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Multilevel white matter degeneration associated cognitive dysfunction in mild cognitive impairment

Molecular Psychiatry (2025)Cite this article

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Abstract

Mild cognitive impairment (MCI), the prodromal stage of dementia, is characterized by cognitive dysfunction and white matter (WM) disruption. To investigate the WM microstructure degeneration at different scales in MCI, the orientation-sensitive fixel-based analysis was performed with fixelwise, fiberwise fiber-specific measures in 50 patients with MCI compared to 75 healthy controls. Moreover, to clarify the patterns of the organization operating at different scales in MCI, the potential mediated effects of structural connectome in networkwise on the associations between microstructure alterations of 24 anatomical tracts and cognitive dysfunction were analyzed. Compared to healthy controls, specific tracts were widely disrupted in fiberwise in patients with MCI, represented by the decrease of fiber density and cross-section in most commissural fibers and many association fibers, which was consistent with previous findings. The associations between WM microstructural degeneration and multi-domain cognitive dysfunction were also observed. Interestingly, the structural connectome between visual and salience networks played a potential mediating role in the relationship between disruption of WM microstructure and worse language performance, and we also found a similar situation in the memory domain. The present study provides mechanistic insight into the relationship between microstructure damage and cognitive dysfunction in prodromal dementia under a multilevel WM hierarchy.

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Fig. 1: Illustration for multilevel fixel-based analysis.
Fig. 2: Group comparisons of FBA measures.
Fig. 3: Mediation model hypothesis and potential main effects of the model.
Fig. 4: Mediation results in patients with MCI and HC, respectively.

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Data availability

The data and relevant code that support the findings of this study are available upon reasonable request to the corresponding author. ADNI data are available and can be searched from adni.loni.usc.edu after applying to the ADNI database.

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Acknowledgements

Thank Konstantinos Ioannou and Konstantinos Chiotis from Karolinska Institutet for their assistance in formatting. Data collection and sharing for the Alzheimer’s Disease Neuroimaging Initiative (ADNI) is funded by the National Institute on Aging (National Institutes of Health Grant U19AG024904). The grantee organization is the Northern California Institute for Research and Education. In the past, ADNI has also received funding from the National Institute of Biomedical Imaging and Bioengineering, the Canadian Institutes of Health Research, and private sector contributions through the Foundation for the National Institutes of Health (FNIH) including 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.

Funding

This work was supported by STI2030-Major Projects (2022ZD0208500), Key-Area Research and Development Program of Guangdong Province (2023B0303030002), the National Natural Science Foundation of China (grant numbers U20A20191, 62336002, 62306035, 62373056, 62406025), the Beijing Natural Science Foundation (IS23115).

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Authors and Affiliations

  1. School of Medical Technology, Beijing Institute of Technology, Haidian District, Beijing, China

    Yu Chen, Tiantian Liu, Li-Zhi Cao, Li Wang, Xiaoying Tang, Jinglong Wu, Jian Zhang & Tianyi Yan

  2. Advanced Research Institute of Multidisciplinary Sciences, Beijing Institute of Technology, Haidian District, Beijing, China

    Shintaro Funahashi

  3. Department of Radiology, Harbin Medical University, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang, China

    Wei Meng

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TY, YC, JZ and TL contributed to the conception and design of the work; TY, YC, TL, LC and JZ analyzed data, interpreted results of experiments and prepared figures; TY, YC, JZ, TL and LW drafted and revised the manuscript; SF, XT, JW and WM provided study supervision. Although the investigators for ADNI contributed to providing data, they did not participate in the analysis or writing of this manuscript. All authors read and approved the final manuscript.

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Correspondence to Tiantian Liu, Jian Zhang or Tianyi Yan.

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Data acquisition of ADNI was conducted in compliance with the protocol (NCT02854033), in accordance with GCP guidelines, all relevant regulations and laws. All subjects were informed about the aims of the study and signed a consent form under the approval of the Institutional Review Boards (IRB) and Research Ethics Boards (REB). More details on ethics approval and consent to participate in ADNI can be found at https://adni.loni.usc.edu/.

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Chen, Y., Liu, T., Cao, LZ. et al. Multilevel white matter degeneration associated cognitive dysfunction in mild cognitive impairment. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03179-7

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