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Associations between white matter microstructure and amyloid burden in preclinical Alzheimer’s disease: a multimodal imaging investigation.
Open accessAbstract
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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“Recent evidence in patients indicates that this increase in FA could be related to soluble Aβ rising in the early stage of AD (Racine et al., 2014).”
From Early stage alterations in white matter and decreased functional interhemispheric hippocampal connectivity in the 3xTg mouse model of Alzheimer’s disease. (2019) · cites this paper as Racine et al., 2014
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“Diffusion tensor imaging (DTI) metrics or structural connectome alterations showed correlations with amyloid burden (Racine et al., 2014) or levels of cerebrospinal fluid amyloid and tau (Tucholka et al., 2018).”
From Effects of Alzheimer’s and Vascular Pathologies on Structural Connectivity in Early- and Late-Onset Alzheimer’s Disease (2021) · cites this paper as Racine et al., 2014
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Remyelination in the CNS: from biology to therapy
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Metadata
- 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)
- 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
- gold
- doi.org
- 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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