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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.
Afiliação
  • Young AL; Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, SE5 8AF, UK.
  • Vogel JW; Centre for Medical Image Computing, Department of Computer Science, University College London, London, WC1V 6LJ, UK.
  • Robinson JL; Department of Clinical Sciences, SciLifeLab, Lund University, SE-222 42 Lund, Sweden.
  • McMillan CT; Clinical Memory Research Unit, Lund University, SE-222 42 Lund, Sweden.
  • Ossenkoppele R; Penn Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
  • Wolk DA; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
  • Irwin DJ; Penn Frontotemporal Degeneration Center, Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • Elman L; Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
  • Grossman M; Clinical Memory Research Unit, Lund University, SE-222 42 Lund, Sweden.
  • Lee VMY; Alzheimer Center Amsterdam, Neurology, Vrije Universiteit Amsterdam, Amsterdam UMC location VUmc, 1081 HZ Amsterdam, The Netherlands.
  • Lee EB; Amsterdam Neuroscience, Neurodegeneration, 1081 HV Amsterdam, The Netherlands.
  • Hansson O; Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Brain ; 146(7): 2975-2988, 2023 07 03.
Article em En | MEDLINE | ID: mdl-37150879
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Degeneração Lobar Frontotemporal / Demência Frontotemporal / Proteinopatias TDP-43 / Doença de Alzheimer / Esclerose Lateral Amiotrófica Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Degeneração Lobar Frontotemporal / Demência Frontotemporal / Proteinopatias TDP-43 / Doença de Alzheimer / Esclerose Lateral Amiotrófica Tipo de estudo: Observational_studies / Risk_factors_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article