White matter hyperintensities influence distal cortical β-amyloid accumulation in default mode network pathways

Doaa G. Ali; Ahmed A. Bahrani; Riham H. El Khouli; Brian T. Gold; Yang Jiang; Valentinos Zachariou; Donna M. Wilcock; Gregory A. Jicha

doi:10.1002/brb3.3209

White matter hyperintensities influence distal cortical β-amyloid accumulation in default mode network pathways

Doaa G. Ali, Ahmed A. Bahrani, Riham H. El Khouli, Brian T. Gold, Yang Jiang, Valentinos Zachariou, Donna M. Wilcock, Gregory A. Jicha

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

2 Scopus citations

Abstract

Background and purpose: Cerebral small vessel disease (SVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Yet, the role of SVD in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that WMHs influence amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults. Methods: Regional standard uptake value ratios (SUVr) from Aβ-PET and white matter hyperintensity (WMH) volumes from three-dimensional magnetic resonance imaging FLAIR images were analyzed across a sample of 72 clinically unimpaired (mini-mental state examination ≥26), older adults (mean age 74.96 and standard deviation 8.13) from the Alzheimer's Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ-PET SUVr in the connected cortical DMN regions was analyzed using linear regression models adjusted for age, sex, ApoE, and total brain volumes. Results: The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus were associated with increased regional SUVr in the inferior parietal lobule (p =.011). Conclusion: The findings suggest that the relation between Aβ in parietal cortex is associated with SVD in downstream white matter (WM) pathways in preclinical AD. The biological relationships and interplay between Aβ and WM microstructure alterations that precede overt WMH development across the continuum of AD progression warrant further study.

Original language	English
Article number	e3209
Journal	Brain and Behavior
Volume	13
Issue number	10
DOIs	https://doi.org/10.1002/brb3.3209
State	Published - Oct 2023

Bibliographical note

Publisher Copyright:
© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.

Funding

We thank the Alzheimer's Disease Neuroimaging Initiative for access to their data and the many participants who made this study possible. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH-12-2-0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol-Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This work was supported by NIH P30 AG072946 and the generous philanthropic support of the Robert T. & Nyles Y. McCowan endowment to the Sanders-Brown Center on Aging and the B. Wayne Hughes Memorial Fund. We thank the Alzheimer's Disease Neuroimaging Initiative for access to their data and the many participants who made this study possible. Data collection and sharing for this project was funded by the Alzheimer's Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904) and DOD ADNI (Department of Defense award number W81XWH‐12‐2‐0012). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: AbbVie, Alzheimer's Association; Alzheimer's Drug Discovery Foundation; Araclon Biotech; BioClinica, Inc.; Biogen; Bristol‐Myers Squibb Company; CereSpir, Inc.; Cogstate; Eisai Inc.; Elan Pharmaceuticals, Inc.; Eli Lilly and Company; EuroImmun; F. Hoffmann‐La Roche Ltd and its affiliated company Genentech, Inc.; Fujirebio; GE Healthcare; IXICO Ltd.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Lumosity; Lundbeck; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; NeuroRx Research; Neurotrack Technologies; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Piramal Imaging; Servier; Takeda Pharmaceutical Company; and Transition Therapeutics. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health ( www.fnih.org ). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer's Therapeutic Research Institute at the University of Southern California. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of Southern California. This work was supported by NIH P30 AG072946 and the generous philanthropic support of the Robert T. & Nyles Y. McCowan endowment to the Sanders‐Brown Center on Aging and the B. Wayne Hughes Memorial Fund.

Funders	Funder number
Araclon Biotech
DOD ADNI
Sanders-Brown Center on Aging
Sanders-Brown Center on Aging
National Institutes of Health (NIH)	U01 AG024904, P30 AG072946
U.S. Department of Defense	W81XWH‐12‐2‐0012
National Institute on Aging
National Institute of Biomedical Imaging and Bioengineering
Alzheimer's Association
Alzheimer's Drug Discovery Foundation
Biogen IDEC
University of Southern California
AbbVie
DoD Alzheimer's Disease Neuroimaging Initiative
BioClinica Inc.
Northern California Institute for Research and Education

Keywords

default mode network
neuroimaging
preclinical Alzheimer's disease
regional standardized uptake value ratio
white matter hyperintensities

ASJC Scopus subject areas

Behavioral Neuroscience

Access to Document

10.1002/brb3.3209

Cite this

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title = "White matter hyperintensities influence distal cortical β-amyloid accumulation in default mode network pathways",

abstract = "Background and purpose: Cerebral small vessel disease (SVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Yet, the role of SVD in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that WMHs influence amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults. Methods: Regional standard uptake value ratios (SUVr) from Aβ-PET and white matter hyperintensity (WMH) volumes from three-dimensional magnetic resonance imaging FLAIR images were analyzed across a sample of 72 clinically unimpaired (mini-mental state examination ≥26), older adults (mean age 74.96 and standard deviation 8.13) from the Alzheimer's Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ-PET SUVr in the connected cortical DMN regions was analyzed using linear regression models adjusted for age, sex, ApoE, and total brain volumes. Results: The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus were associated with increased regional SUVr in the inferior parietal lobule (p =.011). Conclusion: The findings suggest that the relation between Aβ in parietal cortex is associated with SVD in downstream white matter (WM) pathways in preclinical AD. The biological relationships and interplay between Aβ and WM microstructure alterations that precede overt WMH development across the continuum of AD progression warrant further study.",

keywords = "default mode network, neuroimaging, preclinical Alzheimer's disease, regional standardized uptake value ratio, white matter hyperintensities",

author = "Ali, \{Doaa G.\} and Bahrani, \{Ahmed A.\} and \{El Khouli\}, \{Riham H.\} and Gold, \{Brian T.\} and Yang Jiang and Valentinos Zachariou and Wilcock, \{Donna M.\} and Jicha, \{Gregory A.\}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.",

year = "2023",

month = oct,

doi = "10.1002/brb3.3209",

language = "English",

volume = "13",

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AU - Ali, Doaa G.

AU - Bahrani, Ahmed A.

AU - El Khouli, Riham H.

AU - Gold, Brian T.

AU - Jiang, Yang

AU - Zachariou, Valentinos

AU - Wilcock, Donna M.

AU - Jicha, Gregory A.

PY - 2023/10

Y1 - 2023/10

N2 - Background and purpose: Cerebral small vessel disease (SVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Yet, the role of SVD in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that WMHs influence amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults. Methods: Regional standard uptake value ratios (SUVr) from Aβ-PET and white matter hyperintensity (WMH) volumes from three-dimensional magnetic resonance imaging FLAIR images were analyzed across a sample of 72 clinically unimpaired (mini-mental state examination ≥26), older adults (mean age 74.96 and standard deviation 8.13) from the Alzheimer's Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ-PET SUVr in the connected cortical DMN regions was analyzed using linear regression models adjusted for age, sex, ApoE, and total brain volumes. Results: The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus were associated with increased regional SUVr in the inferior parietal lobule (p =.011). Conclusion: The findings suggest that the relation between Aβ in parietal cortex is associated with SVD in downstream white matter (WM) pathways in preclinical AD. The biological relationships and interplay between Aβ and WM microstructure alterations that precede overt WMH development across the continuum of AD progression warrant further study.

AB - Background and purpose: Cerebral small vessel disease (SVD) has been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Yet, the role of SVD in potentially contributing to AD pathology is unclear. The main objective of this study was to test the hypothesis that WMHs influence amyloid β (Aβ) levels within connected default mode network (DMN) tracts and cortical regions in cognitively unimpaired older adults. Methods: Regional standard uptake value ratios (SUVr) from Aβ-PET and white matter hyperintensity (WMH) volumes from three-dimensional magnetic resonance imaging FLAIR images were analyzed across a sample of 72 clinically unimpaired (mini-mental state examination ≥26), older adults (mean age 74.96 and standard deviation 8.13) from the Alzheimer's Disease Neuroimaging Initiative (ADNI3). The association of WMH volumes in major fiber tracts projecting from cortical DMN regions and Aβ-PET SUVr in the connected cortical DMN regions was analyzed using linear regression models adjusted for age, sex, ApoE, and total brain volumes. Results: The regression analyses demonstrate that increased WMH volumes in the superior longitudinal fasciculus were associated with increased regional SUVr in the inferior parietal lobule (p =.011). Conclusion: The findings suggest that the relation between Aβ in parietal cortex is associated with SVD in downstream white matter (WM) pathways in preclinical AD. The biological relationships and interplay between Aβ and WM microstructure alterations that precede overt WMH development across the continuum of AD progression warrant further study.

KW - default mode network

KW - neuroimaging

KW - preclinical Alzheimer's disease

KW - regional standardized uptake value ratio

KW - white matter hyperintensities

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White matter hyperintensities influence distal cortical β-amyloid accumulation in default mode network pathways

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

Access to Document

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