Cerebral microhemorrhages and gait dysfunction in aging

衰老过程中的脑微出血和步态功能障碍

基本信息

批准号：
10171741
负责人：
ZOLTAN Istvan UNGVARI
金额：
$ 29.73万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10171741
关键词：
Address Affect Aging Antioxidants Blood Vessels Caliber Cerebrovascular Disorders Cerebrum Clinical Clinical Research Collagen Complex Consequentialism Data Development Elderly Equilibrium Etiology Extracellular Matrix Fractals Functional disorder Gait Gait abnormality Genetic Goals Hemorrhage Homeostasis Human Hypertension Impaired cognition Impairment Individual Inhibition of Matrix Metalloproteinases Pathway Injury Institutionalization Knowledge Lead Link MMP3 gene Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Methods Mission Mitochondria Motor Mus Neurologic Deficit Neurons Outcome Oxidation-Reduction Oxidative Stress Pathogenesis Pattern Phenotype Positioning Attribute Pre-Clinical Model Predisposition Prevention Prevention approach Production Property Public Health Reactive Oxygen Species Research Risk Factors Role Rupture Scheme Severities Structure Testing Therapeutic Intervention United States National Institutes of Health White Matter Disease Work age related aged attenuation base catalase cerebral microbleeds cerebral microvasculature cerebrovascular cerebrovascular lesion clinically relevant disability disability burden equilibration disorder experience fall risk falls gait examination innovation mouse model novel novel therapeutic intervention overexpression preservation prevent preventive intervention

项目摘要

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.

步态和平衡疾病是老年人跌倒最常见的原因之一。最近的临床研究确定一种新型的微血管病因，该病因促成了较早的步态异常：脑微血管出血（CMHS）。在古老的高血压中，高血压是CMHS的主要危险因素，这与小型脑内视频的破裂和逐渐损害神经元功能。虽然CMH会影响一个三分之一的老年人，他们的发病机理仍然完全晦涩难懂，没有治疗性介入可用于预防。该应用的中心假设，即高血压加剧了Mito- 老化的脑血管中的软骨氧化物应激，导致MMP激活，胶原蛋白降解和细胞外基质的重塑，促进微血管脆弱。由此产生的CMHS损害了精细电机芯 - 讨论，促进步态和平衡异常。我们基于此假设的预测是线粒体氧化应激或MMP激活的抑制将保护脑血管的结构完整性防止CMHS的发展，并保留衰老中的正常收集和平衡功能。基于我们的前在该领域和我们的初步数据中，我们的潮流经验，我们可以使用Innova-的良好位置检验我们的假设 CMHS的Tive小鼠模型和小鼠步态分析的高级方法。具体目的：1）确定如何 CMHS的数量，大小和定位会影响老年小鼠的步态和平衡功能。拟议的研究将使用新颖，敏感和翻译高度相关的方法来表征与CMH相关的分形异常步态周期的特性，并建立CMHS和步态的严重性，数量和定位之间的联系老年小鼠异常。 GIT异常对CMH相关认知障碍的预测能力将因此可以确定。 2）确定年龄相关的细胞外基质组成，MMP激活和 CMHS相关。我们的假设是衰老加剧了MMP的激活，胶原蛋白降解和重塑细胞外基质，促进微血管脆弱和CMH。 3）确定线粒体氧的作用在衰老中对CMHS的敏感性增加的特性应力。我们的假设是过氧化氢酶焦油的过表达在脑结构完整性上使用线粒体靶向抗氧化剂的线粒体或治疗大脑的结构完整性船只。拟议的研究将共同确定一种基本机制，负责与年龄有关 CMHS的促进，因此血管诱导的神经系统缺陷 - 线粒体衍生的ROS。脑血管结构完整性的生产和结果降解。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发展出小说，翻译相关的介入预防CMHS的策略，保护聚集和平衡功能。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Traumatic brain injury-induced cerebral microbleeds in the elderly.

DOI：
10.1007/s11357-020-00280-3
发表时间：
2021-03
期刊：
GeroScience
影响因子：
5.6
作者：
Toth L;Czigler A;Horvath P;Kornyei B;Szarka N;Schwarcz A;Ungvari Z;Buki A;Toth P
通讯作者：
Toth P