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


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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Notes/Citation Information

Published in Journal of Neuropathology & Experimental Neurology, v. 75, issue 6.

© 2016 American Association of Neuropathologists, Inc. All rights reserved.

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Funding Information

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.