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Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts

Limbic‐predominant age‐related TAR‐DNA‐binding protein‐43 (TDP‐43) encephalopathy with hippocampal sclerosis pathology (LATE‐NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP‐43‐pathology, leading to cognitive dysfunction and dementia. Polymorphisms...

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Autores principales: Hokkanen, Suvi R. K., Kero, Mia, Kaivola, Karri, Hunter, Sally, Keage, Hannah A. D., Kiviharju, Anna, Raunio, Anna, Tienari, Pentti J., Paetau, Anders, Matthews, Fiona E., Fleming, Jane, Graff, Caroline, Polvikoski, Tuomo M., Myllykangas, Liisa, Brayne, Carol
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065086/
https://www.ncbi.nlm.nih.gov/pubmed/31376286
http://dx.doi.org/10.1111/bpa.12773
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author Hokkanen, Suvi R. K.
Kero, Mia
Kaivola, Karri
Hunter, Sally
Keage, Hannah A. D.
Kiviharju, Anna
Raunio, Anna
Tienari, Pentti J.
Paetau, Anders
Matthews, Fiona E.
Fleming, Jane
Graff, Caroline
Polvikoski, Tuomo M.
Myllykangas, Liisa
Brayne, Carol
author_facet Hokkanen, Suvi R. K.
Kero, Mia
Kaivola, Karri
Hunter, Sally
Keage, Hannah A. D.
Kiviharju, Anna
Raunio, Anna
Tienari, Pentti J.
Paetau, Anders
Matthews, Fiona E.
Fleming, Jane
Graff, Caroline
Polvikoski, Tuomo M.
Myllykangas, Liisa
Brayne, Carol
author_sort Hokkanen, Suvi R. K.
collection PubMed
description Limbic‐predominant age‐related TAR‐DNA‐binding protein‐43 (TDP‐43) encephalopathy with hippocampal sclerosis pathology (LATE‐NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP‐43‐pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE‐NC + HS risk factors in brain bank collections. To replicate these results in independent population‐representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75‐Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin–eosin (n = 744) and anti‐pTDP‐43 (n = 713), and evaluated for LATE‐NC + HS and TDP‐43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE‐NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (χ(2)(2) = 20.61, P < 0.001) and T‐allele (χ(2)(1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A‐allele (χ(2)(1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE‐NC + HS and non‐LATE‐NC + HS neuropathology cases. Dentate gyrus TDP‐43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE‐NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE‐NC + HS. The association between TMEM106B and LATE‐NC + HS may be independent of dentate TDP‐43 pathology.
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spelling pubmed-70650862020-03-16 Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts Hokkanen, Suvi R. K. Kero, Mia Kaivola, Karri Hunter, Sally Keage, Hannah A. D. Kiviharju, Anna Raunio, Anna Tienari, Pentti J. Paetau, Anders Matthews, Fiona E. Fleming, Jane Graff, Caroline Polvikoski, Tuomo M. Myllykangas, Liisa Brayne, Carol Brain Pathol Research Articles Limbic‐predominant age‐related TAR‐DNA‐binding protein‐43 (TDP‐43) encephalopathy with hippocampal sclerosis pathology (LATE‐NC + HS) is a neurodegenerative disorder characterized by severe hippocampal CA1 neuron loss and TDP‐43‐pathology, leading to cognitive dysfunction and dementia. Polymorphisms in GRN, TMEM106B and ABCC9 are proposed as LATE‐NC + HS risk factors in brain bank collections. To replicate these results in independent population‐representative cohorts, hippocampal sections from brains donated to three such studies (Cambridge City over 75‐Cohort [CC75C], Cognitive Function and Ageing Study [CFAS], and Vantaa 85+ Study) were stained with hematoxylin–eosin (n = 744) and anti‐pTDP‐43 (n = 713), and evaluated for LATE‐NC + HS and TDP‐43 pathology. Single nucleotide polymorphism genotypes in GRN rs5848, TMEM106B rs1990622 and ABCC9 rs704178 were determined. LATE‐NC + HS (n = 58) was significantly associated with the GRN rs5848 genotype (χ(2)(2) = 20.61, P < 0.001) and T‐allele (χ(2)(1) = 21.04, P < 0.001), and TMEM106B rs1990622 genotype (Fisher's exact test, P < 0.001) and A‐allele (χ(2)(1) = 25.75, P < 0.001). No differences in ABCC9 rs704178 genotype or allele frequency were found between LATE‐NC + HS and non‐LATE‐NC + HS neuropathology cases. Dentate gyrus TDP‐43 pathology associated with GRN and TMEM106B variations, but the association with TMEM106B nullified when LATE‐NC + HS cases were excluded. Our results indicate that GRN and TMEM106B are associated with severe loss of CA1 neurons in the aging brain, while ABCC9 was not confirmed as a genetic risk factor for LATE‐NC + HS. The association between TMEM106B and LATE‐NC + HS may be independent of dentate TDP‐43 pathology. John Wiley and Sons Inc. 2019-08-27 /pmc/articles/PMC7065086/ /pubmed/31376286 http://dx.doi.org/10.1111/bpa.12773 Text en © 2019 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Hokkanen, Suvi R. K.
Kero, Mia
Kaivola, Karri
Hunter, Sally
Keage, Hannah A. D.
Kiviharju, Anna
Raunio, Anna
Tienari, Pentti J.
Paetau, Anders
Matthews, Fiona E.
Fleming, Jane
Graff, Caroline
Polvikoski, Tuomo M.
Myllykangas, Liisa
Brayne, Carol
Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts
title Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts
title_full Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts
title_fullStr Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts
title_full_unstemmed Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts
title_short Putative risk alleles for LATE‐NC with hippocampal sclerosis in population‐representative autopsy cohorts
title_sort putative risk alleles for late‐nc with hippocampal sclerosis in population‐representative autopsy cohorts
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065086/
https://www.ncbi.nlm.nih.gov/pubmed/31376286
http://dx.doi.org/10.1111/bpa.12773
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