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Cited by 136Dementia and Cognitive Impairment ResearchAdvanced Neuroimaging Techniques and ApplicationsAlzheimer's disease research and treatments

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Associations between white matter microstructure and amyloid burden in preclinical Alzheimer’s disease: a multimodal imaging investigation.

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Racine, Annie M., Adluru, Nagesh, Alexander, Andrew L., Christian, Bradley T., Okonkwo, Ozioma C., Oh, Jennifer, Cleary, Caitlin A., Birdsill, Alex, Hillmer, Ansel T., Murali, Dhanabalan, Barnhart, Todd E., Gallagher, Catherine L., Carlsson, Cynthia M., Rowley, Howard A., Dowling, N. Maritza, Asthana, Sanjay, Sager, Mark A., Bendlin, Barbara B., Johnson, Sterling C.·2014·NeuroImage: Clinical
DOI 10.1016/j.nicl.2014.02.001PMC PMC4053642
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Abstract

Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (Aβ+), amyloid indeterminate (Aβi), or amyloid negative (Aβ-) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ- in all three ROIs and in Aβi compared to Aβ- in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses showing that cognitive function in these participants is not associated with any of the four DTI metrics, the present results suggest an early relationship between PiB and DTI, which may be a meaningful indicator of the initiating or compensatory mechanisms of AD prior to cognitive decline.

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Crossref · 10.1016/j.nicl.2014.02.001

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Graphical abstract CC BY-NC-ND · PubMed Central
Fig. 1 Regions of interest. The 3 ROIs assessed in this study are the cingulum-CC, which is the cingulum adjacent to the corpus callosum (green), the lateral fornix (blue), and the cingulum-HC, which is the part of the cingulum that extends from the posterior cingulum to the hippocampus (magenta).
Fig. 1 Regions of interest. The 3 ROIs assessed in this study are the cingulum-CC, which is the cingulum adjacent to the corpus callosum (green), the lateral fornix (blue), and the cingulum-HC, which is the part of the cingulum that extends from the posterior cingulum to the hippocampus (magenta).CC BY-NC-ND · PubMed Central
Fig. 2 Fractional anisotropy group differences in ROIs. Significant group differences in fractional anisotropy within the three ROIs displayed on FSL's FMRIB58_FA template transformed to this study's population space. Regions where Aβ + had significantly higher FA than Aβ − (p(FWE) < .05, blue), Aβi had significantly higher FA than Aβ − (p(FWE) < .05, red), both Aβ + and Aβi had significantly higher FA than Aβ − (p(FWE) < .05, purple), Aβ + showed a trend of higher FA compared to Aβ − (p(uncorr) < .001, yellow), Aβi showed a trend of higher FA compared to Aβ − (p(uncorr) < .001, cyan), and both Aβ + and Aβi showed a trend of higher FA compared to Aβ − (p(uncorr) < .001, light green). A.) Sagittal slices from left to right. B.) Coronal slices from posterior to anterior. Left is on the left.
Fig. 2 Fractional anisotropy group differences in ROIs. Significant group differences in fractional anisotropy within the three ROIs displayed on FSL's FMRIB58_FA template transformed to this study's population space. Regions where Aβ + had significantly higher FA than Aβ − (p(FWE) < .05, blue), Aβi had significantly higher FA than Aβ − (p(FWE) < .05, red), both Aβ + and Aβi had significantly higher FA than Aβ − (p(FWE) < .05, purple), Aβ + showed a trend of higher FA compared to Aβ − (p(uncorr) < .001, yellow), Aβi showed a trend of higher FA compared to Aβ − (p(uncorr) < .001, cyan), and both Aβ + and Aβi showed a trend of higher FA compared to Aβ − (p(uncorr) < .001, light green). A.) Sagittal slices from left to right. B.) Coronal slices from posterior to anterior. Left is on the left.CC BY-NC-ND · PubMed Central
Fig. 3 Fractional anisotropy whole-brain group differences. Significant group differences (p(FWE) < .05) from whole-brain analyses in FA displayed on FSL's FMRIB58_FA template transformed to this study's population space. Regions where Aβ + had higher FA than Aβ − (blue), Aβi had higher FA than Aβ − (red), and both Aβ + and Aβi had higher FA than Aβ − (purple). A.) Sagittal slices from left to right. B.) Coronal slices from posterior to anterior. Left is on the left.
Fig. 3 Fractional anisotropy whole-brain group differences. Significant group differences (p(FWE) < .05) from whole-brain analyses in FA displayed on FSL's FMRIB58_FA template transformed to this study's population space. Regions where Aβ + had higher FA than Aβ − (blue), Aβi had higher FA than Aβ − (red), and both Aβ + and Aβi had higher FA than Aβ − (purple). A.) Sagittal slices from left to right. B.) Coronal slices from posterior to anterior. Left is on the left.CC BY-NC-ND · PubMed Central
Fig. 4 Mean diffusivity whole-brain group differences. Significant group differences from whole-brain analyses in MD displayed on FSL's FMRIB58_FA template transformed to this study's population space. Higher mean diffusivity was observed in Aβ − compared to Aβ + sin fronto-lateral GM, p(FWE) = 0.024. Left is on the left.
Fig. 4 Mean diffusivity whole-brain group differences. Significant group differences from whole-brain analyses in MD displayed on FSL's FMRIB58_FA template transformed to this study's population space. Higher mean diffusivity was observed in Aβ − compared to Aβ + sin fronto-lateral GM, p(FWE) = 0.024. Left is on the left.CC BY-NC-ND · PubMed Central
Fig. 5 Mean diffusivity and PiB DVR correlation. Moderate correlation between PiB DVR and MD from the significant MD cluster from Table 4 and Fig. 4. Spearman coefficient = − 0.392.
Fig. 5 Mean diffusivity and PiB DVR correlation. Moderate correlation between PiB DVR and MD from the significant MD cluster from Table 4 and Fig. 4. Spearman coefficient = − 0.392.CC BY-NC-ND · PubMed Central

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Authors
Racine, A. M., Adluru, N., Alexander, A. L., Christian, B. T., Okonkwo, O. C., Oh, J., Cleary, C. A., Birdsill, A., Hillmer, A. T., Murali, D., Barnhart, T. E., Gallagher, C. L., Carlsson, C. M., Rowley, H. A., Dowling, N. M., Asthana, S., Sager, M. A., Bendlin, B. B., & Johnson, S. C.
Affiliations
  • University of Wisconsin–Madison (US)
  • University of Wisconsin System (US)
Corresponding author
Johnson, Sterling C.
ORCID
Venue
NeuroImage: Clinical
Publisher
Elsevier BV
Published
2014
Volume
4
Pages
604-614
ISSN
2213-1582 (ISSN-L)
DOI
10.1016/j.nicl.2014.02.001
PMC
PMC4053642
OpenAlex
W2060171712
Cited by
136
References
100
Citations by year
2026: 7 · 2025: 8 · 2024: 11 · 2023: 7 · 2022: 7 · 2021: 11 · 2020: 15 · 2019: 12 · 2018: 16 · 2017: 12 · 2016: 11 · 2015: 15 · 2014: 2
FWCI
10.18
Type
journal article
Language
en
Open access
Licence
Locations
  • NeuroImage Clinical (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • NIH (AG021155, AG000213, AG027161, AG037639, AG033514)
  • Veterans Administration Merit Review Grant (I01CX000165)
  • Alzheimer's Association
  • Clinical and Translational Science Award (UL1RR025011)
  • University of Wisconsin, Madison
  • NSF (0849122)
  • Helen Bader Foundation
  • Northwestern Mutual Foundation
  • Extendicare Foundation
  • Veterans Administration
  • Waisman Center, University of Wisconsin-Madison
Topics
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
Keywords
preclinical Alzheimer's disease, brain amyloid burden, white matter microstructure, diffusion tensor imaging, fractional anisotropy, mean diffusivity, PiB PET, Pittsburgh compound B, cingulum, Wisconsin Registry for Alzheimer's Prevention, multimodal neuroimaging, compensatory mechanisms
MeSH terms
Aged, Alzheimer Disease, Brain, Female, Humans, Male, Middle Aged, Sensitivity and Specificity, Reproducibility of Results, Amyloid beta-Peptides, Positron-Emission Tomography, Diffusion Tensor Imaging, Molecular Imaging, Multimodal Imaging, White Matter

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