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Distinct clinicopathologic clusters of persons with TDP-43 proteinopathy

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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.

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Acknowledgements

We are extremely grateful to the many patients, clinicians, and other colleagues, who have worked so hard to provide and organize these data. NIH Grants R01 NS118584, P30 AG028383, R01 AG057187, R56 AG057191, and R21 AG061551 helped fund the project. The NACC database is funded by NIA/NIH Grant U01 AG016976. NACC data are contributed by the NIA-funded ADCs: P30 AG019610 (PI Eric Reiman, MD), P30 AG013846 (PI Neil Kowall, MD), P30 AG062428-01 (PI James Leverenz, MD) P50 AG008702 (PI Scott Small, MD), P50 AG025688 (PI Allan Levey, MD, PhD), P50 AG047266 (PI Todd Golde, MD, PhD), P30 AG010133 (PI Andrew Saykin, PsyD), P50 AG005146 (PI Marilyn Albert, PhD), P30 AG062421-01 (PI Bradley Hyman, MD, PhD), P30 AG062422-01 (PI Ronald Petersen, MD, PhD), P50 AG005138 (PI Mary Sano, PhD), P30 AG008051 (PI Thomas Wisniewski, MD), P30 AG013854 (PI Robert Vassar, PhD), P30 AG008017 (PI Jeffrey Kaye, MD), P30 AG010161 (PI David Bennett, MD), P50 AG047366 (PI Victor Henderson, MD, MS), P30 AG010129 (PI Charles DeCarli, MD), P50 AG016573 (PI Frank LaFerla, PhD), P30 AG062429-01(PI James Brewer, MD, PhD), P50 AG023501 (PI Bruce Miller, MD), P30 AG035982 (PI Russell Swerdlow, MD), P30 AG028383 (PI Linda Van Eldik, PhD), P30 AG053760 (PI Henry Paulson, MD, PhD), P30 AG010124 (PI John Trojanowski, MD, PhD), P50 AG005133 (PI Oscar Lopez, MD), P50 AG005142 (PI Helena Chui, MD), P30 AG012300 (PI Roger Rosenberg, MD), P30 AG049638 (PI Suzanne Craft, PhD), P50 AG005136 (PI Thomas Grabowski, MD), P30 AG062715-01 (PI Sanjay Asthana, MD, FRCP), P50 AG005681 (PI John Morris, MD), P50 AG047270 (PI Stephen Strittmatter, MD, PhD). The National Institutes of Health, National Institute on Aging (NIH-NIA) supported this work through the following Grants: ADGC, U01 AG032984, RC2 AG036528; Samples from the National Cell Repository for Alzheimer’s Disease (NCRAD), which receives government support under a cooperative agreement Grant (U24 AG21886) awarded by the National Institute on Aging (NIA), were used in this study. Data for this study were prepared, archived, and distributed by the National Institute on Aging Alzheimer’s Disease Data Storage Site (NIAGADS) at the University of Pennsylvania (U24-AG041689-01); NACC, U01 AG016976; NIA LOAD (Columbia University), U24 AG026395, U24 AG026390, R01AG041797; Banner Sun Health Research Institute P30 AG019610; Boston University, P30 AG013846, U01 AG10483, R01 CA129769, R01 MH080295, R01 AG017173, R01 AG025259, R01 AG048927, R01AG33193, R01 AG009029; Columbia University, P50 AG008702, R37 AG015473, R01 AG037212, R01 AG028786; Duke University, P30 AG028377, AG05128; Emory University, AG025688; Group Health Research Institute, UO1 AG006781, UO1 HG004610, UO1 HG006375, U01 HG008657; Indiana University, P30 AG10133, R01 AG009956, RC2 AG036650; Johns Hopkins University, P50 AG005146, R01 AG020688; Massachusetts General Hospital, P50 AG005134; Mayo Clinic, P50 AG016574, R01 AG032990, KL2 RR024151; Mount Sinai School of Medicine, P50 AG005138, P01 AG002219; New York University, P30 AG08051, UL1 RR029893, 5R01AG012101, 5R01AG022374, 5R01AG013616, 1RC2AG036502, 1R01AG035137; North Carolina A&T University, P20 MD000546, R01 AG28786-01A1; Northwestern University, P30 AG013854; Oregon Health & Science University, P30 AG008017, R01 AG026916; Rush University, P30 AG010161, R01 AG019085, R01 AG15819, R01 AG17917, R01 AG030146, R01 AG01101, RC2 AG036650, R01 AG22018; TGen, R01 NS059873; University of Alabama at Birmingham, P50 AG016582; University of Arizona, R01 AG031581; University of California, Davis, P30 AG010129; University of California, Irvine, P50 AG016573; University of California, Los Angeles, P50 AG016570; University of California, San Diego, P50 AG005131; University of California, San Francisco, P50 AG023501, P01 AG019724; University of Michigan, P50 AG008671; University of Pennsylvania, P30 AG010124; University of Pittsburgh, P50 AG005133, AG030653, AG041718, AG07562, AG02365; University of Southern California, P50 AG005142; University of Texas Southwestern, P30 AG012300; University of Miami, R01 AG027944, AG010491, AG027944, AG021547, AG019757; University of Washington, P50 AG005136, R01 AG042437; University of Wisconsin, P50 AG033514; Vanderbilt University, R01 AG019085; and Washington University, P50 AG005681, P01 AG03991, P01 AG026276. The Kathleen Price Bryan Brain Bank at Duke University Medical Center is funded by NINDS grant # NS39764, NIMH MH60451 and by Glaxo Smith Kline. Support was also from the Alzheimer’s Association (LAF, IIRG-08-89720; MP-V, IIRG-05-14147), the US Department of Veterans Affairs Administration, Office of Research and Development, Biomedical Laboratory Research Program, and BrightFocus Foundation (MP-V, A2111048). P.S.G.-H. is supported by Wellcome Trust, Howard Hughes Medical Institute, and the Canadian Institute of Health Research. Genotyping of the TGEN2 cohort was supported by Kronos Science. The TGen series was also funded by NIA grant AG041232 to AJM and MJH, The Banner Alzheimer’s Foundation, The Johnnie B. Byrd Sr. Alzheimer’s Institute, the Medical Research Council, and the state of Arizona and also includes samples from the following sites: Newcastle Brain Tissue Resource, MRC London Brain Bank for Neurodegenerative Diseases (funding via the Medical Research Council),South West Dementia Brain Bank (funding via numerous sources including the Higher Education Funding Council for England (HEFCE), Alzheimer’s Research Trust (ART), BRACE as well as North Bristol NHS Trust Research and Innovation Department and DeNDRoN), The Netherlands Brain Bank (funding via numerous sources including Stichting MS Research, Brain Net Europe, Hersenstichting Nederland Breinbrekend Werk, International Parkinson Fonds, Internationale Stiching Alzheimer Onderzoek), Institut de Neuropatologia, Servei Anatomia Patologica, Universitat de Barcelona. ADNI data collection and sharing was funded by the National Institutes of Health Grant U01 AG024904 and Department of Defense award number W81XWH-12-2-0012. Tissue also was provided by the Newcastle Brain Tissue Resource, which is funded in part by a grant from the UK Medical Research Council (G0400074), by Brains for Dementia research, a joint venture between Alzheimer’s Society and Alzheimer’s Research UK and by the NIHR Newcastle Biomedical Research Centre awarded to the Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University. ADNI is funded by the NIA, the NIBIB, and through generous contributions from the following: AbbVie, Alzheimer’s Association; Alzheimer’s Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the NIH. The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the AD Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. We thank Drs. Dallas Anderson and Marilyn Miller from NIA who are ex-officio ADGC members.

Funding

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

Author information

Authors and Affiliations

  1. Department of Biostatistics, University of Kentucky, Lexington, KY, 40536, USA

    Yuriko Katsumata & David W. Fardo

  2. Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, 40536, USA

    Yuriko Katsumata, Erin L. Abner, Richard J. Kryscio, Frederick A. Schmitt, David W. Fardo & Peter T. Nelson

  3. Department of Epidemiology, University of Kentucky, Lexington, KY, 40536, USA

    Erin L. Abner & Shama Karanth

  4. Department of Epidemiology, National Alzheimer’s Coordinating Center, University of Washington, Seattle, WA, 98105, USA

    Merilee A. Teylan & Charles N. Mock

  5. Department of Epidemiology, University of Washington, Seattle, WA, 98105, USA

    Charles N. Mock

  6. Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX, 77030, USA

    Matthew D. Cykowski

  7. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Edward B. Lee

  8. Department of Biology, Brigham Young University, Provo, UT, 84602, USA

    Kevin L. Boehme

  9. Department of Medicine, University of Washington, Seattle, WA, 98104, USA

    Shubhabrata Mukherjee

  10. Brigham Young University–Hawaii, Laie, HI, 96762, USA

    John S. K. Kauwe

  11. Biology Department, Brigham Young University, Provo, UT, 84602, USA

    John S. K. Kauwe

  12. Department of Statistics, University of Kentucky, Lexington, KY, 40536, USA

    Richard J. Kryscio

  13. Department of Neurology, University of Kentucky, Lexington, KY, 40536, USA

    Frederick A. Schmitt

  14. Department of Pathology, University of Kentucky, Rm 311 Sanders-Brown Center on Aging, 800 S. Limestone Avenue, Lexington, KY, 40536, USA

    Peter T. Nelson

Authors
  1. Yuriko Katsumata
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  2. Erin L. Abner
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  3. Shama Karanth
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  4. Merilee A. Teylan
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  5. Charles N. Mock
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  6. Matthew D. Cykowski
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  7. Edward B. Lee
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  8. Kevin L. Boehme
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  9. Shubhabrata Mukherjee
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  10. John S. K. Kauwe
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  11. Richard J. Kryscio
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  12. Frederick A. Schmitt
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  13. David W. Fardo
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  14. Peter T. Nelson
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Contributions

YK was responsible for study conception, data analysis and interpretation, and drafting the manuscript. PTN was responsible for study conception, supervision, data interpretation, and drafting the manuscript. ELA was responsible for study conception, data interpretation, and drafting the manuscript. All other authors were involved in critical revision of the manuscript for important intellectual content.

Corresponding author

Correspondence to Peter T. Nelson.

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Katsumata, Y., Abner, E.L., Karanth, S. et al. Distinct clinicopathologic clusters of persons with TDP-43 proteinopathy. Acta Neuropathol 140, 659–674 (2020). https://doi.org/10.1007/s00401-020-02211-0

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

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