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Purpose <p>Type 2 diabetes mellitus (T2DM) increases the risk of cognitive impairment through metabolic-neurodegenerative interactions, yet the underlying neural mechanisms remain unclear. This study investigates whether glycemic control modulates the relationships among glymphatic dysfunction, cortical thinning, and cognition in T2DM, with a focus on whether glymphatic impairment is associated with chronic hyperglycemia-related neurostructural decline.</p> Methods <p>T2DM patients were stratified by glycemic control (Hemoglobin A1c &lt; 7.5% vs. ≥ 7.5%). All participants underwent neuropsychological assessments and magnetic resonance imaging (MRI) to quantify cortical thickness, choroid plexus volume (CPV), perivascular space (PVS) volume, and the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. Group comparisons, Spearman correlations, and mediation analyses were used to examine the pathways linking glycemic control, glymphatic function, and cortical structure.</p> Results <p>A total of 54 poorly controlled T2DM patients, 38 well-controlled T2DM patients, and 99 healthy controls were included. Poorly controlled T2DM patients exhibited worse cognitive performance compared with healthy controls. Both T2DM groups showed reduced cortical thickness in the insula, fusiform gyrus, and supramarginal gyrus relative to healthy controls, with insular atrophy significantly associated with enlarged CPV. Markers of glymphatic dysfunction, including enlarged CPV, increased PVS volume, and reduced DTI-ALPS index, were most pronounced in the poorly controlled T2DM group. Cortical thickness and glymphatic measures each correlated with cognitive performance. Mediation analysis indicated that CPV showed associations consistent with a mediating role in the relationship between HbA1c and left insular cortical thinning.</p> Conclusion <p>Compared with other subgroups, in the poorly controlled T2DM group, glymphatic changes were more pronounced, and the glymphatic-cognitive associations were more evident. Furthermore, CPV showed associations consistent with a mediating role in the relationship between hyperglycemia and cortical thinning in T2DM patients. These findings suggest that the glymphatic system may serve as an associative link between systemic metabolic dysregulation and structural neurodegeneration, offering potential imaging biomarkers for early neurological risk assessment in T2DM.</p>

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Glymphatic dysfunction is associated with hyperglycemia-related cortical thinning in patients with type 2 diabetes mellitus

  • 期刊论文

  • 发表日期：

    2026年7月13日

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  • Shuyue Fan,
  • Yujie Zhang,
  • Yong Luo,
  • Rong Huang,
  • Xin Wang,
  • Yu-Chen Chen,
  • Yong Xiao,
  • Wenqing Xia

摘要

Purpose

Type 2 diabetes mellitus (T2DM) increases the risk of cognitive impairment through metabolic-neurodegenerative interactions, yet the underlying neural mechanisms remain unclear. This study investigates whether glycemic control modulates the relationships among glymphatic dysfunction, cortical thinning, and cognition in T2DM, with a focus on whether glymphatic impairment is associated with chronic hyperglycemia-related neurostructural decline.

Methods

T2DM patients were stratified by glycemic control (Hemoglobin A1c < 7.5% vs. ≥ 7.5%). All participants underwent neuropsychological assessments and magnetic resonance imaging (MRI) to quantify cortical thickness, choroid plexus volume (CPV), perivascular space (PVS) volume, and the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index. Group comparisons, Spearman correlations, and mediation analyses were used to examine the pathways linking glycemic control, glymphatic function, and cortical structure.

Results

A total of 54 poorly controlled T2DM patients, 38 well-controlled T2DM patients, and 99 healthy controls were included. Poorly controlled T2DM patients exhibited worse cognitive performance compared with healthy controls. Both T2DM groups showed reduced cortical thickness in the insula, fusiform gyrus, and supramarginal gyrus relative to healthy controls, with insular atrophy significantly associated with enlarged CPV. Markers of glymphatic dysfunction, including enlarged CPV, increased PVS volume, and reduced DTI-ALPS index, were most pronounced in the poorly controlled T2DM group. Cortical thickness and glymphatic measures each correlated with cognitive performance. Mediation analysis indicated that CPV showed associations consistent with a mediating role in the relationship between HbA1c and left insular cortical thinning.

Conclusion

Compared with other subgroups, in the poorly controlled T2DM group, glymphatic changes were more pronounced, and the glymphatic-cognitive associations were more evident. Furthermore, CPV showed associations consistent with a mediating role in the relationship between hyperglycemia and cortical thinning in T2DM patients. These findings suggest that the glymphatic system may serve as an associative link between systemic metabolic dysregulation and structural neurodegeneration, offering potential imaging biomarkers for early neurological risk assessment in T2DM.