathleen S.^c | White, Lon R.^{g; h} | Montine, Thomas J.^b

Affiliations: [a] Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA | [b] Department of Pathology, Stanford University, Stanford, CA, USA | [c] Department of Pathology, University of Washington, Seattle, WA, USA | [d] Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA | [e] Geriatric Research, Education, and Clinical Center, VA Health Care System, Minneapolis, MN, USA | [f] Department of Family Medicine and Public Health, University of California, San Diego, CA, USA | [g] Pacific Health Research and Education Institute (PHREI), Honolulu, HI, USA | [h] Department of Geriatric Medicine, University of Hawaii John A. Burns School of Medicine, Honolulu, HI, USA

Correspondence: [*] Correspondence to: Margaret E. Flanagan, Department of Laboratory Medicine and Pathology, University of Minnesota, Mayo Mail Code 609, 420 Delaware Street SE, Minneapolis, MN 55455, USA. Tel.: +1 612 625 6419; E-mail: mflanaga@umn.edu.

Abstract: Transactive response binding protein-43 (TDP-43) cytoplasmic neuronal and glial aggregates (pathologic TDP-43) have been described in multiple brain diseases. We describe the associations between neuropathologically confirmed TDP-43 and cognition in two population-based cohorts: the Nun Study (NS) and the Honolulu-Asia Aging Study (HAAS). In the HAAS, there was a significant association between hippocampal sclerosis (HS) and TDP-43 (OR = 11.04, p < 0.0001, 95% CI 3.57–34.13). In the NS, there were significant associations between TDP-43 and HS (OR = 16.44, p > 0.001 95%, CI 7.10–38.00) and Alzheimer’s disease (AD) severity (OR = 1.74, p = 0.009, 95% CI 1.15–2.64). When cognitive scores were added to the model, HS remained significant but the other variables were not. When HS was removed from the model, the overall model remained significant and the associations between cognitive performance and TDP-43 (OR = 2.11, p = 0.022, 95% CI 1.11–4.02) were significant. In the NS, there was a significant association between cognitive performance and TDP-43 (OR 1.94 p = 0.005, 95% CI 1.22–3.09) (HS remained significant, but AD did not). When HS was removed from the model, only CERAD was significant (OR = 2.43 p < 0.001, 95% CI 1.58–3.74). These results support a consistent association between pathologic TDP-43, HS, and the development of cognitive impairment in two large studies of brain aging, while the relationship between AD pathology and TDP-43 may vary according to cohort-specific features.

Keywords: Alzheimer’s disease, associations, hippocampal sclerosis, TDP43

DOI: 10.3233/JAD-180162

Journal: Journal of Alzheimer's Disease, vol. 66, no. 4, pp. 1549-1558, 2018