Three-dimensional-arterial spin labeling perfusion correlation with diabetes-associated cognitive dysfunction and vascular endothelial growth factor in type 2 diabetes mellitus rat

doi:10.4239/wjd.v12.i4.499

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World Journal of Diabetes

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World J Diabetes. Apr 15, 2021; 12(4): 499-513
Published online Apr 15, 2021. doi: 10.4239/wjd.v12.i4.499

Three-dimensional-arterial spin labeling perfusion correlation with diabetes-associated cognitive dysfunction and vascular endothelial growth factor in type 2 diabetes mellitus rat

Ju-Wei Shao, Jin-De Wang, Qian He, Ying Yang, Ying-Ying Zou, Wei Su, Shu-Tian Xiang, Jian-Bo Li, Jing Fang

Ju-Wei Shao, Qian He, Wei Su, Shu-Tian Xiang, Jian-Bo Li, Department of Radiology, The Second People’s Hospital of Yunnan Province, The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China

Ju-Wei Shao, College of Public Health, Kunming Medical University, Kunming 650500, Yunnan Province, China

Jin-De Wang, College of Clinical Medicine, Kunming Medical University, Kunming 650500, Yunnan Province, China

Ying Yang, Department of Endocrinology and Metabolism, The Second People’s Hospital of Yunnan Province, The Affiliated Hospital of Yunnan University, Kunming 650021, Yunnan Province, China

Ying-Ying Zou, Department of Pathology and Pathophysiology, Kunming Medical University, Kunming 650021, Yunnan Province, China

Jing Fang, Institute for Health Sciences, Kunming Medical University, Kunming 650500, Yunnan Province, China

Author contributions: Shao JW designed experiments, performed the literature review, and wrote the draft of the paper; Wang JD and Zou YY helped establish the type 2 diabetes mellitus rat models and assisted in the histopathologic procedures; Li JB scanned the rats; Su W collected the data; He Q and Xiang ST corrected the data; Yang Y also contributed to the writing and editing of the manuscript, which was critically revised and edited by Fang J; All authors approved the final version.

Supported by The Endocrine Clinical Medical Center of Yunnan Province, No. ZX20190202; the Fund of the Diabetic Innovation Team in Yunnan Province, No. 2019HC002; the Special Joint Fund from Yunnan Provincial Department of Science and Technology and Kunming Medical University, Kunming, Yunnan, China, No. 2018FE001(-267); and the SKY Image Research Fund, China, No. Z-2014-07-2003-12.

Institutional animal care and use committee statement: All animal experiments conformed to the internationally accepted principles for the care and use of laboratory animals (Kunming Medical University Institutional Review Board, Approval No. kmmu 2020410).

Conflict-of-interest statement: No potential conflicts of interest.

Data sharing statement: Technical appendix, statistical code, and data set available from the corresponding author at fangjing07@126.com. Participants gave informed consent for data sharing. No additional data are available.

ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.

Corresponding author: Jing Fang, MD, Professor, Institute for Health Sciences, Kunming Medical University, No. 1168 Chunrong West Road, Yuhua Street, Chenggong District, Kunming 650031, Yunnan Province, China. fangjing07@126.com

Received: December 11, 2020
Peer-review started: December 11, 2020
First decision: January 11, 2021
Revised: January 12, 2021
Accepted: March 7, 2021
Article in press: March 7, 2021
Published online: April 15, 2021
Processing time: 118 Days and 2.1 Hours

Abstract

BACKGROUND

Type 2 diabetes mellitus (T2DM) has been strongly associated with an increased risk of developing cognitive dysfunction and dementia. The mechanisms of diabetes-associated cognitive dysfunction (DACD) have not been fully elucidated to date. Some studies proved lower cerebral blood flow (CBF) in the hippocampus was associated with poor executive function and memory in T2DM. Increasing evidence showed that diabetes leads to abnormal vascular endothelial growth factor (VEGF) expression and CBF changes in humans and animal models. In this study, we hypothesized that DACD was correlated with CBF alteration as measured by three-dimensional (3D) arterial spin labeling (3D-ASL) and VEGF expression in the hippocampus.

AIM

To assess the correlation between CBF (measured by 3D-ASL and VEGF expression) and DACD in a rat model of T2DM.

METHODS

Forty Sprague-Dawley male rats were divided into control and T2DM groups. The T2DM group was established by feeding rats a high-fat diet and glucose to induce impaired glucose tolerance and then injecting them with streptozotocin to induce T2DM. Cognitive function was assessed using the Morris water maze experiment. The CBF changes were measured by 3D-ASL magnetic resonance imaging. VEGF expression was determined using immunofluorescence.

RESULTS

The escape latency time significantly reduced 15 wk after streptozotocin injection in the T2DM group. The total distance traveled was longer in the T2DM group; also, the platform was crossed fewer times. The percentage of distance in the target zone significantly decreased. CBF decreased in the bilateral hippocampus in the T2DM group. No difference was found between the right CBF value and the left CBF value in the T2DM group. The VEGF expression level in the hippocampus was lower in the T2DM group and correlated with the CBF value. The escape latency negatively correlated with the CBF value. The number of rats crossing the platform positively correlated with the CBF value.

CONCLUSION

Low CBF in the hippocampus and decreased VEGF expression might be crucial in DACD. CBF measured by 3D-ASL might serve as a noninvasive imaging biomarker for cognitive impairment associated with T2DM.

Keywords: Diabetes-associated cognitive dysfunction; Diabetes mellitus; Type 2; Perfusion imaging; Receptors; Vascular endothelial growth factor; Hippocampus; Three-dimensional pseudo-continuous arterial spin labeling

Core Tip: This study aimed to assess the correlation between cerebral blood flow measured by three-dimensional arterial spin labeling, vascular endothelial growth factor expression, and diabetes-associated cognitive dysfunction in a rat model of type 2 diabetes (T2D). Our results showed low cerebral blood flow in the hippocampus and decreased vascular endothelial growth factor expression might be crucial in diabetes-associated cognitive dysfunction. Cerebral blood flow measured by three-dimensional arterial spin labeling might serve as a noninvasive imaging biomarker for cognitive impairment associated with T2D. This study would help in the early detection of diabetes-associated cognitive dysfunction and guide treatment.