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      “New Old Pathologies”: AD, PART, and Cerebral Age-Related TDP-43 With Sclerosis (CARTS)

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          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.

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          Author and article information

          Journal
          J Neuropathol Exp Neurol
          J. Neuropathol. Exp. Neurol
          jnen
          jnen
          Journal of Neuropathology and Experimental Neurology
          Oxford University Press
          0022-3069
          1554-6578
          June 2016
          20 May 2016
          : 75
          : 6
          : 482-498
          Affiliations
          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).
          Author notes

          This study was supported by NIH grants R01 NR014189, R01 NS061933, R01 AG19241, P01 AG17553, P30 AG028383, P30 AG0-10124, P01 AG0-17586, and U01 AG016976. Antibodies used were generously provided by the following: NAB228 (Aβ) from Dr. Eddie Lee, PHF-1 (P-Tau) from Dr. Peter Davies, and 1D3 (P-TDP-43) from Dr. Manuela Neumann.

          The authors have no duality or conflicts of interest to declare.

          Send correspondence to: Peter T. Nelson, MD, PhD, Department of Pathology, Division of Neuropathology, Room 311, Sanders-Brown Center on Aging, 800 S. Limestone Avenue, University of Kentucky, Lexington, KY 40536-0230; E-mail: pnels2@ 123456email.uky.edu
          Article
          PMC6366658 PMC6366658 6366658 nlw033
          10.1093/jnen/nlw033
          6366658
          27209644
          90914f3e-0ae0-46f5-b803-c48c1e7d7c48
          © 2016 American Association of Neuropathologists, Inc. All rights reserved.
          History
          : 22 March 2016
          Page count
          Pages: 17
          Categories
          Review Article

          VCID.,Arteriosclerosis,Plaques,Neurofibrillary tangles,Genome-wide association study,Frontotemporal lobar degeneration,Cerebrovascular disease

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