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Distinct characteristics of limbic-predominant age-related TDP-43 encephalopathy in Lewy body disease

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Abstract

Limbic-predominant age-related TDP-43 encephalopathy (LATE) is characterized by the accumulation of TAR-DNA-binding protein 43 (TDP-43) aggregates in older adults. LATE coexists with Lewy body disease (LBD) as well as other neuropathological changes including Alzheimer’s disease (AD). We aimed to identify the pathological, clinical, and genetic characteristics of LATE in LBD (LATE-LBD) by comparing it with LATE in AD (LATE-AD), LATE with mixed pathology of LBD and AD (LATE-LBD + AD), and LATE alone (Pure LATE). We analyzed four cohorts of autopsy-confirmed LBD (n = 313), AD (n = 282), LBD + AD (n = 355), and aging (n = 111). We assessed the association of LATE with patient profiles including LBD subtype and AD neuropathologic change (ADNC). We studied the morphological and distributional differences between LATE-LBD and LATE-AD. By frequency analysis, we staged LATE-LBD and examined the association with cognitive impairment and genetic risk factors. Demographic analysis showed LATE associated with age in all four cohorts and the frequency of LATE was the highest in LBD + AD followed by AD, LBD, and Aging. LBD subtype and ADNC associated with LATE in LBD or AD but not in LBD + AD. Pathological analysis revealed that the hippocampal distribution of LATE was different between LATE-LBD and LATE-AD: neuronal cytoplasmic inclusions were more frequent in cornu ammonis 3 (CA3) in LATE-LBD compared to LATE-AD and abundant fine neurites composed of C-terminal truncated TDP-43 were found mainly in CA2 to subiculum in LATE-LBD, which were not as numerous in LATE-AD. Some of these fine neurites colocalized with phosphorylated α-synuclein. LATE-LBD staging showed LATE neuropathological changes spread in the dentate gyrus and brainstem earlier than in LATE-AD. The presence and prevalence of LATE in LBD associated with cognitive impairment independent of either LBD subtype or ADNC; LATE-LBD stage also associated with the genetic risk variants of TMEM106B rs1990622 and GRN rs5848. These data highlight clinicopathological and genetic features of LATE-LBD.

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Acknowledgements

DCK is currently affiliated with the John’s Hopkins University School of Medicine. We thank Manuela Neumann and Elisabeth Kremmer for providing the phosphorylation specific TDP-43 antibody TAR5P-1D3. We thank all of our colleagues in CNDR who helped with this study as well as all off the patients and their families.

Funding

MTU (201870008) and NU (201860169) report fellowships from the Japan Society for the Promotion of Science (JSPS). MTU report fellowships from the Uehara Memorial Foundation. KAQC reports Alzheimer’s Association Research Fellowship to Promote Diversity (AARF-D-619473) and the RAPID Program in Dementia (AARF-D-619473-RAPID). TFT (K23-NS11416-01A1), DAW (P30 AG010124), VMYL (T32-AG000255), EBL (P30 AG072979, P01 AG066597), and JQT (U19 AG062418, P50 NS053488) report grants from the US National Institute of Aging (NIA) or the US National Institute of Neurological Disorders and Stroke (NINDS) of National Institutes of Health (NIH) during this study. DJI reports grants from LBDA, Penn IOA. Data were contributed to this study by the Center on Alpha-synuclein Strains in Alzheimer Disease & Related Dementias at the University of Pennsylvania Perelman School of Medicine (U19 AG062418, Trojanowski JQ-PI) and the former Morris K. Udall Center at the University of Pennsylvania Perelman School of Medicine (P50 NS053488, Trojanowski JQ-PI).

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Authors and Affiliations

  1. Center for Neurodegenerative Disease Research, Perelman School of Medicine at the University of Pennsylvania, Maloney Building, 3rd Floor, 3600 Spruce Street, Philadelphia, PA, 19104-2676, USA

    Maiko T. Uemura, John L. Robinson, Jennifer D. McBride, EunRan Suh, Yan Xu, Sílvia Porta, Norihito Uemura, Vivianna M. Van Deerlin, Kurt R. Brunden, Virginia M.-Y. Lee & John Q. Trojanowski

  2. Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Maiko T. Uemura, John L. Robinson, Jennifer D. McBride, EunRan Suh, Yan Xu, Sílvia Porta, Norihito Uemura, Vivianna M. Van Deerlin, Kurt R. Brunden, Virginia M.-Y. Lee, Edward B. Lee & John Q. Trojanowski

  3. Department of Neurology, Penn Frontotemporal Degeneration Center, University of Pennsylvania, Philadelphia, PA, USA

    Katheryn A. Q. Cousins & David J. Irwin

  4. Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Thomas F. Tropea, Daniel C. Kargilis & David A. Wolk

  5. Alzheimer’s Disease Research Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Sharon X. Xie, Vivianna M. Van Deerlin, David A. Wolk, Virginia M.-Y. Lee, Edward B. Lee & John Q. Trojanowski

  6. Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Sharon X. Xie

  7. Penn Digital Neuropathology Laboratory, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4283, USA

    David J. Irwin

  8. Institute on Aging, Perelman School of Medicine at the University of Pennsylvania, Pennsylvania, PA, USA

    David A. Wolk & David J. Irwin

  9. Penn Memory Center at the Penn Neuroscience Center, Perelman Center for Advanced Medicine, Philadelphia, USA

    David A. Wolk

  10. Penn Lewy Body Dementia Association Research Center of Excellence, Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104-4283, USA

    David J. Irwin

  11. Translational Neuropathology Research Laboratory, Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Pennsylvania, PA, USA

    Edward B. Lee

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  1. Maiko T. Uemura
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  18. John Q. Trojanowski
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Contributions

MTU, JLR, DJI, EBL, and JQT designed the study. MTU, JLR, JDM, SXX, NU, EBL, and JQT collected and analyzed pathological data. MTU, KAQC, SXX, and DJI collected and analyzed cognitive data. MTU, TFT, DCK, ES, SXX and VMVD analyzed genetic data. MTU drafted the article and all other authors assisted with revisions and approved the final version.

Corresponding authors

Correspondence to Maiko T. Uemura or John Q. Trojanowski.

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Conflict of interest

DAW reports grants from Merck, Biogen, and Avid/Eli Lilly. He has received personal fees from GE Healthcare, Functional Neuromodulation, and Neuronix. EBL and JQT are members of Acta Neuropathologica’s Editorial Board but were not involved in the editorial handling of this article.

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Uemura, M.T., Robinson, J.L., Cousins, K.A.Q. et al. Distinct characteristics of limbic-predominant age-related TDP-43 encephalopathy in Lewy body disease. Acta Neuropathol 143, 15–31 (2022). https://doi.org/10.1007/s00401-021-02383-3

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