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Data-driven neuropa...
Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies
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- Young, Alexandra L. (författare)
- King's College London
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- Vogel, Jacob W. (författare)
- Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,LU profilområde: Proaktivt åldrande,Lunds universitets profilområden,Clinical Memory Research,Lund University Research Groups,LU Profile Area: Proactive Ageing,Lund University Profile areas
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- Robinson, John L. (författare)
- University of Pennsylvania
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visa fler...
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- McMillan, Corey T. (författare)
- University of Pennsylvania
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- Ossenkoppele, Rik (författare)
- Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,LU profilområde: Proaktivt åldrande,Lunds universitets profilområden,Clinical Memory Research,Lund University Research Groups,LU Profile Area: Proactive Ageing,Lund University Profile areas,Vrije Universiteit Amsterdam,Amsterdam Neuroscience
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- Wolk, David A. (författare)
- University of Pennsylvania
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- Irwin, David J. (författare)
- University of Pennsylvania
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- Elman, Lauren (författare)
- University of Pennsylvania
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- Grossman, Murray (författare)
- University of Pennsylvania
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- Lee, Virginia M.Y. (författare)
- University of Pennsylvania
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- Lee, Edward B. (författare)
- University of Pennsylvania
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- Hansson, Oskar (författare)
- Lund University,Lunds universitet,Klinisk minnesforskning,Forskargrupper vid Lunds universitet,LU profilområde: Proaktivt åldrande,Lunds universitets profilområden,Clinical Memory Research,Lund University Research Groups,LU Profile Area: Proactive Ageing,Lund University Profile areas,Skåne University Hospital
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(creator_code:org_t)
- 2023
- 2023
- Engelska 14 s.
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Ingår i: Brain. - 0006-8950. ; 146:7, s. 2975-2988
- Relaterad länk:
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http://dx.doi.org/10... (free)
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visa fler...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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 characterize 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 individuals with and without Alzheimer’s disease 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- amyotrophic lateral sclerosis
- frontotemporal lobar degeneration
- limbic-predominant age-related TDP-43 encephalopathy
- machine learning
- neuropathological staging
Publikations- och innehållstyp
- art (ämneskategori)
- ref (ämneskategori)
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Brain
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Young, Alexandra ...
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Vogel, Jacob W.
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Robinson, John L ...
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McMillan, Corey ...
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Ossenkoppele, Ri ...
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Wolk, David A.
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visa fler...
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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, Edward B.
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Hansson, Oskar
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visa färre...
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