Free water derived by multi‐shell diffusion MRI reflects tau/neuroinflammatory pathology in Alzheimer's disease
Open accessAbstract
Introduction: Free‐water (FW) imaging, a new analysis method for diffusion magnetic resonance imaging (MRI), can indicate neuroinflammation and degeneration. We evaluated FW in Alzheimer's disease (AD) using tau/inflammatory and amyloid positron emission tomography (PET). Methods: Seventy‐one participants underwent multi‐shell diffusion MRI, 18 F‐THK5351 PET, 11 C‐Pittsburgh compound B PET, and neuropsychological assessments. They were categorized into two groups: healthy controls (HCs) ( n = 40) and AD‐spectrum group (AD‐S) ( n = 31) using the Centiloid scale with amyloid PET and cognitive function. We analyzed group comparisons in FW and PET, correlations between FW and PET, and correlation analysis with neuropsychological scores. Results: In AD‐S group, there was a significant positive correlation between FW and 18 F‐THK5351 in the temporal lobes. In addition, there were negative correlations between FW and cognitive function in the temporal lobe and cingulate gyrus, and negative correlations between 18 F‐THK5351 and cognitive function in the same regions. Discussion: FW imaging could be a biomarker for tau in AD alongside clinical correlations.
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White-matter free water has shown associations with cognitive performance and subsequent decline, particularly in limbic tracts.
“White-matter free water has shown associations with cognitive performance and subsequent decline, particularly in limbic tracts (Nakaya et al., 2022; Peter et al., 2025).”
From 40 Years of diffusion MRI in the brain: From history to emerging frontiers (2026) · cites this paper as Nakaya et al., 2022
The Discussion (page not provided) reports an association between free water and cognitive performance, including a prior finding based on whole-brain white-matter regions. Nakaya et al.’s own cognitive correlations concern cortical regions, particularly the temporal lobe; the cited passages do not establish subsequent cognitive decline or an association particularly in limbic white-matter tracts. (LLM, conf=0.86)
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Diffusion Imaging of Gray Matter Microstructure in Alzheimer’s Disease
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Free-water imaging of the nucleus basalis of Meynert in apolipoprotein E4 carriers
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Early White Matter Microstructure Alterations in Infants with Down Syndrome
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Early White Matter Microstructure Alterations in Infants with Down SyndromePreprint
Azrak, O., Garic, D., Nasir, A., Swanson, M. R., Grzadzinski, R., Al‐Ali, K., Shen, M. D., Girault, J. B., John, T. S., Pandey, J., et al. (2025) · medRxiv · doi:10.1101/2025.02.26.25322913 · Cited by 1 · see citing works
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“White-matter free water has shown associations with cognitive performance and subsequent decline, particularly in limbic tracts (Nakaya et al., 2022; Peter et al., 2025).”
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- Authors
- Nakaya, M., Sato, N., Matsuda, H., Maikusa, N., Shigemoto, Y., Sone, D., Yamao, T., Ogawa, M., Kimura, Y., Chiba, E., Ohnishi, M., Kato, K., Okita, K., Tsukamoto, T., Yokoi, Y., Sakata, M., & Abe, O.
- Affiliations
- National Center of Neurology and Psychiatry (JP)
- Jikei University School of Medicine (JP)
- Fukushima Medical University (JP)
- The University of Tokyo (JP)
- Corresponding author
- Sato, Noriko
- ORCID
- Venue
- Alzheimer's & Dementia: Translational Research & Clinical Interventions
- Publisher
- Wiley
- Published
- 2022-01
- Volume
- 8
- Issue
- 1
- Pages
- e12356-e12356
- ISSN
- 2352-8737 (ISSN-L)
- PMC
- PMC9594557
- OpenAlex
- W4307581412
- Cited by
- 41
- References
- 58
- Citations by year
- 2026: 8 · 2025: 18 · 2024: 10 · 2023: 4 · 2022: 1
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Alzheimer s & Dementia Translational Research & Clinical Interventions (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Japan Society for the Promotion of Science (20K08068)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
- Keywords
- free-water imaging, Alzheimer's disease, tau pathology, neuroinflammation, amyloid PET, 18F-THK5351, Pittsburgh compound B, multi-shell diffusion MRI, cognitive function, temporal lobe, cingulate gyrus, biomarkers
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