Resilience to Mobility Impairment: Neural Correlates and Protective Factors

描述(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，随着年龄的增长，这些问题会恶化，它们与更大的残疾、住院和死亡风险有关。有强有力的紧急证据表明，脑部结构异常，如白质高信号(WMH)，与下肢活动受限有关。我们的初步数据表明，尽管体重指数很高，但仍能保持机动性和功能的“有弹性”老年人的比例高得惊人。在我们的两项独立研究中，超过40%的WMH患者的平均步态快于预期，身体功能“正常”，10年存活率更高。这些成年人也有“正常”的信息处理速度，这是一种与行动能力密切相关的认知领域。我们认为，这种明显的恢复力与独特的神经激活模式有关，并与关键流动性相关区域内微结构异常的缓慢累积有关(目标1)。这些特征在一个时间点获得的标准结构MRI上看不到，需要先进的纵向MRI方法。基于以前的工作和我们的试点工作，我们假设较高的神经激活抵消了整体WMH对功能的不利影响(目标2)。目标3将探讨风险因素与复原力之间的关系。特别是，我们将测试危险因素(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结构异常的累积来增强韧性。虽然已知这些危险因素的横截面水平较高与WMH有关，但它们的纵向轨迹对脑功能和微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，Rosano博士和Aizenstein博士提议在自1996年以来一直在进行的父母纵向NIA流行病学研究-Health ABC研究(健康、老龄化和身体成分研究)的老年参与者中获得重复的脑MRI。参与者在2007-08年间接受了第一次脑部磁共振成像，测量了微结构(PI：Dr.Rosano，K23AG028966-01，R01 AG029232)。拟议的第二次核磁共振成像将测量大脑功能(神经激活)，以及微观结构。这项研究经济高效地利用了关于心脏代谢和炎症风险因素的纵向数据，以及14年来确定的住院和中风情况。虽然Rosano博士的MRI研究仍在进行中，但获得第二次MRI以测量纵向微结构变化、最大限度地提高参与者的保留率并将成本降至最低是绝对关键的。这一建议不同于罗萨诺博士目前对大脑横截面结构测量的研究，因为它将专注于功能(神经激活)和纵向微结构变化。这一研究项目的结果可能有助于阐明身体残疾的潜在机制，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.