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Empirical pathologi...
Empirical pathological staging and subtyping of TDP-43 proteinopathies
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- Young, Alexandra L. (author)
- King's College London,University College London
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- Vogel, Jacob W. (author)
- University of Pennsylvania
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- Robinson, John (author)
- University of Pennsylvania
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- McMillan, Corey T. (author)
- University of Pennsylvania
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- Ossenkoppele, Rik (author)
- Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups,Amsterdam UMC - Vrije Universiteit Amsterdam
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- Wolk, David A. (author)
- University of Pennsylvania
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- Irwin, David J. (author)
- University of Pennsylvania
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- Elman, Lauren (author)
- University of Pennsylvania
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- Grossman, Murray (author)
- University of Pennsylvania
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- Lee, Virginia M.Y. (author)
- University of Pennsylvania
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- Lee, Eddie B. (author)
- University of Pennsylvania
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- Trojanowski, John Q. (author)
- University of Pennsylvania
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- Hansson, Oskar (author)
- Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,Clinical Memory Research,Lund University Research Groups
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(creator_code:org_t)
- 2022-12-20
- 2022
- English.
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In: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 18:S4
- Related links:
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http://dx.doi.org/10...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
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- Background: Pathological aggregation of tar DNA-binding protein 43 (TDP-43) in the brain is the primary cause of many cases of frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS) and limbic-predominant age-related TDP-43 encephalopathy (LATE). It is therefore imperative to establish empirical staging systems to characterize and distinguish stereotypical patterns and commonplace deviations of different TDP-43 proteinopathies. Method: We use ordinal ratings of TDP-43 burden from 19 brain regions to perform data-driven disease progression modeling (SuStaIn) to find the most likely trajectories for FTLD-TDP (n = 108), ALS (n = 137) and LATE (n = 283) from the CNDR Brain Bank at the University of Pennsylvania. Subtype number was defined using cross-validated information criterion. Each individual was assigned a subtype and stage. Multivariate OLS models tested differences between subtypes. Stages were compared to age and existing staging schemes. Cross-validated logistic regression was used for 3-way classification using SuStaIn information only. Result: SuStaIn provided data-driven staging of TDP-43 proteinopathies complementing previously described human-defined staging schema, further providing additional detail (Fig1A-C; Fig3A-C). SuStaIn also identified two distinct subtypes within FTLD-TDP and a further two within ALS (Fig1D). FTLD-TDP subtypes differed in TDP-43 type and Alzheimer’s disease pathology (Table1); ALS subtypes were differentiated by age (Table 2) and by antemortem clinical characteristics. No subtypes were observed for the LATE group. Progression along data-driven stages was positively associated with age in LATE individuals, but negatively associated with age in individuals with FTLD-TDP (Fig2). Using only regional TDP-43 severity, our data driven model could distinguish individuals diagnosed with ALS, FTD or LATE with a cross-validated balanced precision of 0.93 and balanced recall of 0.92, and these metrics improved to 0.95 and 0.96 when combined with a logistic regression model (Fig3). Very little stage overlap was found between FTLD-TDP and LATE, but stages that did overlap showed subtly different patterns (Fig4). Conclusion: We provide an empirical pathological staging system for ALS, FTLD-TDP and LATE, which is sufficient for staging and accurate classification. We demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns, whilst LATE exhibits a homogeneous progression pattern.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
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- By the author/editor
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Young, Alexandra ...
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Vogel, Jacob W.
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Robinson, John
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McMillan, Corey ...
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Ossenkoppele, Ri ...
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Wolk, David A.
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show more...
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Irwin, David J.
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Elman, Lauren
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Grossman, Murray
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Lee, Virginia M. ...
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Lee, Eddie B.
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Trojanowski, Joh ...
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Hansson, Oskar
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Alzheimer's and ...
- By the university
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Lund University