Super-resolution ultrasound imaging reveals temporal cerebrovascular changes with disease progression in female 5×FAD mouse model of Alzheimer's disease: correlation with pathological impairmentsResearch in context
Haoming Lin,
Zidan Wang,
Yingtao Liao,
Zhifan Yu,
Huiqin Xu,
Ting Qin,
Jianbo Tang,
Xifei Yang,
Siping Chen,
Xin Chen,
Xinyu Zhang,
Yuanyuan Shen
Affiliations
Haoming Lin
National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, 518071, China
Zidan Wang
National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, 518071, China
Yingtao Liao
National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, 518071, China; Department of Radiation Oncology, Huizhou Central People's Hospital, Huizhou, 516001, Guangdong, China
Zhifan Yu
National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, 518071, China
Huiqin Xu
National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, 518071, China
Ting Qin
National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, 518071, China
Jianbo Tang
Department of Biomedical Engineering, Southern University of Science and Technology, Shenzhen, 518071, China
Xifei Yang
Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Centre for Disease Control and Prevention, Shenzhen, 518055, China
Siping Chen
National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, 518071, China
Xin Chen
National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, 518071, China
Xinyu Zhang
National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, 518071, China
Yuanyuan Shen
National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, Guangdong Key Laboratory of Biomedical Measurements and Ultrasound Imaging, School of Biomedical Engineering, Medical School, Shenzhen University, Shenzhen, 518071, China; Corresponding author. School of Biomedical Engineering, Lihu Campus of Shenzhen University, 1066 Xueyuan Avenue, Nanshan District, Shenzhen, 518071, China.
Summary: Background: Vascular dysfunction is closely associated with the progression of Alzheimer's disease (AD). A critical research gap exists that no studies have explored the in vivo temporal changes of cerebrovascular alterations with AD progression in mouse models, encompassing both structure and flow dynamics at micron-scale resolution across the early, middle, and late stages of the disease. Methods: In this study, ultrasound localisation microscopy (ULM) was applied to image the cerebrovascular alterations of the transgenic female 5×FAD mouse model across different stages of disease progression: early (4 months), moderate (7 months), and late (12 months). Age-matched non-transgenic (non-Tg) littermates were used as controls. Immunohistology examinations were performed to evaluate the influence of disease progression on the β-amyloid (Aβ) load and microvascular alterations, including morphological changes and the blood–brain barrier (BBB) leakage. Findings: Our findings revealed a significant decline in both vascular density and flow velocity in the retrosplenial cortex of 5×FAD mice at an early stage, which subsequently became more pronounced in the visual cortex and hippocampus as the disease progressed. Additionally, we observed a reduction in vascular length preceding diminished flow velocities in cortical penetrating arterioles during the early stages. The quantification of vascular metrics derived from ULM imaging showed significant correlations with those obtained from vascular histological images. Immunofluorescence staining identified early vascular abnormalities in the retrosplenial cortex. As the disease advanced, there was an exacerbation of Aβ accumulation and BBB disruption in a regionally variable manner. The vascular changes observed through ULM imaging exhibited a negative correlation with amyloid load and were associated with the compromise of the BBB integrity. Interpretation: Through high-resolution, in vivo imaging of cerebrovasculature, this study reveals significant spatiotemporal dysfunction in cerebrovascular dynamics accompanying disease progression in a mouse model of AD, enhancing our understanding of its pathophysiology. Funding: This study is supported by grants from National Key Research and Development Program of China (2020YFA0908800), National Natural Science Foundation of China (12074269, 82272014, 82327804, 62071310), Shenzhen Basic Science Research (20220808185138001, JCYJ20220818095612027, JCYJ20210324093006017), STI 2030-Major Projects (2021ZD0200500) and Guangdong Natural Science Foundation (2024A1515012591, 2024A1515011342).
