ORIGINAL RESEARCH article
Front. Aging Neurosci.
Sec. Alzheimer's Disease and Related Dementias
This article is part of the Research TopicImaging Biomarkers in Neurodegenerative Diseases: Advances and ChallengesView all 12 articles
Association of Perivascular Diffusion with White-matter Microstructural Integrity, Free Water, Aβ Burden, and Cognition: Diffusion Tensor vs. Kurtosis Tensor
Provisionally accepted
Zhiming Zeng1*
Xin Jia1Shushu Han2Cuidie Zeng1Jing Bi1Lingchen Liu1Yueming Wu1Tengao Gao1
Lei Liang3
Fangxiao Cheng1- 1Peking University, Beijing, China
- 2Chinese Academy of Medical Sciences Fuwai Hospital Shenzhen Hospital, Shenzhen, China
- 3Aerospace Center Hospital, Beijing, China
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ABSTRACT Background: Perivascular diffusion holds great potential for the non-invasive assessment of glymphatic system (GS). However, Gaussian model-based diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) is limited by microstructural alterations. This study aimed to compare cross-sectional and longitudinal trajectories of diffusion kurtosis imaging ALPS (DKI-ALPS) and DTI-ALPS, and investigate their association with white-matter (WM) microstructural integrity, free water (FW), Aβ burden, and cognitive impairment (CI). Methods: This study included 128 healthy controls (HCs) and 83 CIs who underwent multi-shell diffusion-weighted MRI (dMRI). Four dMRI indices were quantified: DTI-ALPS and DKI-ALPS to assess the GS function; peak width of skeletonized mean diffusivity (PSMD) to evaluate the WM microstructural integrity; and FW-WM to quantify the extracellular fluid accumulation in WM. Cohen's d was reported as the measures of effect size, with generalized linear models (GLM) adjusting for confounding factors. Functional principal component analysis (FPCA) was employed to determine the trajectories of dMRI indices. Results: CIs exhibited significantly lower DTI-ALPS (1.28 vs. 1.37; P = 0.007; Cohen's d = 0.383) and DKI-ALPS (1.37 vs. 1.63, P < 0.001; Cohen's d = 0.770) compared with HCs. GLMs confirmed the group differences in DKI-ALPS. DTI-ALPS was positively correlated with DKI-ALPS (r = 0.551; P < 0.001), with stronger associations in HCs than in CIs (r, 0.628 vs. 0.370; all P < 0.05). Both DTI-ALPS and DKI-ALPS were negatively correlated with PSMD (r, -0.327 and -0.251; all P < 0.05) and FW-WM (r, -0.317 and -0.393; all P < 0.05). FPCA revealed distinct trajectories of DTI-ALPS, DKI-ALPS, PSMD, and FW-WM between HCs and CIs, and the Cohen's d of 1st PFC score was 0.685, 0.977, 0.573, and 1.004, respectively (all P < 0.001). Compared with baseline dMRI measurements, the trajectory patterns exhibited stronger correlations with Aβ burden (DTI-ALPS, 0.277 vs. −0.217; DKI-ALPS, 0.552 vs. −0.468; PSMD, 0.278 vs. 0.201; FW-WM, 0.313 vs. 0.113) and cognitive performance. Conclusions: Our study indicates that DKI-ALPS provides an accurate assessment of GS function compared with DTI-ALPS. Longitudinal trajectories, particularly trajectory of DKI-ALPS, demonstrate stronger associations with Aβ burden and cognitive decline.
Keywords: cognitive impairment, Diffusion along the perivascular space, Free water, Peak widthof skeletonized mean diffusivity, trajectory patterns
Received: 28 Oct 2025; Accepted: 13 Feb 2026.
Copyright: © 2026 Zeng, Jia, Han, Zeng, Bi, Liu, Wu, Gao, Liang and Cheng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Zhiming Zeng
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