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

据预测，到2050年，阿尔茨海默病（AD）将影响约1380万美国人， 万亿美元。胰岛素抵抗（IR），即细胞对胰岛素的反应性降低，通常是 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AD风险增加。申请人Auriel Willette博士最近发现， 核磁共振成像（MRI）和正电子发射断层扫描（PET）数据显示，中年晚期的IR是 与萎缩、葡萄糖摄取减少和前额叶皮质（PFC）淀粉样蛋白沉积有关， 受早期AD的影响，有助于执行功能。他之前还发现， 在老年恒河猴中，限制（CR）降低IR，减少与IR相关的PFC萎缩，并改善 认知绩效该项目的目标是确定先前验证的间歇性CR饮食是否 降低中晚期成人的IR，包括5个自由采食日和连续2天 消耗530千卡（5-2 CR），改善执行功能性能，改变PFC功能 执行任务时的MRI（fMRI）激活。为了完成这个项目，Willette博士需要额外的 在人类5-2 CR，临床试验，基于任务的功能磁共振成像神经成像，认知测试， AD神经病理学和胰岛素信号传导特异性内分泌学。威利特博士在 国家老龄化研究所，马克马特森博士，是在CR，神经科学的领导者，并进行CR临床 审判Willette博士将与跨学科的校内和校外共同导师团队合作， 进行本研究需要培训。具体来说，威利特博士将增加他两年的临床 通过NIA临床总监Josephine埃根博士的临床试验培训获得经验 和临床研究实验室主任，马特森博士和迪米特里奥斯Kapogiannis博士，一个终身职位的轨道 神经科医生，进行过几次临床试验。Willette博士将发展基于任务的fMRI方面的专业知识， Kapogiannis博士的认知测试，亚瑟克雷默博士，认知和衰老领域的领导者， 30年的神经影像学经验，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，Mattson和奥布莱恩博士是动物模型方面的公认专家， 老年人分别。对于胰岛素信号传导，埃根博士是该领域的高级研究员和先驱。 胰岛素调节、肠促胰岛素和葡萄糖代谢。在目标1和目标2（K99辅导阶段），40人在认知方面 一个正常的，中年晚期的IR女性在一次特定的访问中将从事一系列的执行功能任务 在MRI扫描仪之外，执行fMRI颜色词Stroop任务，诱导PFC大脑活动， 执行fMRI能量密集的食物偏好任务，该任务也通过对食物的认知评估激活PFC。 该测试将在基线时和5-2 CR（n=20）或随意对照饮食（n=20）8周后进行。 将每2周进行一次依从性访视。该项目将通过以下实验室进行： 海港医院的临床研究，NIA的临床研究单位。NIA科学审查委员会 已经批准了这个项目，并通过校内研究计划有足够的资源， 专职人员的时间要及时完成。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，管理研讨会和前瞻性研讨会 独立调查员，包括赠款写作和终身教职跟踪主题。在目标3（R 00独立阶段）中， 博士Willette将联合收割机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IR。除了认知和功能磁共振成像，他将获得和处理 氟代脱氧葡萄糖数据（FDG-PET）检查PFC的静息葡萄糖摄取。他将获得FDG-PET培训 在K99阶段，来自布拉德利克里斯蒂安博士，高级PET研究员和PET物理学联合主任， 威斯康星大学麦迪逊分校鉴于MCI患者的IR高于认知正常的成年人， 与认知和大脑测量的关联可能比中年晚期队列更强。5-2的 CR干预有望改善执行功能，稳定fMRI PFC活性，并增加PFC 葡萄糖摄取这些结果将对早期AD的可能干预措施产生重大影响。

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.