Characterizing Alzheimer's Risk in Retired Night Shift Workers: Cognitive Function, Brain Volume, and Brain Bioenergetics

项目总结/摘要 夜班工作在当前24小时的全球社会中很常见，并且越来越被认为是一个危险因素 阿尔茨海默病（AD）和相关痴呆症（ADRD）。然而，我们对它知之甚少。 持续性、恢复或轮班工作导致AD/ADRD的途径。神经元 代谢下降（即，脑生物能量学的破坏）有助于AD/ADRD的发展和进展， 轮班工作中的反复睡眠和昼夜节律中断会损害外周能量代谢。这 K 01提案将通过比较阿尔茨海默病风险和大脑的指数来推进这些发现。 退休夜班工人和退休日工之间的生物能量学。N = 40例受试者（n = 20例退休 夜班工人，n = 20名退休的白天工人），年龄65-80岁，来自已建立的队列，将进行 神经认知评估（例如，情景记忆、执行功能）和7特斯拉神经成像。结构 磁共振成像将评估海马、后扣带回皮质和压后皮质 体积和磷磁光谱将评估大脑生物能量学，包括腺苷 三磷酸盐、磷酸肌酸和无机磷酸盐。这项研究将比较退休的夜班工人 和退休的日工对认知功能，脑容量和大脑生物能量学，并将研究 退休夜班工人脑生物能量学与脑容量的关系进行是次 研究，莱勒博士将追求的培训计划，将提高他的知识和技能， 阿尔茨海默病相关认知功能、脑结构和神经生物学的评估（即， 生物能量学和AD特异性蛋白质病）。他还将学习如何将这些方法融入他的 睡眠和昼夜节律以及AD/ADRD研究的新兴计划。这次培训，沿着调查结果 从拟议的研究，将允许博士莱勒开始他的职业生涯作为一个独立的研究者， 长期睡眠和昼夜节律中断在阿尔茨海默病中发挥的作用，以提供有效的预防 为退休的夜班工人工作。研究结果可能会影响我们对AD/ADRD风险的方法， 现任和前任轮班工人，导致在结束时早期识别风险个体，或 即使是在轮班工作的职业生涯中。结果将为未来的研究提供信息，使用实验方法来测试 因果关系，为干预措施的制定和传播提供信息，并阐明精准医学 预防和减轻AD/ADRD临床过程的方法。这些干预措施可能包括 潜在可修改的行为（例如，睡眠和昼夜节律增强）和药理学（例如， 用于AD/ADRD干预和/或预防的生物能量增强化合物）疗法。拟议 研究将产生公共卫生相关数据，有助于降低AD/ADRD风险，并为行为提供信息。 和以生物能量学为重点的治疗，以预防和减轻阿尔茨海默病的临床过程， 与痴呆症相关的疾病在大部分现任和前任美国工人中存在。

PROJECT SUMMARY/ABSTRACT Night shift work is common in the current 24-hour global society and is increasingly recognized as a risk factor for Alzheimer’s Disease (AD) and related dementias (ADRD). However, we know very little about the persistence, recovery from, or pathways through which shift work contributes to AD/ADRD. Neuronal metabolic decline (i.e., disrupted brain bioenergetics) contributes to AD/ADRD development and progression, and the repeated sleep and circadian disruptions in shift work compromise peripheral energy metabolism. This K01 proposal will advance these findings by comparing indices of Alzheimer’s disease risk and brain bioenergetics between retired night shift workers and retired day workers. N = 40 participants (n = 20 retired night shift workers, n = 20 retired day workers) ages 65-80 from an established cohort will perform neurocognitive assessments (e.g., episodic memory, executive function) and 7 Tesla neuroimaging. Structural magnetic resonance imaging will assess hippocampal, posterior cingulate cortex, and retrosplenial cortex volume and phosphorous magnetic spectroscopy will assess brain bioenergetics, including adenosine triphosphate, phosphocreatine, and inorganic phosphate. This study will compare retired night shift workers and retired day workers on cognitive function, brain volume, and brain bioenergetics, and will examine the association of brain bioenergetics with brain volume among retired night shift workers. To conduct this research, Dr. Lehrer will pursue a program of training that will advance his knowledge and skills in the assessment of Alzheimer’s disease-related cognitive function, brain structure, and neurobiology (i.e., bioenergetics and AD-specific proteinopathy). He will also learn how to integrate these methods into his emerging program of sleep and circadian rhythm and AD/ADRD research. This training, along with findings from the proposed study, will allow Dr. Lehrer to launch his career as an independent investigator studying the role that long-term sleep and circadian disruption plays in Alzheimer’s disease to inform impactful prevention efforts for retired night shift workers. Study findings could influence our approach to AD/ADRD risk among current and former shift workers, leading to early identification of at-risk individuals at the conclusion of, or even during a career in shift work. Results will inform future studies using experimental approaches to test causal relationships, inform development and dissemination of interventions, and elucidate precision medicine approaches to prevent and attenuate the clinical course of AD/ADRD. Such interventions may include potentially modifiable behavioral (e.g., sleep and circadian rhythm enhancement) and pharmacological (e.g., bioenergetics-boosting compounds) therapies for AD/ADRD intervention and/or prevention. The proposed study will generate public health-relevant data that will help to reduce AD/ADRD risk and inform behavioral and bioenergetics-focused therapies to prevent and mitigate the clinical course of Alzheimer’s disease and related dementias among a large portion of current and former U.S. workers.