LATE-NC Stage 3

Authors

• Ryan K. Shahidehpour, University of Kentucky College of MedicineFollow
• Yuriko Katsumata, University of KentuckyFollow
• Dennis W. Dickson, Mayo Clinic College of Medicine and Science
• Nikhil B. Ghayal, Mayo Clinic College of Medicine and Science
• Khine Zin Aung, University of Kentucky College of Medicine
• Xian Wu, University of Kentucky College of MedicineFollow
• Panhavuth Phe, University of Kentucky College of Medicine
• Gregory A. Jicha, University of KentuckyFollow
• Allison M. Neltner, University of Kentucky College of Medicine
• Jessalin R.C. Archer, University of Kentucky College of Medicine
• Maria M. Corrada, University of California Irvine
• Claudia H. Kawas, University of California Irvine
• S. Ahmad Sajjadi, University of California Irvine
• Davis C. Woodworth, University of California Irvine
• Syed A. Bukhari, Stanford University
• Thomas J. Montine, Stanford University
• David W. Fardo, University of KentuckyFollow
• Peter T. Nelson, University of KentuckyFollow

Abstract

A diagnostic rubric is required to distinguish between limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP). In LATE-NC Stage 3, TDP-43 proteinopathy is present in the middle frontal gyrus (MFG), thus posing a potential diagnostic challenge in differentiating these severe LATE-NC cases from FTLD-TDP. LATE-NC Stage 3 cases and other TDP-43 proteinopathies were analyzed from the University of Kentucky (total n = 514 with TDP-43 pathology assessed), The 90+ Study at the University of California Irvine (n = 458), and the Mayo Clinic (n = 5067) brain banks. Digital pathology was used to quantify pathology burden in a select subset of cases (n = 51), complemented by a previously-described manual counting method and expert neuropathologic examinations to evaluate qualitative features such as FTLD-TDP types and subtypes of neuronal cytoplasmic inclusions (NCIs). To evaluate clinical and genetic characteristics of LATE-NC Stage 3, data were analyzed from the National Alzheimer’s Coordinating Center (NACC) Neuropathology Data set and correlated with findings from the Alzheimer’s Disease Genetics Consortium (ADGC). When using TDP-43 proteinopathy quantification in the MFG as a diagnostic criterion, more than 90% of cases could be classified as either LATE-NC Stage 3 or FTLD-TDP. Diagnostically challenging scenarios included a subset of FTLD-TDP Type B cases with relatively mild MFG TDP-43 pathology and a novel non-LATE-NC, non-FTLD-TDP pathologic subtype with severe MFG TDP-43 pathology. Taking these potential pitfalls into account, a classification schema was developed that could correctly diagnose all included cases. There was no difference in the Alzheimer’s disease pathological load in LATE-NC Stages 2 versus 3. In genetic analyses, the GRN (rs5848) risk allele was preferentially associated with LATE-NC Stage 3, whereas TMEM106B and APOE risk-associated variants were not. In conclusion, LATE-NC Stage 3 could be differentiated reliably from FTLD-TDP and other TDP-43-opathies, based on a data-driven diagnostic rubric.

Document Type

Article

Publication Date

6-1-2025

Notes/Citation Information

Publisher Copyright: © The Author(s) 2025.

Digital Object Identifier (DOI)

10.1007/s00401-025-02876-5

Archival?

Archival

Repository Citation

Shahidehpour, Ryan K.; Katsumata, Yuriko; Dickson, Dennis W.; Ghayal, Nikhil B.; Aung, Khine Zin; Wu, Xian; Phe, Panhavuth; Jicha, Gregory A.; Neltner, Allison M.; Archer, Jessalin R.C.; Corrada, Maria M.; Kawas, Claudia H.; Ahmad Sajjadi, S.; Woodworth, Davis C.; Bukhari, Syed A.; Montine, Thomas J.; Fardo, David W.; and Nelson, Peter T., "LATE-NC Stage 3" (2025). Biostatistics Faculty Publications. 118.
https://uknowledge.uky.edu/biostatistics_facpub/118