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Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies

TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterise TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and...

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Autores principales: Young, Alexandra L, Vogel, Jacob W, Robinson, John L, McMillan, Corey T, Ossenkoppele, Rik, Wolk, David A., Irwin, David J., Elman, Lauren, Grossman, Murray, Lee, Virginia M-Y, Lee, Edward B, Hansson, Oskar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915837/
https://www.ncbi.nlm.nih.gov/pubmed/36778217
http://dx.doi.org/10.1101/2023.01.31.23285242
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author Young, Alexandra L
Vogel, Jacob W
Robinson, John L
McMillan, Corey T
Ossenkoppele, Rik
Wolk, David A.
Irwin, David J.
Elman, Lauren
Grossman, Murray
Lee, Virginia M-Y
Lee, Edward B
Hansson, Oskar
author_facet Young, Alexandra L
Vogel, Jacob W
Robinson, John L
McMillan, Corey T
Ossenkoppele, Rik
Wolk, David A.
Irwin, David J.
Elman, Lauren
Grossman, Murray
Lee, Virginia M-Y
Lee, Edward B
Hansson, Oskar
author_sort Young, Alexandra L
collection PubMed
description TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterise TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n=126), amyotrophic lateral sclerosis (ALS, n=141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer’s disease (n=304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating AD+ and Ad- individuals and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies.
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spelling pubmed-99158372023-02-11 Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies Young, Alexandra L Vogel, Jacob W Robinson, John L McMillan, Corey T Ossenkoppele, Rik Wolk, David A. Irwin, David J. Elman, Lauren Grossman, Murray Lee, Virginia M-Y Lee, Edward B Hansson, Oskar medRxiv Article TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterise TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n=126), amyotrophic lateral sclerosis (ALS, n=141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer’s disease (n=304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating AD+ and Ad- individuals and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies. Cold Spring Harbor Laboratory 2023-02-02 /pmc/articles/PMC9915837/ /pubmed/36778217 http://dx.doi.org/10.1101/2023.01.31.23285242 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Young, Alexandra L
Vogel, Jacob W
Robinson, John L
McMillan, Corey T
Ossenkoppele, Rik
Wolk, David A.
Irwin, David J.
Elman, Lauren
Grossman, Murray
Lee, Virginia M-Y
Lee, Edward B
Hansson, Oskar
Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies
title Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies
title_full Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies
title_fullStr Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies
title_full_unstemmed Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies
title_short Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies
title_sort data-driven neuropathological staging and subtyping of tdp-43 proteinopathies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9915837/
https://www.ncbi.nlm.nih.gov/pubmed/36778217
http://dx.doi.org/10.1101/2023.01.31.23285242
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