Cerebral microhemorrhages and gait dysfunction in aging

步态和平衡障碍是老年人福尔斯最常见的原因之一。近期临床研究 确定导致老年人步态异常的一种新的微血管病因：脑微血管 （CMH）.在老年人中，高血压是CMH的主要危险因素， 脑内小血管破裂并逐渐损害神经元功能。虽然CMH影响一个 三分之一的老年人，其发病机制仍然完全不清楚，没有治疗干预， 可用于预防。本申请的中心假设是高血压加重线粒体- 老年脑血管中的脑氧化应激，其导致MMPs活化、胶原降解和 细胞外基质重塑，促进微血管脆弱性。由此产生的CMH损害精细运动协调- 倾斜，促进步态和平衡异常。基于这一假设，我们的预测是， 线粒体氧化应激或抑制MMP活化将保护脑血管结构的完整性 预防CMH的发展，并在衰老过程中保持正常的步态和平衡功能。基于我们的前- 在这一领域的丰富经验和我们的初步数据，我们很好地定位，以测试我们的假设，使用创新， CMH小鼠模型和小鼠步态分析的先进方法。具体目标：（1）确定 CMH的数量、大小和定位影响老年小鼠的步态和平衡功能。拟议的研究将 使用新的，敏感的和高度相关的方法来表征CMH相关的分形异常 步态周期的性质，并建立CMH的严重程度，数量和定位与步态之间的联系 老年小鼠的异常。步态异常对CMH相关认知功能障碍的预测能力也将 所以你要坚定2)确定细胞外基质成分、MMP活化和MMP-2表达与年龄相关的变化， CMH相关。我们的假设是，衰老加剧了基质金属蛋白酶的激活，胶原降解和重塑 细胞外基质，促进微血管脆性和CMH。3)确定线粒体氧化- 配位应激增加了老年人对CMH的易感性。我们的假设是过氧化氢酶的过度表达- 或用靶向抗氧化剂治疗对大脑结构完整性的影响 船舶.总之，拟议的研究将确定一个基本机制，负责与年龄有关的前， CMH的恶化，以及由此引起的血管诱导的神经功能缺损-增加了脑源性ROS 脑血管结构完整性的产生和相应的退化。这些结果将有一个 重要的积极影响，因为它们将使我们能够开发新的、预防性相关的干预性药物， 预防CMH，保护老年人步态和平衡功能的策略。

Gait and balance disorders are among the most common causes of falls in older adults. Recent clinical studies identify a novel microvascular etiology that contributes to gait abnormalities in the elderly: cerebral micro- hemorrhages (CMHs). In the elderly hypertension is the major risk factor for CMHs, which are associated with rupture of small intracerebral vessels and progressively impair neuronal function. Although CMHs affect one third of older individuals, their pathogenesis remains completely obscure and there are no therapeutic interven- tions available for prevention. The central hypothesis of this application that hypertension exacerbates mito- chondrial oxidative stress in aged cerebral vessels, which results in activation of MMPs, collagen degradation and remodeling of the extracellular matrix, promoting microvascular fragility. The resulting CMHs impair fine motor coor- dination, promoting gait and balance abnormalities. Our prediction based on this hypothesis is that attenuation of mitochondrial oxidative stress or inhibition of MMP activation will protect the structural integrity of cerebral vessels preventing the development of CMHs and preserving normal gait and balance function in aging. Based on our ex- tensive experience in this field and our preliminary data, we are well positioned to test our hypotheses using innova- tive mouse models of CMHs and advanced methods of gait analysis in mice. Specific Aims: 1) Determine how the number, size and localization of CMHs impact gait and balance function in aged mice. The proposed studies will use novel, sensitive and translationally highly relevant methods to characterize CMH-related abnormalities of fractal properties of gait cycle and establish the link between the severity, number and localization of the CMHs and gait abnormalities in aged mice. The predictive power of gait abnormalities to CMH-related cognitive impairment will al- so be determined. 2) Determine how age-related changes in extracellular matrix composition, MMP activation and CMHs relate. Our hypothesis is that aging exacerbates activation of MMPs, collagen degradation and remodeling of the extracellular matrix, promoting microvascular fragility and CMHs. 3) Determine the role of mitochondrial oxi- dative stress in increased susceptibility to CMHs in aging. Our hypothesis is that overexpression of catalase tar- geted to the mitochondria or treatment with the mitochondria-targeted antioxidant on structural integrity of cerebral vessels. Together, the proposed studies will identify a fundamental mechanism responsible for age-related ex- acerbation of CMHs, and thus vascular-induced neurological deficits —increased mitochondria-derived ROS production and consequential degradation of cerebrovascular structural integrity. These outcomes will have an important positive impact, since they will enable us to develop novel, translationally relevant interventional strategies for prevention of CMHs, protecting gait and balance function in the elderly.