TDP-43 Proteinopathy in Aging: Associations with Risk-Associated Gene Variants and with Brain Parenchymal Thyroid Hormone Levels

Authors

Peter T. Nelson, University of KentuckyFollow
Zsombor Gal, University of Kentucky
Wang-Xia Wang, University of KentuckyFollow
Dana M. Niedowicz, University of KentuckyFollow
Sergey C. Artiushin, University of KentuckyFollow
Samuel Wycoff, University of KentuckyFollow
Angela Wei, University of KentuckyFollow
Gregory A. Jicha, University of KentuckyFollow
David W. Fardo, University of KentuckyFollow

Abstract

TDP-43 proteinopathy is very prevalent among the elderly (affecting at least 25% of individuals over 85 years of age) and is associated with substantial cognitive impairment. Risk factors implicated in age-related TDP-43 proteinopathy include commonly inherited gene variants, comorbid Alzheimer's disease pathology, and thyroid hormone dysfunction. To test parameters that are associated with aging-related TDP-43 pathology, we performed exploratory analyses of pathologic, genetic, and biochemical data derived from research volunteers in the University of Kentucky Alzheimer's Disease Center autopsy cohort (n = 136 subjects). Digital pathologic methods were used to discriminate and quantify both neuritic and intracytoplasmic TDP-43 pathology in the hippocampal formation. Overall, 46.4% of the cases were positive for TDP-43 intracellular inclusions, which is consistent with results in other prior community-based cohorts. The pathologies were correlated with hippocampal sclerosis of aging (HS-Aging) linked genotypes. We also assayed brain parenchymal thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels. In cases with SLCO1A2/IAPP or ABCC9 risk associated genotypes, the T3/T4 ratio tended to be reduced (p = .051 using 2-tailed statistical test), and in cases with low T3/T4 ratios (bottom quintile), there was a higher likelihood of HS-Aging pathology (p = .025 using 2-tailed statistical test). This is intriguing because the SLCO1A2/IAPP and ABCC9 risk associated genotypes have been associated with altered expression of the astrocytic thyroid hormone receptor (protein product of the nearby gene SLCO1C1). These data indicate that dysregulation of thyroid hormone signaling may play a role in age-related TDP-43 proteinopathy.

Document Type

Article

Publication Date

5-2019

Notes/Citation Information

Published in Neurobiology of Disease, v. 125.

© 2019 Published by Elsevier Inc.

© 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.nbd.2019.01.013

Funding Information

Funding included grants P30 AG028383, R01 AG057187, and R01 AG042475 from the National Institute on Aging (NIA)/National Institutes of Health (NIH).

Repository Citation

Nelson, Peter T.; Gal, Zsombor; Wang, Wang-Xia; Niedowicz, Dana M.; Artiushin, Sergey C.; Wycoff, Samuel; Wei, Angela; Jicha, Gregory A.; and Fardo, David W., "TDP-43 Proteinopathy in Aging: Associations with Risk-Associated Gene Variants and with Brain Parenchymal Thyroid Hormone Levels" (2019). Pathology and Laboratory Medicine Faculty Publications. 38.
https://uknowledge.uky.edu/pathology_facpub/38