Cited by 158Dementia and Cognitive Impairment ResearchAlzheimer's disease research and treatmentsAmyotrophic Lateral Sclerosis Research

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

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Nelson, Peter T., Trojanowski, John Q., Abner, Erin L., Al-Janabi, Omar M., Jicha, Gregory A., Schmitt, Frederick A., Smith, Charles D., Fardo, David W. +7 more·2016·Journal of Neuropathology & Experimental Neurology

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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Crossref · 10.1093/jnen/nlw033

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  • As TDP-43 distribution increases from limbic regions to other parts of the brain, it is associated with worsening cognition and medial temporal atrophy on antemortem brain imaging.

    “As the distribution of TDP-43 increases from limbic regions to other parts of the brain, it is associated with worsening cognition and with medial temporal atrophy on antemortem brain imaging [130, 132, 133].”

    From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [130]

  • Primary age-related tauopathy (PART) and aging-related tau astrogliopathy (ARTAG) are independent tau pathologies commonly observed in patients over 80 years of age, and PART may account for a proportion of misdiagnosed clinical AD cases in the elderly.

    “Primary age-related tauopathy (PART) and aging-related tau astrogliopathy (ARTAG) are independent tau pathologies commonly observed in patients over 80 years of age, and PART may account for a proportion of the misdiagnosed clinical AD cases in the elderly [130, 141, 142].”

    From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [130]

  • Hippocampal sclerosis of aging almost always includes TDP-43 deposits and sometimes arteriolosclerosis.

    “Hippocampal sclerosis of aging is now recognized to almost always include TDP-43 deposits and sometimes arteriolosclerosis that lead to intracellular and neuritic deposits of TDP-43 in the hippocampus during the preclinical state and eventually hippocampal sclerosis and cerebral atrophy in the disease state [130, 131].”

    From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [130]

  • PART lesions are found in hippocampus and adjacent regions similar to Braak I-IV, but PART lacks amyloid plaques and has distinct morbidity and age range.

    “Lesions are found in the hippocampus and adjacent regions similar to those observed in Braak I-IV, but PART is distinct from AD in that it lacks amyloid plaques, and it has distinct morbidity and age range [130, 142].”

    From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [130]

  • ARTAG represents astrocytic tau pathology distinct from primary tauopathies including PSP, CBD and GGT, associated with 4R tau deposits in subpial or perivascular thorn-shaped astrocytes or granular fuzzy astrocytes in gray matter.

    “ARTAG represents astrocytic tau pathology distinct from that observed in primary tauopathies including PSP, CBD and GGT. It is associated with 4R tau deposits in subpial or perivascular thorn-shaped astrocytes or granular fuzzy astrocytes in gray matter [130].”

    From The neuropathological diagnosis of Alzheimer's disease (2019) · cites this paper as [130]

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Authors
Nelson, P. T., Trojanowski, J. Q., Abner, E. L., Al-Janabi, O. M., Jicha, G. A., Schmitt, F. A., Smith, C. D., Fardo, D. W., Wang, W.-X., Kryscio, R. J., Neltner, J. H., Kukull, W. A., Cykowski, M. D., Van Eldik, L. J., & Ighodaro, E. T.
Affiliations
Houston Methodist (US)
Venue
Journal of Neuropathology & Experimental Neurology
Published
2016-05-21
Volume
75
Issue
6
Pages
482-498
ISSN
  • 0022-3069 (ISSN-L)
  • 1554-6578
OpenAlex
W2400971574
Cited by
158
References
281
Citations by year
2026: 8 · 2025: 11 · 2024: 6 · 2023: 12 · 2022: 11 · 2021: 11 · 2020: 21 · 2019: 19 · 2018: 28 · 2017: 21 · 2016: 10
FWCI
23.10
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuropathology & Experimental Neurology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UKnowledge (University of Kentucky) (submittedVersion)
  • HighWire Press Open Archive (submittedVersion)
Funders
  • National Institute on Aging (P30AG028383, U01AG016976, P30AG010124, P01AG017586, K25AG043546, U19AG010483)
  • National Institute of Neurological Disorders and Stroke (F30NS090714)
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
Alzheimer's disease, primary age-related tauopathy, TDP-43 pathology, CART, disease classification, genetic risk factors, gene regulatory networks, TMEM106B, ABCC9, arteriolosclerosis, oldest old, cognitive impairment
MeSH terms
Aged, 80 and over, Aging, Alzheimer Disease, Animals, DNA-Binding Proteins, Female, Hippocampus, Humans, Sclerosis, Tauopathies

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