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. 2025 Jun;31(6):e70478.
doi: 10.1111/cns.70478.

The Relationship Between Glymphatic Function, White Matter Hyperintensity and Cognition: A Structural Equation Model MRI Study

Lin Wu  1   2 , Kaixiao Chen  1   2 , Zhi Zhang  3 , Han Wang  4 , Daojun Hong  4 , Meng Li  5   6 , Fuqing Zhou  1   2
Affiliations

The Relationship Between Glymphatic Function, White Matter Hyperintensity and Cognition: A Structural Equation Model MRI Study

Lin Wu et al. CNS Neurosci Ther. 2025 Jun.

Abstract

Background: White matter hyperintensity (WMH) is associated with glymphatic dysfunction. Few studies have focused on the causal effects of the dysfunction of the glymphatic circulation pathways (inflow and outflow pathway) on WMH and cognitive function.

Methods: This study investigated the directional effects between glymphatic circulation, WMH lesions, and cognitive function in older adults based on structural equation models. The lateral ventricle choroid plexus (ChP), the coupling strength between blood oxygen signals in gray matter and cerebrospinal fluid flow, the diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index, and meningeal lymphatic vessels (MLVs) were analyzed for quantitative analysis of the glymphatic circulation.

Results: Compared to healthy controls, participants with WMH had greater ChP volume, lower DTI-ALPS index, and reduced MLVs function, all associated with worse cognitive performance. Both ChP/LatVent (p = 0.009) and DTI-ALPS (p < 0.001) are significant predictors of WMH volume. Deep WMH (DWMH) partially mediated the relationship between glymphatic function (ChP/LatVent, β = 0.108, p = 0.044; DTI-ALPS, β = 0.122, p = 0.032) and cognition. Structural equation models revealed that glymphatic outflow negatively influenced WMH (β = -0.572, p < 0.001), and WMH had a significantly negative effect on cognitive function (β = -0.705, p = 0.006).

Conclusions: Our results suggest that DWMH plays a mediating role in glymphatic decline and cognitive abnormalities, and that diminished glymphatic circulation affects WMH volume, leading to decreased cognitive function.

Keywords: cognition; glymphatic function; structural equation modeling; white matter hyperintensity.

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Conflict of interest statement

Associated data: This section collects any data citations, data availability statements, or Supporting Information included in this article.

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Participant flow diagram.
FIGURE 2
FIGURE 2
Box and whisker plots of ChP (a), dorsal MLVs (b), and DTI‐ALPS (c) data. p values are adjusted for age, sex, and education.
FIGURE 3
FIGURE 3
Mediation effect of WMH volume on the relationship between glymphatic inflow/outflow and cognition. (a) DWMH partially mediated the association between glymphatic circulation and MoCA scores. (b) PWMH did not significantly mediate the relationship between glymphatic function and MoCA scores. *p < 0.05; **p < 0.001.
FIGURE 4
FIGURE 4
Structural equation model. A1: ChP/LatVent A2: Maximum strength of global BOLD–CSF coupling; B1: Average‐DTI‐ALPS, B2: Dorsal TTP, B3: Dorsal AUC, B4: Dorsal Kep; C1: PWMH, C2:DWMH, C3:Fazekas score; D1: MMSE, D2: MoCA. “**” indicates statistically significant results (p < 0.01).
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