Insulin Resistance, Biomarkers of Brain Function, and Intermittent Calorie Restriction

阿尔茨海默病(AD)预计到2050年将影响大约1380万美国人，花费1.2 每年一万亿美元。胰岛素抵抗(IR)是一种细胞对胰岛素的反应性降低，典型的 是由肥胖引起的。在中年后期，IR与记忆和执行功能的缺陷有关 性能和增加的AD风险。申请者奥里尔·威莱特博士最近在使用Magic 中老年晚期IR的磁共振成像(MRI)和正电子发射断层扫描(PET)资料 与大脑区域前额叶皮质萎缩、葡萄糖摄取减少和淀粉样蛋白沉积有关 受早期AD的影响，从属于执行功能。他之前还发现，长期摄入的卡路里 老年猕猴的限制(CR)可降低IR，减少与IR相关的PFC萎缩，并改善 认知表现。该项目的目标是确定先前验证的间歇性CR饮食是否 减少中老年晚期的IR，由五个临时天数和连续两天组成 消耗530千卡(5-2 CR)，改善执行功能表现并改变PFC功能 核磁共振(FMRI)在执行任务期间的激活。为了完成这个项目，威莱特博士需要额外的 监督人类5-2 CR、临床试验、基于任务的功能磁共振神经成像、认知测试、 AD神经病理学，以及与胰岛素信号相关的内分泌学。威莱特博士的主要导师 美国国家老龄研究所马克·马特森博士是CR、神经科学和开展CR临床的领导者 审判。威莱特博士将与一个由校内和校外共同导师组成的跨学科团队合作，以获得 进行这项研究所需的培训。具体地说，威莱特医生将在他两年的临床工作中增加 通过NIA临床主任约瑟芬·伊根博士接受临床试验培训的经验 临床调查实验室主任马特森博士和迪米特里奥斯·卡波吉安尼斯博士，终身教职 神经病学家，曾进行过几次临床试验。威莱特博士将开发基于任务的功能磁共振成像方面的专业知识 认知测试来自Kapogiannis博士、Arthur Kramer博士，认知与衰老领域的领先者 30年的神经成像经验，以及约翰·霍普金斯大学神经病学主席理查德·奥布莱恩博士 大学。对于AD神经病理学，马特森博士和奥布莱恩博士是动物模型和 分别是年长的成年人。对于胰岛素信号，伊根博士是该领域的资深研究员和先驱。 胰岛素调节、胰岛素和葡萄糖代谢。在目标1和目标2(K99指导阶段)中，认知方面为40 在特定的就诊中，患有胰岛素抵抗的正常中年女性将参与一系列执行功能任务 在核磁共振扫描仪之外，执行一项诱发PFC大脑活动的fMRI颜色词Stroop任务，以及 执行fMRI能量密集型食物偏好任务，该任务也通过对食物的认知评估来激活PFC。 这项测试将在基线和5-2 CR(n=20)或临时对照饮食(n=20)的8周后进行。 将每两周进行一次合规访问。该项目将通过 在NIA的临床研究部门--港湾医院进行临床调查。美国国家航空航天局科学审查委员会 已经批准了这一项目，并通过校内研究计划拥有足够的资源和 专人时间要及时完成。其他培训将包括以下课程 临床试验，衰老的神经生物学，伦理学，管理研讨会，以及未来的研讨会 独立调查人员，包括拨款撰写和终身教职跟踪主题。在目标3(R00独立阶段)中， 威莱特博士将结合他以前和新的培训，对老年患者进行类似的5-2 CR干预 轻度认知障碍(MCI)和胰岛素抵抗。除了认知和功能磁共振成像，他还将获得和处理 氟脱氧葡萄糖数据(FDG-PET)检查PFC的静息葡萄糖摄取。他将接受FDG-PET培训 在K99阶段期间，来自Bradley Christian博士，高级PET研究员和 威斯康星大学麦迪逊分校。鉴于MCI的IR比认知正常的成年人更高， 与认知和大脑测量的关联可能比中年后期的队列更强。5比2 CR干预有望改善执行功能，稳定fMRI PFC活动，并增加PFC 葡萄糖摄取。这些结果将对早期AD的可能干预产生重大影响。

Alzheimer's disease (AD) is projected by 2050 to affect approximately 13.8 million Americans and cost 1.2 trillion dollars per year. Insulin resistance (IR), a reduced cellular responsiveness to insulin, is typically induced by obesity. In late middle-age, IR is associated with deficits in memory and executive function performance and increased AD risk. The applicant, Dr. Auriel Willette, recently found using Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) data that IR in late middle-aged adults is associated with atrophy, lower glucose uptake, and amyloid deposition in prefrontal cortex (PFC), a brain area impacted by early AD that subserves executive function. He also previously found that long-term calorie restriction (CR) in aged rhesus macaques lowers IR, reduces PFC atrophy associated with IR, and improves cognitive performance. The goal of this project is to determine if a previously validated intermittent CR diet that reduces IR in late middle-aged adults, composed of five ad libitum days and two consecutive days of consuming 530 kilocalories (5-2 CR), improves executive function performance and changes PFC functional MRI (fMRI) activation during executive tasks. To accomplish this project, Dr. Willette requires additional supervised research training in human 5-2 CR, clinical trials, task-based fMRI neuroimaging, cognitive testing, AD neuropathology, and endocrinology specific to insulin signaling. Dr. Willette's primary mentor at the National Institute on Aging, Dr. Mark Mattson, is a leader in CR, neuroscience, and conducting CR clinical trials. Dr. Willette will work with a cross-disciplinary team of intramural and extramural co-mentors to gain the required training for performing this study. Specifically, Dr. Willette will add to his two years of clinical experience by being trained in conducting clinical trials through Dr. Josephine Egan, the NIA Clinical Director and Chief of the Laboratory of Clinical Investigation, Dr. Mattson, and Dr. Dimitrios Kapogiannis, a tenure-track Neurologist who has conducted several clinical trials. Dr. Willette will develop expertise in task-based fMRI and cognitive testing from Dr. Kapogiannis, Dr. Arthur Kramer, a leader in the field of cognition and aging with over 30 years of neuroimaging experience, and Dr. Richard O'Brien, Chair of Neurology at Johns Hopkins University. For AD neuropathology, Drs. Mattson and O'Brien are established experts in animal models and older adults respectively. For insulin signaling, Dr. Egan is a senior investigator and pioneer in the field of insulin regulation, incretins, and glucose metabolism. In Aims 1 and 2 (K99 mentored phase), 40 cognitively normal, late middle-aged women with IR on a given visit will engage in a battery of executive function tasks outside of the MRI scanner, perform a fMRI color-word Stroop task that induces PFC brain activity, and perform a fMRI energy-dense food preference task that also activates PFC through cognitive appraisal of food. This testing will occur at baseline and after 8 weeks of either 5-2 CR (n=20) or an ad libitum control diet (n=20). Compliance visits will be conducted every 2 weeks. This project will be conducted through the Laboratory of Clinical Investigation at Harbor Hospital, the NIA's clinical research unit. The NIA Scientific Review Committee has approved this project, and through the Intramural Research Program has adequate resources and dedicated personnel time to be completed in a timely manner. Additional training will include coursework in clinical trials, neurobiology of aging, ethics, management seminars, and workshops for prospective independent investigators including grant writing and tenure-track topics. In Aim 3 (R00 independent phase), Dr. Willette will combine his previous and new training to conduct a similar 5-2 CR intervention in aged patients with Mild Cognitive Impairment (MCI) and IR. In addition to cognition and fMRI, he will acquire and process fluorodeoxyglucose data (FDG-PET) to examine resting glucose uptake in PFC. He will gain FDG-PET training during the K99 phase from Dr. Bradley Christian, senior PET researcher and co-director of PET Physics at the University of Wisconsin-Madison. Given that IR is higher in MCI compared to cognitively normal adults, associations with cognition and brain measures may be stronger than in the late middle-aged cohort. The 5-2 CR intervention is expected to improve executive function, stabilize fMRI PFC activity, and increase PFC glucose uptake. These outcomes would have a substantial impact on possible interventions for early AD.