Depression in dementia caregivers: Linking brain structure and sleep-wake risks

摘要 迫切需要将神经科学工具整合到晚年抑郁(LLD)病因学的研究中。我的 目的是开发证据，帮助针对LLD的神经生物学基础制定预防策略 脆弱性。现有的几项研究表明，LLD的病理生理学特征是高负荷的 结构磁共振成像(SMRI)测量了小血管病变、脑白质损伤和 关键网络的萎缩，例如那些附属于执行和中央内脏控制的网络。在此基础上继续发展 扩展现有文献，有必要澄清LLD中涉及的特定结构变化 发病机制。此外，还需要关于可预防的风险因素的证据。 病理性脑结构老化。作为我研究项目的基础的概念模型提出 24小时睡眠-觉醒活动障碍是特定大脑结构的关键且未被研究的危险因素 增加LLD风险的改变。领导未来的研究，将程序化地推进神经科学 在抑郁症预防方面，我需要在我过去接受的危险因素流行病学和LLD神经生物学培训的基础上 在几个领域。首先，我需要高风险抑郁症预防科学方面的临床研究培训 老年人，如痴呆症照顾者。其次，我必须做好准备，引领多模式、纵向 神经成像研究。第三，我必须为领导评估和解释健康状况的研究做好准备 24小时睡眠-觉醒活动测量的相关性。因此，这款K01将为我提供：(1)顶石 现场培训经验管理伦理的，多学科的临床研究与老年人谁 患抑郁症的风险很高，外加目前LLD预防方法的导师指导培训 以及高危人群LLD的心理社会/行为基础；(2)新技能的收集、加工、 分析和解释多模式神经成像数据，外加神经解剖学/系统的正式课程 神经生物学，以及(3)测量和处理24小时睡眠-觉醒活动测量的新技术技能， 再加上临床睡眠医学方面的基础知识来解释这些指标。为实现这些培训目标并 关于LLD病因的公共卫生相关知识，我建议纵向研究LLD的变化 老年非正式痴呆症照顾者中的抑郁症，他们正在经历提供护理的压力。这群人 与公共卫生的相关性越来越大，患抑郁症的风险非常高。我们的初步数据显示 紧张的痴呆症照顾者的LLD可能是由于大脑结构连接中断所致。纵向 这一组的神经成像研究需要通过评估是否/哪一项来扩展我们的初步发现 特定的大脑结构特征预示着未来抑郁症负担的增加。此外, 痴呆症照顾者通常睡眠不足和白天活动受限，这两种情况都是抑郁症 可能增加大脑结构老化速度的危险因素(例如，通过激活促炎级联反应 或导致血管疾病)。因此，我建议进行一项前瞻性研究(n=90)，其中包括最先进的7- 特斯拉sMRI和活动睡眠唤醒活动测量在首次访问和18个月的随访中重复进行- 向上。这将使我能够测试和改进一个模型，其中特定的睡眠-觉醒活动干扰是 与大脑结构变化相关，影响LLD风险的关键网络。科学的和 职业发展的结果将是：(1)确定特定的大脑结构网络和睡眠-觉醒 预测痴呆症照顾者抑郁症状严重程度增加的活动模式，(2) 将特定的睡眠-觉醒活动特征与病理脑结构相联系的模型的改进 衰老和抑郁症状，以及(3)具有知识、技能和 开发验证性研究(R01)支持神经生物学知情预防策略所需的数据 为了LLD。

Abstract There is a great need to integrate neuroscientific tools into the study of late-life depression (LLD) etiology. My goal is to develop evidence that will help target prevention strategies to the neurobiological basis of LLD vulnerability. Several existing studies demonstrate that LLD pathophysiology is characterized a high burden of structural magnetic resonance imaging (sMRI) measured small vessel disease, white matter damage, and atrophy in key networks, such as those subserving executive and central visceral controls. To build on and extend current literature, there is a need to clarify the specific structural alterations involved in LLD pathogenesis. There is also a fundamental need for evidence regarding the preventable risk factors for pathological brain structural aging. The conceptual model that underlies my research program proposes that 24-hour sleep-wake activity disturbances are a key and understudied risk factor for the specific brain structural alterations that increase LLD risk. To lead future studies that will programmatically advance the neuroscience of depression prevention, I need to build on my past training in risk factor epidemiology and LLD neurobiology in several areas. First, I need clinical research training in the science of depression prevention for high risk older adults, such as dementia caregivers. Second, I must prepare myself to lead multi-modal, longitudinal neuroimaging studies. Third, I must prepare myself to lead studies assessing and interpreting the health relevance of 24-hour sleep-wake activity measures. Therefore, this K01 will provide me with: (1) A capstone field training experience administering ethical, multidisciplinary clinical research studies with older adults who are at high risk for developing depression, plus mentor-guided training in current LLD prevention approaches and the psychosocial/behavioral basis for LLD in at-risk groups; (2) New technical skills collecting, processing, analyzing, and interpreting multi-modal neuroimaging data, plus formal coursework in neuroanatomy/systems neurobiology, and (3) New technical skills measuring and processing 24-hour sleep-wake activity measures, plus grounding in clinical sleep medicine to interpret these metrics. To accomplish these training goals and advance public health relevant knowledge regarding LLD etiology, I propose to longitudinally study changes in depression among older informal dementia caregivers who are experiencing strain delivering care. This group is increasingly public health relevant and at very high risk for depression. Our preliminary data indicates that LLD in strained dementia caregivers may be due to disrupted brain structural connectivity. Longitudinal neuroimaging studies in this group are needed to extend our preliminary findings by evaluating whether/which specific brain structural characteristics predict future increases in the burden of depression. In addition, dementia caregivers often have inadequate sleep and restricted daytime activity, which are both depression risk factors that may increase the rate of brain structural aging (e.g., by activating pro-inflammatory cascades or contributing to vascular disease). I therefore propose a prospective study (n=90) with state-of-the-art 7- Tesla sMRI and actigraphic sleep-wake activity measures repeated at an initial visit and an 18-month follow- up. This will enable me to test and refine a model wherein specific sleep-wake activity disturbances are associated with brain structural changes affecting the key networks underlying LLD risk. The scientific and career development outcomes will be: (1) identification of the specific brain structural networks and sleep-wake activity patterns that predict increases in depression symptom severity among dementia caregivers, (2) refinement of a model linking specific sleep-wake activity characteristics with both pathological brain structural aging and depression symptoms, and (3) a multidisciplinary research scientist with the knowledge, skills, and data needed to develop a confirmatory study (R01) supporting neurobiologically-informed prevention strategies for LLD.