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White matter hyperintensity-associated iron overload links glymphatic system dysfunction to cognitive impairment in

Yage Qiu1, Ying Hu1, Weina Ding1

  • 1Department of Radiology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.

Neuroimage
|October 10, 2025
PubMed

Insights

Iron overload in white matter hyperintensities mediates cognitive decline in cerebral small vessel disease (CSVD) by linking impaired glymphatic function to memory and executive deficits.

Area of Science:

  • Neuroimaging
  • Neurology
  • Metabolic Disorders

Background:

  • Glymphatic system function is increasingly linked to cognition in cerebral small vessel disease (CSVD).
  • Underlying pathological mechanisms, particularly brain metabolism and iron accumulation in white matter hyperintensities (WMH), require clarification.
  • Iron overload in WMH may be a key factor in the relationship between glymphatic dysfunction and cognitive impairment.

Purpose of the Study:

  • To investigate if WMH iron burden mediates the association between glymphatic dysfunction and cognitive impairment in CSVD patients.
  • To explore the role of iron accumulation in the pathological cascade of CSVD.

Main Methods:

  • 102 CSVD patients and 29 healthy controls (HCs) underwent MRI and cognitive assessments.
  • WMH iron burden quantified using a sub-voxel quantitative approach.
  • Glymphatic function assessed via Diffusion Tensor Image Analysis aLong the Perivascular Space (DTI-ALPS) index.

Main Results:

  • CSVD patients showed higher WMH iron burden, lower DTI-ALPS index, and poorer cognitive performance than HCs.
  • Elevated WMH iron burden correlated with deficits in attention-executive, memory, and visual-spatial domains.
  • Reduced DTI-ALPS index correlated with impaired attention-executive and memory function.
  • WMH iron burden fully mediated the link between DTI-ALPS index and attention-executive function and memory in CSVD patients.

Conclusions:

  • Noninvasively identified WMH iron overload acts as a key mediator between glymphatic dysfunction and cognitive decline in CSVD.
  • Iron overload, potentially representing microglial activation, may be a therapeutic target for managing cognitive impairment in CSVD.
  • This study highlights the intricate relationship between brain metabolism, glymphatic function, and cognition in CSVD.

Keywords:
Cerebral small vessel diseaseCognitive impairmentGlymphatic system dysfunctionIron overloadWhite matter hyperintensity

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