title: Overlapping but distinct TDP-43 and tau pathologic patterns in aged hippocampi.
abstract: Intracellular proteinaceous aggregates (inclusion bodies) are almost always detectable at autopsy in brains of elderly individuals. Inclusion bodies composed of TDP-43 and tau proteins often coexist in the same brain, and each of these pathologic biomarkers is associated independently with cognitive impairment. However, uncertainties remain about how the presence and neuroanatomical distribution of inclusion bodies correlate with underlying diseases including Alzheimer's disease (AD). To address this knowledge gap, we analyzed data from the University of Kentucky AD Center autopsy series (n = 247); none of the brains had frontotemporal lobar degeneration. A specific question for this study was whether neurofibrillary tangle (NFT) pathology outside of the Braak NFT staging scheme is characteristic of brains with TDP-43 pathology but lacking AD, that is those with cerebral age-related TDP-43 with sclerosis (CARTS). We also tested whether TDP-43 pathology is associated with comorbid AD pathology, and whether argyrophilic grains are relatively likely to be present in cases with, vs. without, TDP-43 pathology. Consistent with prior studies, hippocampal TDP-43 pathology was associated with advanced AD - Braak NFT stages V/VI. However, argyrophilic grain pathology was not more common in cases with TDP-43 pathology in this data set. In brains with CARTS (TDP-43[+]/AD[-] cases), there were more NFTs in dentate granule neurons than were seen in TDP-43[-]/AD[-] cases. These dentate granule cell NFTs could provide a proxy indicator of CARTS pathology in cases lacking substantial AD pathology. Immunofluorescent experiments in a subsample of cases found that, in both advanced AD and CARTS, approximately 1% of dentate granule neurons were PHF-1 immunopositive, whereas ∼25% of TDP-43 positive cells showed colocalized PHF-1 immunoreactivity. We conclude that NFTs in hippocampal dentate granule neurons are often present in CARTS, and TDP-43 pathology may be secondary to or occurring in parallel with tauopathy.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY.
authors.forename: Vanessa D
authors.initials: VD
authors.lastname: Smith
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY.|Department of Neuroscience, University of Kentucky, Lexington, KY.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Bachstetter
authors.affiliation: Department of Neuroscience, University of Kentucky, Lexington, KY.|Sanders Brown Center on Aging, University of Kentucky, Lexington, KY.
authors.forename: Eseosa
authors.initials: E
authors.lastname: Ighodaro
authors.affiliation: Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY.
authors.forename: Kelly
authors.initials: K
authors.lastname: Roberts
authors.affiliation: Sanders Brown Center on Aging, University of Kentucky, Lexington, KY.|Department of Epidemiology, University of Kentucky, Lexington, KY.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Abner
authors.affiliation: Department of Biostatistics, University of Kentucky, Lexington, KY.
authors.forename: David W
authors.initials: DW
authors.lastname: Fardo
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kentucky, Lexington, KY.|Department of Neuroscience, University of Kentucky, Lexington, KY.|Sanders Brown Center on Aging, University of Kentucky, Lexington, KY.
authors.forename: Peter T
authors.identifier: 0000-0002-6161-1265
authors.initials: PT
authors.lastname: Nelson
mesh_terms: D000368:Aged; D000375:Aging / Q000378:metabolism* / Q000473:pathology*; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005260:Female; D005455:Fluorescent Antibody Technique; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008297:Male; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012598:Sclerosis / Q000378:metabolism / Q000473:pathology; D012720:Severity of Illness Index; D057177:TDP-43 Proteinopathies / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; C054369:MAPT protein, human; C000598624:TARDBP protein, human; D016875:tau Proteins
keywords: FTLD; HS-aging; colocalization; hippocampal sclerosis; hippocampus; oldest-old