Cerebral microhemorrhages and gait dysfunction in aging

衰老过程中的脑微出血和步态功能障碍

• 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
• 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

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.

步态和平衡障碍是老年人跌倒的最常见原因之一。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学：脑微血管病变 出血(CMHS)。在老年人中，高血压是CMHS的主要危险因素，与 脑内小血管破裂，并逐渐损害神经元功能。尽管CMHS会影响到一个人 三分之一的老年人，他们的发病机制仍然完全不明，也没有治疗干预措施。 可用于预防的疾病。这一应用的中心假设是高血压会加剧有丝分裂。 老年脑血管线粒体氧化应激，导致MMPs激活，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CMHS损害了精细电机的性能- 进食，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基质金属蛋白酶的激活将保护脑血管的结构完整性 防止CMHS的发展，在衰老过程中保持正常的步态和平衡功能。基于我们的前男友- 在这一领域的丰富经验和我们的初步数据，我们很好地利用Innova来检验我们的假设- CMHS小鼠模型和先进的小鼠步态分析方法。具体目标：1)确定如何 CMHS的数量、大小和定位对老年小鼠步态和平衡功能的影响。拟议的研究将 使用新的、灵敏的和翻译上高度相关的方法来表征与CMH相关的分形异常 步态周期的特点，建立CMHS和步态的严重程度、数量和定位之间的联系 衰老小鼠的异常。步态异常对CMH相关认知损害的预测能力也将 所以要下定决心。2)确定与年龄相关的细胞外基质成分、基质金属蛋白酶活性和细胞外基质的变化 CMHS Relate。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CMHS。3)确定线粒体氧化的作用- 变态应激增加了老年人对CMHS的易感性。我们的假设是过氧化氢酶TAR的过度表达- 线粒体或线粒体靶向抗氧化剂治疗对大脑结构完整性的影响 船只。综上所述，拟议的研究将确定导致与年龄相关的前科疾病的基本机制。 CMHS的酸化，从而导致血管诱导的神经功能障碍-线粒体来源的ROS增加 脑血管结构完整性的产生和相应的退化。这些结果将会有一个 重要的积极影响，因为它们将使我们能够开发新颖的、与翻译相关的干预措施 预防老年人CMHS、保护步态和平衡功能的策略。

项目成果

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