Resilience to Mobility Impairment: Neural Correlates and Protective Factors

描述（由申请人提供）：步态缓慢和行走困难是老年人的主要和常见问题，它们随着年龄的增长而恶化，并与更大的残疾、住院和死亡风险相关。有强有力的紧急证据表明，脑结构异常，如白质高强度（WMH），与下肢活动受限有关。我们的初步数据表明，“弹性”老年人的患病率惊人地高，尽管有大量的WMH，他们仍保持了活动能力和功能。在我们的两项独立研究中，超过40%的WMH患者比预期的平均步态更快，身体功能“正常”，10年生存率更高。这些成年人也有“正常”的信息处理速度，这是一个与行动能力密切相关的认知领域。我们认为，这种明显的弹性与独特的神经激活模式和关键移动性相关区域内微观结构异常的缓慢累积有关（目的1）。这些特征在一个时间点获得的标准结构MRI上是不可见的，需要先进的纵向MRI方法。基于先前的工作和我们的试点工作，我们假设更高的神经激活抵消了整体WMH对功能的不利影响（目的2）。目的3将探讨风险因素与心理弹性的关系。特别是，我们将测试风险因素（血压、白细胞介素-6和葡萄糖）的纵向恶化是否可以通过减缓微观结构异常的累积来增强恢复力。虽然已知这些危险因素的更大横截面水平与WMH相关，但它们的纵向轨迹对脑功能和微观结构特征的影响尚未在大量老年人中进行研究。在这个双pi项目中，dr。Rosano和Aizenstein建议对父母纵向NIA流行病学研究-健康ABC研究（健康，衰老和身体成分研究）的老年人参与者进行重复的脑MRI。参与者在2007-08年接受了第一次脑部MRI，测量了微观结构（PI: Dr. Rosano, K23AG028966-01, R01 AG029232）。拟议的第二次MRI将测量大脑功能（神经激活）以及微观结构。这项研究经济有效地利用了14年来心脏代谢和炎症危险因素、住院和中风的纵向数据。虽然Rosano博士的MRI研究正在进行中，但获得第二次MRI以测量纵向微观结构变化，最大限度地提高参与者的保留率并最大限度地降低成本是绝对关键的。这一建议不同于罗萨诺博士目前的横断面脑结构测量研究，因为它将侧重于功能（神经激活）和纵向微观结构变化。这项研究项目的结果可能会揭示身体残疾的机制，并可能帮助我们准备预防和干预研究。

DESCRIPTION (provided by applicant): Slowing gait and difficulty walking are major and common problems of older adults, they worsen with age and they are associated with greater risk of disability, hospitalization and death. There is strong emergent evidence that structural brain abnormalities, such as white matter hyperintensities (WMH), are associated with lower- extremity mobility limitations. Our preliminary data suggest there is a striking high prevalence of 'resilient' elderly, who have preserved mobility and function despite substantial WMH. In two of our independent studies, more than 40% of individuals with substantial WMH have faster than expected mean gait, "normal" physical function and greater 10-year survival rate. These adults also have "normal" information-processing speed, a cognitive domain strongly related to mobility. We propose that this apparent resilience is related to unique neural activation patterns and to slower accrual of micro-structural abnormalities within critical mobility-related regions (Aim 1). These features are not visible on standard structural MRI obtained at one time point and require advanced longitudinal MRI methodology. Based on previous work and our pilot work we hypothesize that higher neural activation offsets the adverse impact of overall WMH on function (Aim 2). Aim 3 will explore the relationship of risk factors and resilience. In particular, we will test whether slower longitudinal worsening of risk factors (blood pressure, interleukine-6 and glucose) can enhance resilience, by slowing down the accrual of micro-structural abnormalities. Although it is known that greater cross-sectional levels of these risk factors are associated with WMH the impact of their longitudinal trajectories on brain functional and micro-structural characteristics has not been examined in large groups of older adults. In this dual-PI project, Drs. Rosano and Aizenstein propose to acquire a repeat brain MRI in older adult participants of a parent longitudinal NIA epidemiologic study - the Health ABC study (Health, Aging and Body Composition Study) ongoing since 1996. Participants have received a 1st brain MRI in 2007-08 with measures of micro-structure (PI: Dr. Rosano, K23AG028966-01, R01 AG029232). The proposed 2nd MRI will measure brain function (neural activation) in addition to micro-structure. This study cost-effectively leverages longitudinal data on cardiometabolic and inflammatory risk factors, as well as hospitalization and strokes ascertained for 14 years. While Dr. Rosano's MRI study is ongoing, it is absolutely critical to obtain a 2nd MRI to measure longitudinal microstructural changes, maximize participants' retention and minimize costs. This proposal differs from Dr. Rosano's current study of cross-sectional structural brain measures, because it will focus on functional (neural activation) and longitudinal micro-structural changes. Results from this research project may shed light on the mechanisms underlying physical disability and may help us prepare prevention and intervention studies.