LATE-NC staging in routine neuropathologic diagnosis: an update

Peter T. Nelson; Edward B. Lee; Matthew D. Cykowski; Irina Alafuzoff; Konstantinos Arfanakis; Johannes Attems; Carol Brayne; Maria M. Corrada; Brittany N. Dugger; Margaret E. Flanagan; Bernardino Ghetti; Lea T. Grinberg; Murray Grossman; Michel J. Grothe; Glenda M. Halliday; Masato Hasegawa; Suvi R.K. Hokkanen; Sally Hunter; Kurt Jellinger; Claudia H. Kawas; C. Dirk Keene; Naomi Kouri; Gabor G. Kovacs; James B. Leverenz; Caitlin S. Latimer; Ian R. Mackenzie; Qinwen Mao; Kirsty E. McAleese; Richard Merrick; Thomas J. Montine; Melissa E. Murray; Liisa Myllykangas; Sukriti Nag; Janna H. Neltner; Kathy L. Newell; Robert A. Rissman; Yuko Saito; S. Ahmad Sajjadi; Katherine E. Schwetye; Andrew F. Teich; Dietmar R. Thal; Sandra O. Tomé; Juan C. Troncoso; Shih Hsiu J. Wang; Charles L. White; Thomas Wisniewski; Hyun Sik Yang; Julie A. Schneider; Dennis W. Dickson; Manuela Neumann

doi:10.1007/s00401-022-02524-2

LATE-NC staging in routine neuropathologic diagnosis: an update

Peter T. Nelson^*, Edward B. Lee, Matthew D. Cykowski, Irina Alafuzoff, Konstantinos Arfanakis, Johannes Attems, Carol Brayne, Maria M. Corrada, Brittany N. Dugger, Margaret E. Flanagan, Bernardino Ghetti, Lea T. Grinberg, Murray Grossman, Michel J. Grothe, Glenda M. Halliday, Masato Hasegawa, Suvi R.K. Hokkanen, Sally Hunter, Kurt Jellinger, Claudia H. KawasC. Dirk Keene, Naomi Kouri, Gabor G. Kovacs, James B. Leverenz, Caitlin S. Latimer, Ian R. Mackenzie, Qinwen Mao, Kirsty E. McAleese, Richard Merrick, Thomas J. Montine, Melissa E. Murray, Liisa Myllykangas, Sukriti Nag, Janna H. Neltner, Kathy L. Newell, Robert A. Rissman, Yuko Saito, S. Ahmad Sajjadi, Katherine E. Schwetye, Andrew F. Teich, Dietmar R. Thal, Sandra O. Tomé, Juan C. Troncoso, Shih Hsiu J. Wang, Charles L. White, Thomas Wisniewski, Hyun Sik Yang, Julie A. Schneider, Dennis W. Dickson, Manuela Neumann

^*Corresponding author for this work

Pathology

Research output: Contribution to journal › Article › peer-review

61 Scopus citations

Abstract

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Original language	English (US)
Pages (from-to)	159-173
Number of pages	15
Journal	Acta Neuropathologica
Volume	145
Issue number	2
DOIs	https://doi.org/10.1007/s00401-022-02524-2
State	Published - Feb 2023

Funding

We acknowledge National Institutes of Health Grants P30 AG072958 (S.-H. J.W.), P30 AG072977 (M.E.F.), K08 AG065463 (M.E.F.), RF1 AG072080 (M.E.F.), K08 AG 065426 (C.S.L), R01 AG038651 (E.L.A.), UF1 AG057707 (T.J.M and L.W), R01 AG021055 (C.K. & M.C.), P30 AG066519 (UCI ADRC), R01 AG061111 (P.T.N.), R01 AG057187 (P.T.N.), P30 AG072946 (P.T.N.), RF1 NS118584 (M.D.C.), P01 AG066597 (E.B.L.), P30 AG072979 (E.B.L.), U19 AG062418 (E.B.L.), P30 AG072959 (Cleveland ADRC), R01 AG062706 (S.A.S.), R01 AG054449 (M.E.M.), R01 AG075802 (M.E.M.), P30 AG 066507 (J.T.), U19 AG033655 (J.T.), RF1 AG069052 (J.G.R), P30 AG072972 (UC Davis ADRC), U19 AG069701 (M.E.M.), K24 AG053435 (L.T.G.), R01 AG067482 (J.A.S.), R01 AG064233 (J.A.S.), R01 AG022018 (J.A.S.), P30 AG010161/P30 AG072975 (J.A.S.), R01 AG064233 (K.A.), U01 AG061357 (B.N.D.), R01 AG052132 (B.N.D.), R01 AG056519 (B.N.D.), R01 AG062517 (B.N.D.), a research grant from the California Department Of Public Health (19-10611) with partial funding from the 2019 California Budget Act (B.N.D.), K23 AG062750 (H.-S. Y.), U19 AG024904 (K.E.S.), R21 AG078538 (K.E.S.), P30 AG 010133 (B.G. and K.N.), P30 AG062677 (Mayo ADRC), P30 AG066512 (T.W.), UF1 NS125417 (R.C.P.), U01 AG006786 (MCSA), R01 AG034676 (REP), P30 AG066509 (UW ADRC), and U19 AG066567 (ACT Study). Academy of Finland (341007) (L.M.); State funding for university-level health research (TYH2020231, TYH2022316) (L.M.); Liv och H\u00E4lsa Foundation (L.M.); Rossy Foundation and the Edmond Safra Philanthropic Foundation (G.G.K.); NOMIS foundation and Alzheimer Forschung Initiative (#21004) (M.N.); and, (#13803) (D.R.T.); UK Medical Research Council (MRC) (MRC/G9901400, U.1052.00.0013, G0900582). Addenbrooke\u2019s Charitable Trust (S.H.), Addenbrooke\u2019s Charitable Trust Grant 900108 (S.H.), Paul G. Allen Foundation (S.H.), ARUK NSG (S.H.), Alzheimer\u2019s Society 554 (AS-PG-2019b-024) (S.H.), and the Nancy and Buster Alvord Endowment (C.D.K.). The Cambridge Brain Bank Laboratory is supported by the National Institute for Health Research, Cambridge Biomedical Research Centre. UK ARUK-PhD2014-19 (S.R.K.H.). Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO: G0F8516N, G065721N) (D.R.T.); Stichting Alzheimer Onderzoek Belgi\u00EB (SAO-FRA: 2020/017) (D.R.T.); KU-Leuven Internal Funds (Belgium) (C14/17/107; C14/22/132; C3/20/057) (D.R.T.), (PDMT2/21/069) (S.O.T.); BrightFocus Foundation (A2022019F) (S.O.T.). \u201CMiguel Servet\u201D program (CP19/00031) (M.J.G.) and a research grant (PI20/00613) (M.J.G.) of the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). Alzheimer\u2019s Society (AS-JF-18-01; K.M.). Society for the Promotion of Research in Experimental Neurology, Vienna, Austria (K.J.)/Alzheimer\u2019s Research UK (ARUK) doctoral studentship (ARUK-PhD2017-34) (R.M.). AMED under Grant Number JP22wm0425019 (to Y.S.).

Keywords

Aging
Dementia
FTD
Hippocampal sclerosis
NCI
Neuroanatomy
Processes
Stages
TDP-43

ASJC Scopus subject areas

Pathology and Forensic Medicine
Clinical Neurology
Cellular and Molecular Neuroscience

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10.1007/s00401-022-02524-2

Cite this

Nelson, P. T., Lee, E. B., Cykowski, M. D., Alafuzoff, I., Arfanakis, K., Attems, J., Brayne, C., Corrada, M. M., Dugger, B. N., Flanagan, M. E., Ghetti, B., Grinberg, L. T., Grossman, M., Grothe, M. J., Halliday, G. M., Hasegawa, M., Hokkanen, S. R. K., Hunter, S., Jellinger, K., ... Neumann, M. (2023). LATE-NC staging in routine neuropathologic diagnosis: an update. Acta Neuropathologica, 145(2), 159-173. https://doi.org/10.1007/s00401-022-02524-2

@article{a3e8aae2bc714271b66c9252485c25d6,

title = "LATE-NC staging in routine neuropathologic diagnosis: an update",

abstract = "An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer{\textquoteright}s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.",

keywords = "Aging, Dementia, FTD, Hippocampal sclerosis, NCI, Neuroanatomy, Processes, Stages, TDP-43",

author = "Nelson, {Peter T.} and Lee, {Edward B.} and Cykowski, {Matthew D.} and Irina Alafuzoff and Konstantinos Arfanakis and Johannes Attems and Carol Brayne and Corrada, {Maria M.} and Dugger, {Brittany N.} and Flanagan, {Margaret E.} and Bernardino Ghetti and Grinberg, {Lea T.} and Murray Grossman and Grothe, {Michel J.} and Halliday, {Glenda M.} and Masato Hasegawa and Hokkanen, {Suvi R.K.} and Sally Hunter and Kurt Jellinger and Kawas, {Claudia H.} and Keene, {C. Dirk} and Naomi Kouri and Kovacs, {Gabor G.} and Leverenz, {James B.} and Latimer, {Caitlin S.} and Mackenzie, {Ian R.} and Qinwen Mao and McAleese, {Kirsty E.} and Richard Merrick and Montine, {Thomas J.} and Murray, {Melissa E.} and Liisa Myllykangas and Sukriti Nag and Neltner, {Janna H.} and Newell, {Kathy L.} and Rissman, {Robert A.} and Yuko Saito and Sajjadi, {S. Ahmad} and Schwetye, {Katherine E.} and Teich, {Andrew F.} and Thal, {Dietmar R.} and Tom{\'e}, {Sandra O.} and Troncoso, {Juan C.} and Wang, {Shih Hsiu J.} and White, {Charles L.} and Thomas Wisniewski and Yang, {Hyun Sik} and Schneider, {Julie A.} and Dickson, {Dennis W.} and Manuela Neumann",

note = "Funding Information: We acknowledge National Institutes of Health Grants P30 AG072958 (S.-H. J.W.), P30 AG072977 (M.E.F.), K08 AG065463 (M.E.F.), RF1 AG072080 (M.E.F.), K08 AG 065426 (C.S.L), R01 AG038651 (E.L.A.), UF1 AG057707 (T.J.M and L.W), R01 AG021055 (C.K. & M.C.), P30 AG066519 (UCI ADRC), R01 AG061111 (P.T.N.), R01 AG057187 (P.T.N.), P30 AG072946 (P.T.N.), RF1 NS118584 (M.D.C.), P01 AG066597 (E.B.L.), P30 AG072979 (E.B.L.), U19 AG062418 (E.B.L.), P30 AG072959 (Cleveland ADRC), R01 AG062706 (S.A.S.), R01 AG054449 (M.E.M.), R01 AG075802 (M.E.M.), P30 AG 066507 (J.T.), U19 AG033655 (J.T.), RF1 AG069052 (J.G.R), P30 AG072972 (UC Davis ADRC), U19 AG069701 (M.E.M.), K24 AG053435 (L.T.G.), R01 AG067482 (J.A.S.), R01 AG064233 (J.A.S.), R01 AG022018 (J.A.S.), P30 AG010161/P30 AG072975 (J.A.S.), R01 AG064233 (K.A.), U01 AG061357 (B.N.D.), R01 AG052132 (B.N.D.), R01 AG056519 (B.N.D.), R01 AG062517 (B.N.D.), a research grant from the California Department Of Public Health (19-10611) with partial funding from the 2019 California Budget Act (B.N.D.), K23 AG062750 (H.-S. Y.), U19 AG024904 (K.E.S.), R21 AG078538 (K.E.S.), P30 AG 010133 (B.G. and K.N.), P30 AG062677 (Mayo ADRC), P30 AG066512 (T.W.), UF1 NS125417 (R.C.P.), U01 AG006786 (MCSA), R01 AG034676 (REP), P30 AG066509 (UW ADRC), and U19 AG066567 (ACT Study). Academy of Finland (341007) (L.M.); State funding for university-level health research (TYH2020231, TYH2022316) (L.M.); Liv och H{\"a}lsa Foundation (L.M.); Rossy Foundation and the Edmond Safra Philanthropic Foundation (G.G.K.); NOMIS foundation and Alzheimer Forschung Initiative (#21004) (M.N.); and, (#13803) (D.R.T.); UK Medical Research Council (MRC) (MRC/G9901400, U.1052.00.0013, G0900582). Addenbrooke{\textquoteright}s Charitable Trust (S.H.), Addenbrooke{\textquoteright}s Charitable Trust Grant 900108 (S.H.), Paul G. Allen Foundation (S.H.), ARUK NSG (S.H.), Alzheimer{\textquoteright}s Society 554 (AS-PG-2019b-024) (S.H.), and the Nancy and Buster Alvord Endowment (C.D.K.). The Cambridge Brain Bank Laboratory is supported by the National Institute for Health Research, Cambridge Biomedical Research Centre. UK ARUK-PhD2014-19 (S.R.K.H.). Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO: G0F8516N, G065721N) (D.R.T.); Stichting Alzheimer Onderzoek Belgi{\"e} (SAO-FRA: 2020/017) (D.R.T.); KU-Leuven Internal Funds (Belgium) (C14/17/107; C14/22/132; C3/20/057) (D.R.T.), (PDMT2/21/069) (S.O.T.); BrightFocus Foundation (A2022019F) (S.O.T.). “Miguel Servet” program (CP19/00031) (M.J.G.) and a research grant (PI20/00613) (M.J.G.) of the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). Alzheimer{\textquoteright}s Society (AS-JF-18-01; K.M.). Society for the Promotion of Research in Experimental Neurology, Vienna, Austria (K.J.)/Alzheimer{\textquoteright}s Research UK (ARUK) doctoral studentship (ARUK-PhD2017-34) (R.M.). AMED under Grant Number JP22wm0425019 (to Y.S.). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2023",

month = feb,

doi = "10.1007/s00401-022-02524-2",

language = "English (US)",

volume = "145",

pages = "159--173",

journal = "Acta Neuropathologica",

issn = "0001-6322",

publisher = "Springer Verlag",

number = "2",

}

Nelson, PT, Lee, EB, Cykowski, MD, Alafuzoff, I, Arfanakis, K, Attems, J, Brayne, C, Corrada, MM, Dugger, BN, Flanagan, ME, Ghetti, B, Grinberg, LT, Grossman, M, Grothe, MJ, Halliday, GM, Hasegawa, M, Hokkanen, SRK, Hunter, S, Jellinger, K, Kawas, CH, Keene, CD, Kouri, N, Kovacs, GG, Leverenz, JB, Latimer, CS, Mackenzie, IR, Mao, Q, McAleese, KE, Merrick, R, Montine, TJ, Murray, ME, Myllykangas, L, Nag, S, Neltner, JH, Newell, KL, Rissman, RA, Saito, Y, Sajjadi, SA, Schwetye, KE, Teich, AF, Thal, DR, Tomé, SO, Troncoso, JC, Wang, SHJ, White, CL, Wisniewski, T, Yang, HS, Schneider, JA, Dickson, DW & Neumann, M 2023, 'LATE-NC staging in routine neuropathologic diagnosis: an update', Acta Neuropathologica, vol. 145, no. 2, pp. 159-173. https://doi.org/10.1007/s00401-022-02524-2

TY - JOUR

T1 - LATE-NC staging in routine neuropathologic diagnosis

T2 - an update

AU - Nelson, Peter T.

AU - Lee, Edward B.

AU - Cykowski, Matthew D.

AU - Alafuzoff, Irina

AU - Arfanakis, Konstantinos

AU - Attems, Johannes

AU - Brayne, Carol

AU - Corrada, Maria M.

AU - Dugger, Brittany N.

AU - Flanagan, Margaret E.

AU - Ghetti, Bernardino

AU - Grinberg, Lea T.

AU - Grossman, Murray

AU - Grothe, Michel J.

AU - Halliday, Glenda M.

AU - Hasegawa, Masato

AU - Hokkanen, Suvi R.K.

AU - Hunter, Sally

AU - Jellinger, Kurt

AU - Kawas, Claudia H.

AU - Keene, C. Dirk

AU - Kouri, Naomi

AU - Kovacs, Gabor G.

AU - Leverenz, James B.

AU - Latimer, Caitlin S.

AU - Mackenzie, Ian R.

AU - Mao, Qinwen

AU - McAleese, Kirsty E.

AU - Merrick, Richard

AU - Montine, Thomas J.

AU - Murray, Melissa E.

AU - Myllykangas, Liisa

AU - Nag, Sukriti

AU - Neltner, Janna H.

AU - Newell, Kathy L.

AU - Rissman, Robert A.

AU - Saito, Yuko

AU - Sajjadi, S. Ahmad

AU - Schwetye, Katherine E.

AU - Teich, Andrew F.

AU - Thal, Dietmar R.

AU - Tomé, Sandra O.

AU - Troncoso, Juan C.

AU - Wang, Shih Hsiu J.

AU - White, Charles L.

AU - Wisniewski, Thomas

AU - Yang, Hyun Sik

AU - Schneider, Julie A.

AU - Dickson, Dennis W.

AU - Neumann, Manuela

N1 - Funding Information: We acknowledge National Institutes of Health Grants P30 AG072958 (S.-H. J.W.), P30 AG072977 (M.E.F.), K08 AG065463 (M.E.F.), RF1 AG072080 (M.E.F.), K08 AG 065426 (C.S.L), R01 AG038651 (E.L.A.), UF1 AG057707 (T.J.M and L.W), R01 AG021055 (C.K. & M.C.), P30 AG066519 (UCI ADRC), R01 AG061111 (P.T.N.), R01 AG057187 (P.T.N.), P30 AG072946 (P.T.N.), RF1 NS118584 (M.D.C.), P01 AG066597 (E.B.L.), P30 AG072979 (E.B.L.), U19 AG062418 (E.B.L.), P30 AG072959 (Cleveland ADRC), R01 AG062706 (S.A.S.), R01 AG054449 (M.E.M.), R01 AG075802 (M.E.M.), P30 AG 066507 (J.T.), U19 AG033655 (J.T.), RF1 AG069052 (J.G.R), P30 AG072972 (UC Davis ADRC), U19 AG069701 (M.E.M.), K24 AG053435 (L.T.G.), R01 AG067482 (J.A.S.), R01 AG064233 (J.A.S.), R01 AG022018 (J.A.S.), P30 AG010161/P30 AG072975 (J.A.S.), R01 AG064233 (K.A.), U01 AG061357 (B.N.D.), R01 AG052132 (B.N.D.), R01 AG056519 (B.N.D.), R01 AG062517 (B.N.D.), a research grant from the California Department Of Public Health (19-10611) with partial funding from the 2019 California Budget Act (B.N.D.), K23 AG062750 (H.-S. Y.), U19 AG024904 (K.E.S.), R21 AG078538 (K.E.S.), P30 AG 010133 (B.G. and K.N.), P30 AG062677 (Mayo ADRC), P30 AG066512 (T.W.), UF1 NS125417 (R.C.P.), U01 AG006786 (MCSA), R01 AG034676 (REP), P30 AG066509 (UW ADRC), and U19 AG066567 (ACT Study). Academy of Finland (341007) (L.M.); State funding for university-level health research (TYH2020231, TYH2022316) (L.M.); Liv och Hälsa Foundation (L.M.); Rossy Foundation and the Edmond Safra Philanthropic Foundation (G.G.K.); NOMIS foundation and Alzheimer Forschung Initiative (#21004) (M.N.); and, (#13803) (D.R.T.); UK Medical Research Council (MRC) (MRC/G9901400, U.1052.00.0013, G0900582). Addenbrooke’s Charitable Trust (S.H.), Addenbrooke’s Charitable Trust Grant 900108 (S.H.), Paul G. Allen Foundation (S.H.), ARUK NSG (S.H.), Alzheimer’s Society 554 (AS-PG-2019b-024) (S.H.), and the Nancy and Buster Alvord Endowment (C.D.K.). The Cambridge Brain Bank Laboratory is supported by the National Institute for Health Research, Cambridge Biomedical Research Centre. UK ARUK-PhD2014-19 (S.R.K.H.). Fonds Wetenschappelijk Onderzoek Vlaanderen (FWO: G0F8516N, G065721N) (D.R.T.); Stichting Alzheimer Onderzoek België (SAO-FRA: 2020/017) (D.R.T.); KU-Leuven Internal Funds (Belgium) (C14/17/107; C14/22/132; C3/20/057) (D.R.T.), (PDMT2/21/069) (S.O.T.); BrightFocus Foundation (A2022019F) (S.O.T.). “Miguel Servet” program (CP19/00031) (M.J.G.) and a research grant (PI20/00613) (M.J.G.) of the Instituto de Salud Carlos III-Fondo Europeo de Desarrollo Regional (ISCIII-FEDER). Alzheimer’s Society (AS-JF-18-01; K.M.). Society for the Promotion of Research in Experimental Neurology, Vienna, Austria (K.J.)/Alzheimer’s Research UK (ARUK) doctoral studentship (ARUK-PhD2017-34) (R.M.). AMED under Grant Number JP22wm0425019 (to Y.S.). Publisher Copyright: © 2022, The Author(s).

PY - 2023/2

Y1 - 2023/2

N2 - An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

AB - An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer’s disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

KW - Aging

KW - Dementia

KW - FTD

KW - Hippocampal sclerosis

KW - NCI

KW - Neuroanatomy

KW - Processes

KW - Stages

KW - TDP-43

UR - http://www.scopus.com/inward/record.url?scp=85144030193&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85144030193&partnerID=8YFLogxK

U2 - 10.1007/s00401-022-02524-2

DO - 10.1007/s00401-022-02524-2

M3 - Article

C2 - 36512061

AN - SCOPUS:85144030193

SN - 0001-6322

VL - 145

SP - 159

EP - 173

JO - Acta Neuropathologica

JF - Acta Neuropathologica

IS - 2

ER -

LATE-NC staging in routine neuropathologic diagnosis: an update

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