Distinct Clinicopathologic Clusters of Persons with TDP-43 Proteinopathy

Authors

Yuriko Katsumata, University of KentuckyFollow
Erin L. Abner, University of KentuckyFollow
Shama Karanth, University of KentuckyFollow
Merilee A. Teylan, University of Washington
Charles N. Mock, University of Washington
Matthew D. Cykowski, Houston Methodist Hospital
Edward B. Lee, University of Pennsylvania
Kevin L. Boehme, Brigham Young University
Shubhabrata Mukherjee, University of Washington
John S. K. Kauwe, Brigham Young University-Hawaii
Richard J. Kryscio, University of KentuckyFollow
Frederick A. Schmitt, University of KentuckyFollow
David W. Fardo, University of KentuckyFollow
Peter T. Nelson, University of KentuckyFollow

Abstract

To better understand clinical and neuropathological features of TDP-43 proteinopathies, data were analyzed from autopsied research volunteers who were followed in the National Alzheimer’s Coordinating Center (NACC) data set. All subjects (n = 495) had autopsy-proven TDP-43 proteinopathy as an inclusion criterion. Subjects underwent comprehensive longitudinal clinical evaluations yearly for 6.9 years before death on average. We tested whether an unsupervised clustering algorithm could detect coherent groups of TDP-43 immunopositive cases based on age at death and extensive neuropathologic data. Although many of the brains had mixed pathologies, four discernible clusters were identified. Key differentiating features were age at death and the severity of comorbid Alzheimer’s disease neuropathologic changes (ADNC), particularly neuritic amyloid plaque densities. Cluster 1 contained mostly cases with a pathologic diagnosis of frontotemporal lobar degeneration (FTLD-TDP), consistent with enrichment of frontotemporal dementia clinical phenotypes including appetite/eating problems, disinhibition and primary progressive aphasia (PPA). Cluster 2 consisted of elderly limbic-predominant age-related TDP-43 encephalopathy (LATE-NC) subjects without severe neuritic amyloid plaques. Subjects in Cluster 2 had a relatively slow cognitive decline. Subjects in both Clusters 3 and 4 had severe ADNC + LATE-NC; however, Cluster 4 was distinguished by earlier disease onset, swifter disease course, more Lewy body pathology, less neocortical TDP-43 proteinopathy, and a suggestive trend in a subgroup analysis (n = 114) for increased C9orf72 risk SNP rs3849942 T allele (Fisher’s exact test p value = 0.095). Overall, clusters enriched with neocortical TDP-43 proteinopathy (Clusters 1 and 2) tended to have lower levels of neuritic amyloid plaques, and those dying older (Clusters 2 and 3) had far less PPA or disinhibition, but more apathy. Indeed, 98% of subjects dying past age 85 years lacked clinical features of the frontotemporal dementia syndrome. Our study revealed discernible subtypes of LATE-NC and underscored the importance of age of death for differentiating FTLD-TDP and LATE-NC.

Document Type

Article

Publication Date

11-2020

Notes/Citation Information

Published in Acta Neuropathologica, v. 140, issue 5.

© Springer-Verlag GmbH Germany, part of Springer Nature 2020

This is a post-peer-review, pre-copyedit version of an article published in Acta Neuropathologica. The final authenticated version is available online at: https://doi.org/10.1007/s00401-020-02211-0

Digital Object Identifier (DOI)

https://doi.org/10.1007/s00401-020-02211-0

Funding Information

This study was funded by grants R56AG057191, R01AG057187, R21AG061551, R01AG054060, and the UK-ADC P30AG028383 from the National Institute on Aging.

Repository Citation

Katsumata, Yuriko; Abner, Erin L.; Karanth, Shama; Teylan, Merilee A.; Mock, Charles N.; Cykowski, Matthew D.; Lee, Edward B.; Boehme, Kevin L.; Mukherjee, Shubhabrata; Kauwe, John S. K.; Kryscio, Richard J.; Schmitt, Frederick A.; Fardo, David W.; and Nelson, Peter T., "Distinct Clinicopathologic Clusters of Persons with TDP-43 Proteinopathy" (2020). Biostatistics Faculty Publications. 48.
https://uknowledge.uky.edu/biostatistics_facpub/48