TY - JOUR
T1 - Isoform-specific patterns of tau burden and neuronal degeneration in MAPT-associated frontotemporal lobar degeneration
AU - Giannini, Lucia A. A.
AU - Ohm, Daniel T.
AU - Rozemuller, Annemieke J. M.
AU - Dratch, Laynie
AU - Suh, EunRan
AU - van Deerlin, Vivianna M.
AU - Trojanowski, John Q.
AU - Netherlands Brain Bank
AU - Lee, Edward B.
AU - van Swieten, John C.
AU - Grossman, Murray
AU - Seelaar, Harro
AU - Irwin, David J.
N1 - Funding Information: This study was supported at the Erasmus University Medical Center by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050103 and 733050513), the Bluefield Project to Cure Frontotemporal Dementia; at the University of Pennsylvania by NIH grants NINDS R01-NS109260-01A1, NIA P01-AG066597, NIA U01-AG052943-01, Penn Institute on Aging and the Wyncote Foundation. Funding Information: We thank all patients and their families for donating their brain for scientific research. We thank colleagues from external clinics for contributing tissue from a subset of cases autopsied in their institute and shipped to Penn for further postmortem analysis. We thank Shamiram Melhem from the Erasmus University Medical Center, and Claire Peterson, Rebecca Lobrovic, Emily Xie and Winifred Trotman from the University of Pennsylvania, for contributing technical laboratory assistance for performing this study. We would like to acknowledge Dr. John Trojanowski (1946-2022), without whose impactful contributions to tau biology and support, this project would not have been feasible. Publisher Copyright: © 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2022/12
Y1 - 2022/12
N2 - Frontotemporal lobar degeneration with MAPT pathogenic variants (FTLD-MAPT) has heterogeneous tau pathological inclusions postmortem, consisting of three-repeat (3R) or four-repeat (4R) tau isoforms, or a combination (3R + 4R). Here, we studied grey matter tau burden, its relation to neuronal degeneration, and regional patterns of pathology in different isoform groups of FTLD-MAPT. We included 38 FTLD-MAPT autopsy cases with 10 different MAPT pathogenic variants, grouped based on predominant tau isoform(s). In up to eleven regions (ten cortical and one striatal), we quantified grey matter tau burden using digital histopathological analysis and assigned semi-quantitative ratings for neuronal degeneration (i.e. 0–4) and separate burden of glial and neuronal tau inclusions (i.e. 0–3). We used mixed modelling to compare pathology measures (1) across the entire cohort and (2) within isoform groups. In the total cohort, tau burden and neuronal degeneration were positively associated and most severe in the anterior temporal, anterior cingulate and transentorhinal cortices. Isoform groups showed distinctive features of tau burden and neuronal degeneration. Across all regions, the 3R isoform group had lower tau burden compared to the 4R group (p = 0.008), while at the same time showing more severe neuronal degeneration than the 4R group (p = 0.002). The 3R + 4R group had an intermediate profile with relatively high tau burden along with relatively severe neuronal degeneration. Neuronal tau inclusions were most frequent in the 4R group (p < 0.001 vs. 3R), while cortical glial tau inclusions were most frequent in the 3R + 4R and 4R groups (p ≤ 0.009 vs. 3R). Regionally, neuronal degeneration was consistently most severe in the anterior temporal cortex within each isoform group. In contrast, the regions with the highest tau burden differed in isoform groups (3R: striatum; 3R + 4R: striatum, inferior parietal lobule, middle frontal cortex, anterior cingulate cortex; 4R: transentorhinal cortex, anterior temporal cortex, fusiform gyrus). We conclude that FTLD-MAPT isoform groups show distinctive features of overall neuronal degeneration and regional tau burden, but all share pronounced anterior temporal neuronal degeneration. These data suggest that distinct isoform-related mechanisms of genetic tauopathies, with slightly divergent tau distribution, may share similar regional vulnerability to neurodegeneration within the frontotemporal paralimbic networks.
AB - Frontotemporal lobar degeneration with MAPT pathogenic variants (FTLD-MAPT) has heterogeneous tau pathological inclusions postmortem, consisting of three-repeat (3R) or four-repeat (4R) tau isoforms, or a combination (3R + 4R). Here, we studied grey matter tau burden, its relation to neuronal degeneration, and regional patterns of pathology in different isoform groups of FTLD-MAPT. We included 38 FTLD-MAPT autopsy cases with 10 different MAPT pathogenic variants, grouped based on predominant tau isoform(s). In up to eleven regions (ten cortical and one striatal), we quantified grey matter tau burden using digital histopathological analysis and assigned semi-quantitative ratings for neuronal degeneration (i.e. 0–4) and separate burden of glial and neuronal tau inclusions (i.e. 0–3). We used mixed modelling to compare pathology measures (1) across the entire cohort and (2) within isoform groups. In the total cohort, tau burden and neuronal degeneration were positively associated and most severe in the anterior temporal, anterior cingulate and transentorhinal cortices. Isoform groups showed distinctive features of tau burden and neuronal degeneration. Across all regions, the 3R isoform group had lower tau burden compared to the 4R group (p = 0.008), while at the same time showing more severe neuronal degeneration than the 4R group (p = 0.002). The 3R + 4R group had an intermediate profile with relatively high tau burden along with relatively severe neuronal degeneration. Neuronal tau inclusions were most frequent in the 4R group (p < 0.001 vs. 3R), while cortical glial tau inclusions were most frequent in the 3R + 4R and 4R groups (p ≤ 0.009 vs. 3R). Regionally, neuronal degeneration was consistently most severe in the anterior temporal cortex within each isoform group. In contrast, the regions with the highest tau burden differed in isoform groups (3R: striatum; 3R + 4R: striatum, inferior parietal lobule, middle frontal cortex, anterior cingulate cortex; 4R: transentorhinal cortex, anterior temporal cortex, fusiform gyrus). We conclude that FTLD-MAPT isoform groups show distinctive features of overall neuronal degeneration and regional tau burden, but all share pronounced anterior temporal neuronal degeneration. These data suggest that distinct isoform-related mechanisms of genetic tauopathies, with slightly divergent tau distribution, may share similar regional vulnerability to neurodegeneration within the frontotemporal paralimbic networks.
KW - Frontotemporal lobar degeneration
KW - Genetic tauopathies
KW - Neuronal degeneration
KW - Tau pathology
UR - http://www.scopus.com/inward/record.url?scp=85139234090&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00401-022-02487-4
DO - https://doi.org/10.1007/s00401-022-02487-4
M3 - Article
C2 - 36066634
SN - 0001-6322
VL - 144
SP - 1065
EP - 1084
JO - Acta Neuropathologica
JF - Acta Neuropathologica
IS - 6
ER -