TDP-43 proteinopathy in aging: associations with risk-associated gene variants and with brain parenchymal thyroid hormone levels
| Autor: | Samuel Wycoff, David W. Fardo, Peter T. Nelson, Gregory A. Jicha, Angela Wei, Zsombor Gal, Dana M. Niedowicz, Wang-Xia Wang, Sergey Artiushin |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Male Aging Physiology SNP SLCO1A2 Organic Anion Transporters Neuropathology Disease Sulfonylurea Receptors Polymorphism Single Nucleotide Article lcsh:RC321-571 03 medical and health sciences 0302 clinical medicine Risk Factors medicine Dementia Humans Genetic Predisposition to Disease lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Aged Aged 80 and over Hippocampal sclerosis Thyroid hormone receptor Triiodothyronine business.industry Thyroid ScanScope Brain Middle Aged medicine.disease Thyroxine 030104 developmental biology medicine.anatomical_structure Neurology TMEM106B TDP-43 Proteinopathies Female business 030217 neurology & neurosurgery GRN Hormone |
| Zdroj: | Neurobiol Dis Neurobiology of Disease, Vol 125, Iss, Pp 67-76 (2019) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|