title: "New Old Pathologies": AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS).
abstract: The pathology-based classification of Alzheimer's disease (AD) and other neurodegenerative diseases is a work in progress that is important for both clinicians and basic scientists. Analyses of large autopsy series, biomarker studies, and genomics analyses have provided important insights about AD and shed light on previously unrecognized conditions, enabling a deeper understanding of neurodegenerative diseases in general. After demonstrating the importance of correct disease classification for AD and primary age-related tauopathy, we emphasize the public health impact of an underappreciated AD "mimic," which has been termed "hippocampal sclerosis of aging" or "hippocampal sclerosis dementia." This pathology affects >20% of individuals older than 85 years and is strongly associated with cognitive impairment. In this review, we provide an overview of current hypotheses about how genetic risk factors (GRN, TMEM106B, ABCC9, and KCNMB2), and other pathogenetic influences contribute to TDP-43 pathology and hippocampal sclerosis. Because hippocampal sclerosis of aging affects the "oldest-old" with arteriolosclerosis and TDP-43 pathologies that extend well beyond the hippocampus, more appropriate terminology for this disease is required. We recommend "cerebral age-related TDP-43 and sclerosis" (CARTS). A detailed case report is presented, which includes neuroimaging and longitudinal neurocognitive data. Finally, we suggest a neuropathology-based diagnostic rubric for CARTS.
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC). pnels2@email.uky.edu.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Nelson
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: John Q
authors.initials: JQ
authors.lastname: Trojanowski
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Erin L
authors.initials: EL
authors.lastname: Abner
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Omar M
authors.initials: OM
authors.lastname: Al-Janabi
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Jicha
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Frederick A
authors.initials: FA
authors.lastname: Schmitt
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Charles D
authors.initials: CD
authors.lastname: Smith
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: David W
authors.initials: DW
authors.lastname: Fardo
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Wang-Xia
authors.initials: WX
authors.lastname: Wang
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Kryscio
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Janna H
authors.initials: JH
authors.lastname: Neltner
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Walter A
authors.initials: WA
authors.lastname: Kukull
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Cykowski
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Van Eldik
authors.affiliation: From the Department of Pathology, Division of Neuropathology (PTN, JHN), Department of Neurology (GAJ, FAS, CDS), Department of Statistics (DWF, RJK), Department of Anatomy and Neurobiology (PTN, JHN, LJVE, ETI), Department of Epidemiology (ELA), and Sanders-Brown Center on Aging (PTN, ELA, OMA-J, GAJ, FAS, CDS, DWF, WXW, RJK, LJVE, ETI), University of Kentucky, Lexington, Kentucky; Department of Pathology & Laboratory Medicine and Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia, Pennsylvannia (JQT); Department of Epidemiology, University of Washington, Seattle, Washington (WAK); and Department of Pathology, Houston Methodist Hospital, Houston, Texas (MDC).
authors.forename: Eseosa T
authors.initials: ET
authors.lastname: Ighodaro
mesh_terms: D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics / Q000473:pathology*; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D012598:Sclerosis / Q000235:genetics / Q000473:pathology; D024801:Tauopathies / Q000235:genetics / Q000473:pathology*
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human
keywords: Arteriosclerosis; Cerebrovascular disease; Frontotemporal lobar degeneration; Genome-wide association study; Neurofibrillary tangles; Plaques; VCID.