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，随着年龄的增长而恶化，并且与残疾、住院和死亡的风险增加有关。有强有力的证据表明，结构性脑异常，如白色物质高信号（WMH），与下肢活动受限。我们的初步数据表明，有一个惊人的高流行率的“弹性”的老年人，谁保留了流动性和功能，尽管大量的WMH。在我们的两项独立研究中，超过40%的WMH患者的平均步态比预期的要快，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，这是一个与移动性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的移动性相关区域（目标1）内的微结构异常的缓慢积累有关。这些特征在同一时间点获得的标准结构MRI上不可见，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，更高的神经激活抵消整体WMH对功能的不利影响（目的2）。目标3将探讨风险因素与复原力的关系。特别是，我们将测试是否缓慢的纵向恶化的风险因素（血压，白细胞介素-6和葡萄糖）可以提高弹性，通过减缓微结构异常的积累。虽然它是已知的，更大的横截面水平的这些危险因素与WMH的影响，他们的纵向轨迹对大脑功能和微观结构特征尚未在大型老年人群体进行检查。在这个双PI项目中，Rosano和Aizenstein博士建议对父母纵向NIA流行病学研究的老年参与者进行重复脑MRI检查-自1996年以来一直在进行的健康ABC研究（健康，衰老和身体成分研究）。参与者在2007-08年接受了第一次脑部MRI，测量了微结构（PI：Dr. Rosano，K23 AG 028966 -01，R 01 AG 029232）。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年来确定的心脏代谢和炎症风险因素以及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绝对至关重要。这个建议不同于Rosano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）和纵向微观结构变化。该研究项目的结果可能揭示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.