Defining microvascular structure and function in the aged cervical spinal cord

摘要 老年人口（≥65岁）是美国增长最快的年龄组。根据 向疾病控制和预防中心报告，65岁或65岁以上的人生活在 美国预计到2030年将翻一番，达到7200万成年人，占美国总人口的20% [1]的文件。正常衰老导致大脑皮层微血管减少近30%， 毛细血管密度下降、血管对代谢需求的反应以及血管生成能力降低。这 正常衰老中血管密度和血液供应减少的现象被认为是 衰老大脑对缺血性损伤的“敏感”性质。老年人的脊髓也容易受伤; 近年来，地面福尔斯坠落导致的脊髓损伤（SCI）是最常见的创伤之一 老年患者在急诊室就诊时所遭受的痛苦。不幸的是，我们几乎不知道 脊髓微血管和血液动力学如何随年龄变化。本研究旨在解决这一问题 知识差距。我们假设，在这些组织中，微血管系统有显著的改变， 颈椎随着年龄的增长，增加了受伤的脆弱性。我们集团最近 开发了新的方法，使用强大的活体超快对比增强超声（CEUS） 成像，以可视化微血管内的血流，具有无与伦比的时间（30，000帧/ 秒）和空间（低至50微米）分辨率。这是与其他成像方式的重要区别， 在距组织表面仅几百微米深的地方检查微血管流动（例如， 激光散斑和双光子成像），超快CEUS成像使我们能够检查脑实质内 在真实的脊髓组织的整个深度内的微血管结构和血流血液动力学- 时间我们将应用这种创新的活体成像研究1）椎管内微血管解剖， 正常老化过程中的功能，以及2）tSCI后与年龄相关的微血管脆弱性。此外，本发明还 男性和女性之间的脑血流量和微血管密度差异已被检测到， 人类和啮齿动物模型。因此，正常老化过程中的微血管变化将在 男女都有。这项研究的结果将是了解性别和年龄相关的改变的基础， 脊髓的静态和动态微血管功能。

Abstract The older population (≥65 years old) represents the fastest growing age group in the United States. According to the Centers for Disease Control and Prevention, the number of people 65 years of age or older living in the United States is projected to double by 2030 to 72 million adults, representing 20% of the total U.S. population [1]. Normal aging results in a nearly 30% reduction of microvasculature in the cerebral cortex with significant drops in capillary density, vascular responses to metabolic demand, and reduced angiogenic capabilities. This phenomenon of reduced blood vessel density and blood supply in normal aging is thought to underlie the “sensitive” nature of the aging brain to ischemic injuries. The aged spinal cord is also vulnerable to injuries; in recent years, ground levels falls resulting in spinal cord injuries (SCI) are among the most common trauma suffered by older patients presenting to the emergency room. Unfortunately we know next to nothing about how spinal cord microvasculature and hemodynamic changes with age. The present study aims to address this knowledge gap. We hypothesize that there are significant alterations to the microvasculature in the cervical spine with aging, which confer increased vulnerability to injuries. Our group has recently developed novel methods, using powerful intravital ultrafast contrast enhanced ultrasound (CEUS) imaging, to visualize blood flow within the microvasculature with unparalleled temporal (30,000 frames per second) and spatial (down to 50 micron) resolution. An important departure from other imaging modalities, where microvascular flow is examined just a few hundred microns deep from the surface of the tissue (e.g., laser speckle and two photon imaging), ultrafast CEUS imaging allows us to examine intraparenchymal microvascular structure and blood flow hemodynamics within the entire depth of the spinal cord tissue in real- time. We will apply this innovative intravital imaging to study 1) intraspinal microvasculature anatomy and function during normal aging, and 2) age-related microvascular vulnerabilities after tSCI. Additionally, cerebral blood flow and microvascular density differences have been detected between males and females in both human and rodent models. Therefore, microvascular changes during normal aging will be examined in both sexes. Results from this study will be foundational to understanding sex and age-related alterations in both the static and dynamic microvascular function of the spinal cord.