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Free-water metrics in medial temporal lobe white matter tract projections relate to longitudinal cognitive decline

Derek B. Archer, Elizabeth E. Moore, Niranjana Shashikumar, Logan Dumitrescu, Kimberly R. Pechman, Bennett A. Landman, Katherine Gifford, Angela L. Jefferson, Timothy J. Hohman
doi: https://doi.org/10.1101/2020.01.06.896217
Derek B. Archer
aVanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine, Nashville, TN
bVanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN
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Elizabeth E. Moore
aVanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine, Nashville, TN
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Niranjana Shashikumar
aVanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine, Nashville, TN
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Logan Dumitrescu
aVanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine, Nashville, TN
bVanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN
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Kimberly R. Pechman
aVanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine, Nashville, TN
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Bennett A. Landman
cVanderbilt University Institute of Imaging Science, Vanderbilt University Medical Center, Nashville, TN, USA
dDepartment of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA
eDepartment of Electrical Engineering, Vanderbilt University, Nashville, TN, USA
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Katherine Gifford
aVanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine, Nashville, TN
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Angela L. Jefferson
aVanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine, Nashville, TN
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  • For correspondence: angela.jefferson@vumc.org
Timothy J. Hohman
aVanderbilt Memory and Alzheimer’s Center, Vanderbilt University School of Medicine, Nashville, TN
bVanderbilt Genetics Institute, Vanderbilt University School of Medicine, Nashville, TN
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Abstract

Objective Hippocampal volume is a sensitive marker of neurodegeneration and a well-established predictor of age-related cognitive impairment. Recently, free-water (FW) magnetic resonance imaging (MRI) has shown associations with pathology in Alzheimer’s disease (AD), but it is still unclear whether these metrics are associated with measures of cognitive impairment. Here, we investigate whether FW and FW-corrected fractional anisotropy (FAT) within medial temporal lobe white matter tracts (cingulum, fornix, uncinate fasciculus, inferior longitudinal fasciculus, and tapetum) provides meaningful contribution to cognition and cognitive decline beyond hippocampal volume.

Participants and Methods Vanderbilt Memory & Aging Project participants (n=319, 73±7 years, 59% male) with normal cognition and mild cognitive impairment (40% of cohort) underwent baseline brain MRI, including structural MRI to quantify hippocampal volume, diffusion MRI to quantify medial temporal lobe white matter tract FW and FAT, and longitudinal neuropsychological assessment with a mean follow-up of 3.5 years. Linear regressions were conducted to determine how hippocampal volume and white matter tract FW and FAT interact with baseline memory and executive function performances. Competitive model analyses determined the unique variance provided by white matter tract FW and FAT beyond that of hippocampal volume and other comorbidities. Linear mixed-effects models were conducted to determine how baseline hippocampal volume and white matter tract FW and FAT interact to explain longitudinal change in memory and executive function performances.

Results FW in the inferior longitudinal fasciculus, tapetum, uncinate fasciculus, and cingulum were robustly associated with baseline memory and executive function. Further, competitive model analysis showed that tract FW contributed unique variance beyond other comorbidities and hippocampal volume for memory (ΔRadj2 range: 0.82-2.00%) and executive function (ΔRadj2 range: 0.88-1.87%). Longitudinal analyses demonstrated significant interactions of hippocampal volume and FAT in the inferior longitudinal fasciculus (p=0.02), tapetum (p=0.02), uncinate fasciculus (p=0.02), and cingulum (p=0.002) with decline in memory. For decline in executive function, we found significant interactions of hippocampal volume and FAT in inferior longitudinal fasciculus (p=0.03), tapetum (p=0.02), uncinate fasciculus (p=0.02), and fornix (p=0.02), as well as cingulum (p=0.02) and fornix (p=0.02) FW.

Conclusions Our results highlight novel associations between FW and FAT measures of medial temporal lobe tract microstructure and cognitive performance such that individuals with smaller hippocampal volumes and lower tract microstructure experience greater cognitive decline. These results suggest that white matter has a unique role in cognitive decline and, therefore, could be used to provide better disease staging, allowing for more precise disease monitoring in AD.

Footnotes

  • Funding: R01-AG059716, K01-AG049164, IIRG-08-88733, R01-AG034962, R01-AG056534, K24-AG046373, F30-AG064847, T32-GM007347

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted January 07, 2020.
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Free-water metrics in medial temporal lobe white matter tract projections relate to longitudinal cognitive decline
Derek B. Archer, Elizabeth E. Moore, Niranjana Shashikumar, Logan Dumitrescu, Kimberly R. Pechman, Bennett A. Landman, Katherine Gifford, Angela L. Jefferson, Timothy J. Hohman
bioRxiv 2020.01.06.896217; doi: https://doi.org/10.1101/2020.01.06.896217
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Free-water metrics in medial temporal lobe white matter tract projections relate to longitudinal cognitive decline
Derek B. Archer, Elizabeth E. Moore, Niranjana Shashikumar, Logan Dumitrescu, Kimberly R. Pechman, Bennett A. Landman, Katherine Gifford, Angela L. Jefferson, Timothy J. Hohman
bioRxiv 2020.01.06.896217; doi: https://doi.org/10.1101/2020.01.06.896217

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