Ultra-high-field neuroimaging in elderly after a two-year exercise intervention

描述(申请人提供)：老化的大脑在受到神经元死亡、血管异常和连接丧失的影响时保持学习能力。对于这种被保存的功能，一个可能的解释是即使在晚年也保持了神经再生的潜力。新出现的强有力的人类活体证据表明，对60多岁的功能正常的老年人进行体力活动(PA)干预后，海马区结构会变得更大。然而，还不知道年老体弱的人是否也会对 PA与海马区扩张有关--如果是的话--变化是否会超过一年。此外，尚不清楚海马区的变化是否仅限于具有神经再生潜力的区域(齿状回)，以及PA对相关脑血管和脑功能指标的影响。解决高龄成年人的这些知识差距将扩大我们对高龄大脑可塑性的理解，特别是对干预的反应。我们建议通过检查先前报道的较年轻老年人的海马结构中与PA相关的影响是否在非常年长和虚弱的成年人中存在超过1年的时间，来解决这一知识差距，这些影响是否对齿状回、微循环和功能连接有显著影响。到目前为止，回答这些问题有两个主要障碍：1)传统的非侵入性成像无法准确测量齿状回；2)高龄成年人可能身体虚弱，不太可能参与并长期坚持PA计划。这项建议通过在7特斯拉对已经参加了一项现有的长期随机临床试验的虚弱老年人应用7Tesla的非侵入性超高场神经成像来解决这些障碍，并将步行与健康教育进行比较(Success Aging：SA)。我们已经在2010年随机采集了65个PTC的超高场脑图像，并有资金在第二年获得所有的脑MRI，估计样本量为n=50，干预前和干预后的MRI，以及仅在干预后的MRI的额外n=30。这是一个处理和分析这些数据的应用程序，用于：1)量化PA与超高场脑标记物(AIM1)的关系；2)确定与PA相关的变化在超高场脑标记物(AIM2)中的定位；3)探索超高场标记物在解释大脑对PA的反应(AIM3)中的作用。这一建议有很高的成功机会，因为它应用了先前验证的神经成像方案来响应先前在这一特殊人群中验证的PA干预。这是以极具成本效益的设计进行这项变革性研究的独特机会，可以利用超高场脑磁共振成像的现有数据、现有的运营基础设施进行招聘、保留、干预和 正在进行的LIFE研究的临床评估和LIFE领导团队的专业知识，CO-I的这项建议。由于随机对照试验的成本很高，这种高度先进的神经成像和干预性研究的结合再次发生的可能性很小。

DESCRIPTION (provided by applicant): The aging brain maintains the ability to learn while being affected by neuronal death, vascular abnormalities and connectivity loss. A possible explanation for this preserved function is the maintenance of neuroregenerative potential even in late-life. Strong emerging human in-vivo evidence indicates that the hippocampal formation becomes larger in response to physical activity (PA) interventions in well-functioning elderly in their late sixties. However, it is not known whether very old and frail individuals also respond to PA with hippocampal expansion and -if they do- whether changes remain beyond one year. Moreover, it is unknown whether hippocampal changes are specific for areas with neuroregenerative potential (the dentate gyrus), and the effects of PA on related cerebrovascular and functional brain measures. Addressing these gaps in knowledge in very old adults will expand our understanding of brain plasticity in very old age, specifically in response to intervention. We propose to address this gap in knowledge by examining whether the PA-related effects previously reported in the hippocampal formation of younger elderly exist in very old and frail adults for periods of time beyond 1 year, whether these effects are significant for the dentate gyrus, microcirculature and functional connectivity. To date, there have been two major barriers to answer these questions: 1) conventional non- invasive imaging cannot precisely measure the dentate gyrus; 2) very old adults are likely to be physically frail and unlikely to participate and adhere to a PA program for long period of times. This proposal addresses these barriers by applying non-invasive Ultra High-Field neuroimaging at 7Tesla in frail older adults who are already participating in an existing long-term randomized clinical trialof walking compared to health education (Successful Aging: SA). We have already acquired Ultra High-Field brain images at the time of randomization in 2010 in 65 ptc and have funds to acquire all brain MRI at the 2nd yr follow-up, for an estimated sample size of n=50 with MRIs pre and post-intervention and an additional n=30 with MRI at the post-intervention only. This is an application to process and analyze these data to: 1) Quantify the relationship of PA with Ultra High-Field brain markers (AIM1); 2) identify the localization of the PA-related changes in Ultra High-Field brain markers (AIM2); 3) Explore the role of Ultra High Field markers in explaining brain response to PA (AIM3).This proposal has a high chance of success because it applies previously validated neuroimaging protocols in response to a type of PA intervention that has also been previously validated in this special population. This is a unique opportunity to conduct this transformative study in a highly cost-effective design, leveraging existing data on Ultra High field brain MRIs, existing operational infrastructure for recruitment, retention, intervention, and clinical assessment of the ongoing LIFE study and the expertise of the LIFE leadership team, Co-I's of this proposal. Because of the high costs of RCTs, it is highly unlikely that this combination of highly advanced neuroimaging and type of intervention study will occur again.