title: Hippocampal Sclerosis but Not Normal Aging or Alzheimer Disease Is Associated With TDP-43 Pathology in the Basal Forebrain of Aged Persons.
abstract: Transactivating responsive sequence (TAR) DNA-binding protein 43-kDa (TDP-43) pathology has been described in various brain diseases, but the full anatomical distribution and clinical and biological implications of that pathology are incompletely characterized. Here, we describe TDP-43 neuropathology in the basal forebrain, hypothalamus, and adjacent nuclei in 98 individuals (mean age, 86 years; median final mini-mental state examination score, 27). On examination blinded to clinical and pathologic diagnoses, we identified TDP-43 pathology that most frequently involved the ventromedial basal forebrain in 19 individuals (19.4%). As expected, many of these brains had comorbid pathologies including those of Alzheimer disease (AD), Lewy body disease (LBD), and/or hippocampal sclerosis of aging (HS-Aging). The basal forebrain TDP-43 pathology was strongly associated with comorbid HS-Aging (odds ratio = 6.8, p = 0.001), whereas there was no significant association between basal forebrain TDP-43 pathology and either AD or LBD neuropathology. In this sample, there were some cases with apparent preclinical TDP-43 pathology in the basal forebrain that may indicate that this is an early affected area in HS-Aging. We conclude that TDP-43 pathology in the basal forebrain is strongly associated with HS-Aging. These results raise questions about a specific pathogenetic relationship between basal forebrain TDP-43 and non-HS-Aging comorbid diseases (AD and LBD).
authors.affiliation: From the Department of Pathology and Genomic Medicine (MDC, HT, SZP) and Houston Methodist Neurological Institute (HT, SZP), Houston Methodist Hospital, Houston, Texas; and Sanders-Brown Center on Aging (LJVE, FAS, GAJ, PTN), Department of Anatomy & Neurobiology(LJVE), Department of Neurology(FAS, GAJ), and Division of Neuropathology, Department of Pathology (PTN), University of Kentucky, Lexington, Kentucky. mdcykowski@houstonmethodist.org.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Cykowski
authors.affiliation: From the Department of Pathology and Genomic Medicine (MDC, HT, SZP) and Houston Methodist Neurological Institute (HT, SZP), Houston Methodist Hospital, Houston, Texas; and Sanders-Brown Center on Aging (LJVE, FAS, GAJ, PTN), Department of Anatomy & Neurobiology(LJVE), Department of Neurology(FAS, GAJ), and Division of Neuropathology, Department of Pathology (PTN), University of Kentucky, Lexington, Kentucky.
authors.forename: Hidehiro
authors.initials: H
authors.lastname: Takei
authors.affiliation: From the Department of Pathology and Genomic Medicine (MDC, HT, SZP) and Houston Methodist Neurological Institute (HT, SZP), Houston Methodist Hospital, Houston, Texas; and Sanders-Brown Center on Aging (LJVE, FAS, GAJ, PTN), Department of Anatomy & Neurobiology(LJVE), Department of Neurology(FAS, GAJ), and Division of Neuropathology, Department of Pathology (PTN), University of Kentucky, Lexington, Kentucky.
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
authors.affiliation: From the Department of Pathology and Genomic Medicine (MDC, HT, SZP) and Houston Methodist Neurological Institute (HT, SZP), Houston Methodist Hospital, Houston, Texas; and Sanders-Brown Center on Aging (LJVE, FAS, GAJ, PTN), Department of Anatomy & Neurobiology(LJVE), Department of Neurology(FAS, GAJ), and Division of Neuropathology, Department of Pathology (PTN), University of Kentucky, Lexington, Kentucky.
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Schmitt
authors.affiliation: From the Department of Pathology and Genomic Medicine (MDC, HT, SZP) and Houston Methodist Neurological Institute (HT, SZP), Houston Methodist Hospital, Houston, Texas; and Sanders-Brown Center on Aging (LJVE, FAS, GAJ, PTN), Department of Anatomy & Neurobiology(LJVE), Department of Neurology(FAS, GAJ), and Division of Neuropathology, Department of Pathology (PTN), University of Kentucky, Lexington, Kentucky.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Jicha
authors.affiliation: From the Department of Pathology and Genomic Medicine (MDC, HT, SZP) and Houston Methodist Neurological Institute (HT, SZP), Houston Methodist Hospital, Houston, Texas; and Sanders-Brown Center on Aging (LJVE, FAS, GAJ, PTN), Department of Anatomy & Neurobiology(LJVE), Department of Neurology(FAS, GAJ), and Division of Neuropathology, Department of Pathology (PTN), University of Kentucky, Lexington, Kentucky.
authors.forename: Suzanne Z
authors.initials: SZ
authors.lastname: Powell
authors.affiliation: From the Department of Pathology and Genomic Medicine (MDC, HT, SZP) and Houston Methodist Neurological Institute (HT, SZP), Houston Methodist Hospital, Houston, Texas; and Sanders-Brown Center on Aging (LJVE, FAS, GAJ, PTN), Department of Anatomy & Neurobiology(LJVE), Department of Neurology(FAS, GAJ), and Division of Neuropathology, Department of Pathology (PTN), University of Kentucky, Lexington, Kentucky.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D066187:Basal Forebrain / Q000378:metabolism / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D012598:Sclerosis
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human
keywords: Aging; Alzheimer disease; Basal forebrain; Frontotemporal lobar degeneration; Hippocampal sclerosis; TDP-43.