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Neuropathologic Features of Antemortem Atrophy-Based Subtypes of Alzheimer Disease
BACKGROUND AND OBJECTIVES: To investigate whether antemortem MRI-based atrophy subtypes of Alzheimer disease (AD) differ in neuropathologic features and comorbid non-AD pathologies at postmortem. METHODS: From the Alzheimer's Disease Neuroimaging Initiative cohort, we included individuals with...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Lippincott Williams & Wilkins
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9421777/ https://www.ncbi.nlm.nih.gov/pubmed/35609990 http://dx.doi.org/10.1212/WNL.0000000000200573 |
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author | Mohanty, Rosaleena Ferreira, Daniel Frerich, Simon Muehlboeck, J-Sebastian Grothe, Michel J. Westman, Eric |
author_facet | Mohanty, Rosaleena Ferreira, Daniel Frerich, Simon Muehlboeck, J-Sebastian Grothe, Michel J. Westman, Eric |
author_sort | Mohanty, Rosaleena |
collection | PubMed |
description | BACKGROUND AND OBJECTIVES: To investigate whether antemortem MRI-based atrophy subtypes of Alzheimer disease (AD) differ in neuropathologic features and comorbid non-AD pathologies at postmortem. METHODS: From the Alzheimer's Disease Neuroimaging Initiative cohort, we included individuals with antemortem MRI evaluating brain atrophy within 2 years before death, antemortem diagnosis of AD dementia/mild cognitive impairment, and postmortem-confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena based on a recent conceptual framework: typicality (spanning limbic-predominant AD to hippocampal-sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathologic evaluation included AD hallmarks, β-amyloid, and tau as well as non-AD pathologies, alpha-synuclein and TAR DNA-binding protein 43 (TDP-43). We also investigated the overall concomitance across these pathologies. Partial correlations assessed the associations between antemortem atrophy subtypes and postmortem neuropathologic outcomes. RESULTS: In 31 individuals (26 AD dementia/5 mild cognitive impairment, mean age = 80 years, 26% females), antemortem typicality was significantly negatively associated with neuropathologic features, including β-amyloid (rho = −0.39 overall), tau (rho = −0.38 regionally), alpha-synuclein (rho = −0.39 regionally), TDP-43 (rho = −0.49 overall), and concomitance of pathologies (rho = −0.59 regionally). Limbic-predominant AD was associated with higher Thal phase, neuritic plaque density, and presence of TDP-43 compared with hippocampal-sparing AD. Regionally, limbic-predominant AD showed a higher presence of tau and alpha-synuclein pathologies in medial temporal structures, a higher presence of TDP-43, and concomitance of pathologies subcortically/cortically compared with hippocampal-sparing AD. Antemortem severity was significantly negatively associated with concomitance of pathologies (rho = −0.43 regionally), such that typical AD showed higher concomitance of pathologies than minimal atrophy AD. DISCUSSION: We provide a direct antemortem-to-postmortem validation, highlighting the importance of understanding atrophy-based heterogeneity in AD relative to AD and non-AD pathologies. We suggest that (1) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non-AD pathologies; and (2) limbic-predominant AD and typical AD subtypes share similar biological pathways, making them more vulnerable to AD and non-AD pathologies compared with hippocampal-sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing the prevailing knowledge of biological heterogeneity in AD and could contribute toward tracking disease progression and designing clinical trials in the future. |
format | Online Article Text |
id | pubmed-9421777 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Lippincott Williams & Wilkins |
record_format | MEDLINE/PubMed |
spelling | pubmed-94217772022-08-30 Neuropathologic Features of Antemortem Atrophy-Based Subtypes of Alzheimer Disease Mohanty, Rosaleena Ferreira, Daniel Frerich, Simon Muehlboeck, J-Sebastian Grothe, Michel J. Westman, Eric Neurology Research Article BACKGROUND AND OBJECTIVES: To investigate whether antemortem MRI-based atrophy subtypes of Alzheimer disease (AD) differ in neuropathologic features and comorbid non-AD pathologies at postmortem. METHODS: From the Alzheimer's Disease Neuroimaging Initiative cohort, we included individuals with antemortem MRI evaluating brain atrophy within 2 years before death, antemortem diagnosis of AD dementia/mild cognitive impairment, and postmortem-confirmed AD neuropathologic change. Antemortem atrophy subtypes were modeled as continuous phenomena based on a recent conceptual framework: typicality (spanning limbic-predominant AD to hippocampal-sparing AD) and severity (spanning typical AD to minimal atrophy AD). Postmortem neuropathologic evaluation included AD hallmarks, β-amyloid, and tau as well as non-AD pathologies, alpha-synuclein and TAR DNA-binding protein 43 (TDP-43). We also investigated the overall concomitance across these pathologies. Partial correlations assessed the associations between antemortem atrophy subtypes and postmortem neuropathologic outcomes. RESULTS: In 31 individuals (26 AD dementia/5 mild cognitive impairment, mean age = 80 years, 26% females), antemortem typicality was significantly negatively associated with neuropathologic features, including β-amyloid (rho = −0.39 overall), tau (rho = −0.38 regionally), alpha-synuclein (rho = −0.39 regionally), TDP-43 (rho = −0.49 overall), and concomitance of pathologies (rho = −0.59 regionally). Limbic-predominant AD was associated with higher Thal phase, neuritic plaque density, and presence of TDP-43 compared with hippocampal-sparing AD. Regionally, limbic-predominant AD showed a higher presence of tau and alpha-synuclein pathologies in medial temporal structures, a higher presence of TDP-43, and concomitance of pathologies subcortically/cortically compared with hippocampal-sparing AD. Antemortem severity was significantly negatively associated with concomitance of pathologies (rho = −0.43 regionally), such that typical AD showed higher concomitance of pathologies than minimal atrophy AD. DISCUSSION: We provide a direct antemortem-to-postmortem validation, highlighting the importance of understanding atrophy-based heterogeneity in AD relative to AD and non-AD pathologies. We suggest that (1) typicality and severity in atrophy reflect differential aspects of susceptibility of the brain to AD and non-AD pathologies; and (2) limbic-predominant AD and typical AD subtypes share similar biological pathways, making them more vulnerable to AD and non-AD pathologies compared with hippocampal-sparing AD, which may follow a different biological pathway. Our findings provide a deeper understanding of associations of atrophy subtypes in AD with different pathologies, enhancing the prevailing knowledge of biological heterogeneity in AD and could contribute toward tracking disease progression and designing clinical trials in the future. Lippincott Williams & Wilkins 2022-07-26 /pmc/articles/PMC9421777/ /pubmed/35609990 http://dx.doi.org/10.1212/WNL.0000000000200573 Text en Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Mohanty, Rosaleena Ferreira, Daniel Frerich, Simon Muehlboeck, J-Sebastian Grothe, Michel J. Westman, Eric Neuropathologic Features of Antemortem Atrophy-Based Subtypes of Alzheimer Disease |
title | Neuropathologic Features of Antemortem Atrophy-Based Subtypes of Alzheimer Disease |
title_full | Neuropathologic Features of Antemortem Atrophy-Based Subtypes of Alzheimer Disease |
title_fullStr | Neuropathologic Features of Antemortem Atrophy-Based Subtypes of Alzheimer Disease |
title_full_unstemmed | Neuropathologic Features of Antemortem Atrophy-Based Subtypes of Alzheimer Disease |
title_short | Neuropathologic Features of Antemortem Atrophy-Based Subtypes of Alzheimer Disease |
title_sort | neuropathologic features of antemortem atrophy-based subtypes of alzheimer disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9421777/ https://www.ncbi.nlm.nih.gov/pubmed/35609990 http://dx.doi.org/10.1212/WNL.0000000000200573 |
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