Glymphatic System Impairment in Type 2 Diabetes Mellitus Associated with Cognitive Function

Jie Gao^1†, Peichun Pan^2†, Jing Li³, Bingqian Gao³, Dongsheng Zhang¹, Min Tang¹, Xuejiao Yan¹, Kai Ai⁴, Xiaoyan Lei¹, Zhongwei Liu⁵, Yuming Zhang⁶, Xiaoling Zhang^1*

Show Less

¹ Department of MRI, Shaanxi Provincial People’s Hospital, Xi’an 710000, Shaanxi, China

² Department of Graduate, Shaanxi University of Chinese Medicine, Xianyang 712000, Shaanxi, China

³ Department of Graduate, Xi’an Medical University, Xi’an 710000, Shaanxi, China

⁴ Department of Clinical Science, Philips Healthcare, Xi’an 710000, Shaanxi, China

⁵ Department of Cardiology, Shaanxi Provincial People’s Hospital, Xi’an 710000, Shaanxi, China

⁶ Department of Anesthesiology, Shaanxi Provincial People’s Hospital, Xi’an 710000, Shaanxi, China

APM 2025 , 10(3), 158–167; https://doi.org/10.18063/APM.v10i3.633

© 2025 by the Author. Licensee Whioce Publishing, Singapore. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )

Abstract

Objective: This study aims to investigate human glymphatic function in type 2 diabetes mellitus (T2DM) using the index for diffusion tensor image analysis along the perivascular space (DTI-ALPS) and to explore the relationship between this proposed measure of glymphatic clearance and cognitive functions. Methods: A total of 17 patients with T2DM and 20 age- and sex-matched health controls (HCs) were included in this study. All participants underwent neurological MRI and cognitive assessments. Both the average and bilateral DTI-ALPS indices, clinical and cognitive measurements were compared between the two groups. The correlations between DTI-ALPS indices and cognitive measurements were analyzed. Results: The average and right DTI-ALPS indices were significantly lower in the T2DM group than them in HC group (P = 0.011, P = 0.005). In HC group, the right DTI-ALPS index was higher than the left (P = 0.039), whereas no hemispheric difference was observed in T2DM. In correlation analyses, a lower DTI-ALPS index was associated with poorer TMT-B performance in T2DM (β = -0.502, P = 0.001), while no other significant correlations were found between DTI-ALPS index and cognitive measures in either group. Conclusion: This study demonstrated impaired glymphatic system function in T2DM patients and it is associated with worse performance in executive functions. The impaired glymphatic function in patients with T2DM may provide a new perspective for understanding the pathophysiology of T2DM-associated cognitive impairment.

Keywords

Diffusion tensor imaging

Glymphatic system

MRI

Type 2 diabetes mellitus

Funding

National Natural Science Foundation of China (Project No.: 82170820); Social Development Science and Technology Research Project of Shaanxi Province of China (Project No.: 2023-YBSF-579)

References

[1] Saeedi P, Petersohn I, Salpea P, et al., 2019, Global and Regional Diabetes Prevalence Estimates for 2019 and Projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition. Diabetes Res Clin Pract, 2019(157): 107843.

[2] Damanik J, Yunir E, 2021, Type 2 Diabetes Mellitus and Cognitive Impairment. Acta Med Indones, 53(2): 213–220.

[3] Moran C, Beare R, Wang W, et al., 2019, Type 2 Diabetes Mellitus, Brain Atrophy, and Cognitive Decline. Neurology, 92(8): e823–e830.

[4] Iliff J, Wang M, Liao Y, et al., 2012, A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β. Sci Transl Med, 4(147): 147.

[5] Hladky S, Barrand M, 2022, The Glymphatic Hypothesis: The Theory and the Evidence. Fluids Barriers CNS, 19(1): 9.

[6] Bah T, Siler D, Ibrahim A, et al., 2023, Fluid Dynamics in Aging-related Dementias. Neurobiol Dis, 2023(177): 105986.

[7] Lee S, Yoo R, Choi S, et al., 2021, Contrast-Enhanced MRI T1 Mapping for Quantitative Evaluation of Putative Dynamic Glymphatic Activity in the Human Brain in Sleep-Wake States. Radiology, 300(3): 661–668.

[8] Benveniste H, Lee H, Ozturk B, et al., 2021, Glymphatic Cerebrospinal Fluid and Solute Transport Quantified by MRI and PET Imaging. Neuroscience, 2021(474): 63–79.

[9] Taoka, T, Masutani Y, Kawai H, et al., 2017, Evaluation of Glymphatic System Activity with the Diffusion MR Technique: Diffusion Tensor Image Analysis Along the Perivascular Space (DTI-ALPS) in Alzheimer’s Disease Cases. Jpn J Radiol, 35(4): 172–178.

[10] Hsu J, Wei Y, Toh C, et al., 2021, Magnetic Resonance Images Implicate That Glymphatic Alterations Mediate Cognitive Dysfunction in Alzheimer Disease. Ann Neurol, 93(1): 164–174.

[11] Toh C, Siow T, 2021, Glymphatic Dysfunction in Patients With Ischemic Stroke. Front Aging Neurosci, 2021(13): 756249.

[12] Kikuta, J, Kamagata K, Taoka T, et al., 2022, Water Diffusivity Changes Along the Perivascular Space After Lumboperitoneal Shunt Surgery in Idiopathic Normal Pressure Hydrocephalus. Front Neurol, 2022(13): 843883.

[13] Song H, Ruan Z, Gao L, et al., 2022, Structural Network Efficiency Mediates the Association Between Glymphatic Function and Cognition in Mild VCI: A DTI-ALPS Study. Front Aging Neurosci, 2022(14): 974114.

[14] Chen Y, Wang M, Su S, et al., 2023, Assessment of the Glymphatic Function in Children with Attention-Deficit/Hyperactivity Disorder. Eur Radiol, 34(3): 1444–1452.

[15] Ma X, Li S, Li C, et al., 2021, Diffusion Tensor Imaging Along the Perivascular Space Index in Different Stages of Parkinson’s Disease. Front Aging Neurosci, 2021(13): 773951.

[16] Jayaraj R, Azimullah S, Beiram R, 2020, Diabetes as a Risk Factor for Alzheimer’s Disease in the Middle East and its Shared Pathological Mediators. Saudi J Biol Sci, 27(2): 736–750.

[17] Li H, Luo Y, Xu Y, et al., 2018, Meloxicam Improves Cognitive Impairment of Diabetic Rats through COX2-PGE2-EPs-cAMP/pPKA Pathway. Mol Pharm, 15(9): 4121–4131.

[18] Tang Y, Yu C, Wu J, et al., 2018, Lychee Seed Extract Protects Against Neuronal Injury and Improves Cognitive Function in Rats with Type II Diabetes Mellitus with Cognitive Impairment. Int J Mol Med, 41(1): 251–263.

[19] Jash K, Gondaliya P, Kirave P, et al., 2020, Cognitive Dysfunction: A Growing Link Between Diabetes and Alzheimer’s Disease. Drug Dev Res, 81(2): 144–164.

[20] Chen R, Shi J, Yin Q, et al., 2018, Morphological and Pathological Characteristics of Brain in Diabetic Encephalopathy. J Alzheimers Dis, 65(1): 15–28.

[21] American Diabetes Association, 2013, Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 36 Suppl 1(Suppl 1): S67–74.

[22] Zhang W, Zhou Y, Wang J, et al., 2021, Glymphatic Clearance Function in Patients with Cerebral Small Vessel Disease. Neuroimage, 2021(238): 118257.

[23] Roy B, Lubera V, Sing K, et al., 2025, Glymphatic System Impairment in Type II Diabetes Mellitus Adults. Res Sq. https://doi.org/10.21203/rs.3.rs-6467065/v1

[24] Hu P, Zou Y, Zhou M, et al., 2025, Association of Diffusion Tensor Imaging Along the Perivascular Space Index with Cognitive Impairment in Type 2 Diabetes Mellitus. Quant Imaging Med Surg, 15(2): 1491–1504.

[25] Chen Q, Ge D, Xu X, et al., 2025, Glymphatic Function Associates with Alzheimer’s Disease-Signature Region Volumes, Plasma Biomarkers and White Matter Hyperintensity Progression in Cognitively Unimpaired Older Adults. Age Ageing, 54(6): afaf141.

[26] Zhang X, Wang Y, Jiao B, et al., 2024, Glymphatic System Impairment in Alzheimer’s Disease: Associations with Perivascular Space Volume and Cognitive Function. Eur Radiol, 34(2): 1314–1323.

[27] Zhou C, Li J, Dong M, et al., 2021, Altered White Matter Microstructures in Type 2 Diabetes Mellitus: A Coordinate-Based Meta-Analysis of Diffusion Tensor Imaging Studies. Front Endocrinol (Lausanne), 2021(12): 658198.

[28] Wang Y, Yang M, Zeng X, et al., 2025, Glymphatic Dysfunction Assessed by DTI-ALPS Index Predicts Early Cognitive Impairment in Acute Subcortical Infarcts: A Prospective Clinical Cohort Study. Front Neurol, 2025(16): 1605889.

[29] Rasmussen M, Mestre H, Nedergaard M, 2018, The Glymphatic Pathway in Neurological Disorders. Lancet Neurol, 17(11): 1016–1024.

[30] Kamagata K, Andica C, Takabayashi K, et al., 2022, Association of MRI Indices of Glymphatic System With Amyloid Deposition and Cognition in Mild Cognitive Impairment and Alzheimer Disease. Neurology, 99(24): e2648–e2660.

[31] Okazawa H, Nogami M, Ishida S, et al., 2024, PET/MRI Multimodality Imaging to Evaluate Changes in Glymphatic System Function and Biomarkers of Alzheimer’s Disease. Sci Rep, 14(1): 12310.

[32] Lashkari A, 2025, The Effects of Diabetes on the Glymphatic System: Recent Advances and Mechanistic Insights. Cardiovasc Diabetol Endocrinol Rep, 11(1): 14.

[33] Iliff J, Wang M, Zeppenfeld D, et al., 2013, Cerebral Arterial Pulsation Drives Paravascular CSF-Interstitial Fluid Exchange in the Murine Brain. J Neurosci, 33(46): 18190–9.

[34] Jiang Q, Zhang L, Ding G, et al., 2017, Impairment of the Glymphatic System After Diabetes. J Cereb Blood Flow Metab, 37(4): 1326–1337.

Previous article in this issue

Next article in this issue