Metabolic Interventions for Sleep, Anesthesia-related Neurocognitive Disorders and Alzheimer's Disease

针对睡眠、麻醉相关神经认知障碍和阿尔茨海默病的代谢干预

• 批准号: 10419578
• 负责人: Christa Joy Nehs
• 金额: $ 55.58万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10419578
• 关键词: Acetoacetates; Acetylcholine; Address; Adenosine; Age; Aging; Alzheimer' s Disease; Alzheimer’s disease biomarker; Anesthesia procedures; Anesthetics; Animals; Antiinflammatory Effect; Anxiety; Biosensor; Blood; Brain; Brain Diseases; Carbohydrates; Clinical; Dementia; Diet; Eating; Elderly; Electroencephalography; Epilepsy; Exercise; Fatty Acids; Fatty acid glycerol esters; General Anesthesia; General anesthetic drugs; Glioblastoma; Glucose; Glutamates; Immune; Impaired cognition; Inflammation; Inflammatory; Inflammatory Response; Insulin Resistance; Interleukin-1; Interleukin-10; Interleukin-17; Interleukin-6; Intervention; Ketone Bodies; Ketones; Lead; Link; Measures; Mental Depression; Metabolic; Methods; Microdialysis; Mitochondria; NF-kappa B; Neurodegenerative Disorders; Neuromodulator; Neurons; Norepinephrine; Parkinson Disease; Pathway interactions; Prefrontal Cortex; Propofol; Purinergic P1 Receptors; Pyruvate; REM Sleep; Rattus; Reactive Oxygen Species; Research; Rodent; Safety; Seizures; Signal Transduction; Sleep; Sleep Fragmentations; Sleep disturbances; Source; Starvation; Testing; Time; Weight; aged; aging brain; aging population; antagonist; autism spectrum disorder; beta-Hydroxybutyrate; brain health; brain metabolism; early detection biomarkers; experimental study; gamma-Aminobutyric Acid; improved; inflammatory marker; innovation; ketogenic diet; liquid chromatography mass spectrometry; metabolomics; mitochondrial dysfunction; neurocognitive disorder; neuronal metabolism; neurotransmitter release; new therapeutic target; non rapid eye movement; normal aging; novel strategies; poor sleep; post-operative cognitive dysfunction; postoperative delirium; sevoflurane; sleep quality

ABSTRACT This objective of this research is to develop metabolic interventions to improve sleep quality and anesthesia safety in the elderly and eventually to treat neurodegenerative diseases like Alzheimer's disease. The aging brain has many changes including mitochondrial dysfunction, insulin resistance and decreased neurotransmitter release leading to poor sleep quality and more complications with general anesthesia. The ability of the brain to use glucose declines with age but the brain's ability to use ketones as fuel remains. Ketone bodies are produced naturally from the breakdown of fatty acids and become a major fuel source for the brain during times of starvation, exercise and high-fat, low-carbohydrate diets. The ketone bodies acetoacetate and beta-hydroxybutyrate not only provide energy to the brain but also have potent signaling and anti-inflammatory effects. The activation of inflammatory pathways, such as nuclear factor kappa B, are thought to be one mechanism through which sleep disturbance and dementia are linked as well as post-operative delirium and post-operative cognitive dysfunction. The inflammatory response is also tightly correlated with the onset and clinical course of Alzheimer's disease and disruptions in sleep are an early biomarker of Alzheimer's disease. Sleep quality declines with normal age as well, losing restorative slow and delta power and becoming more fragmented. Therefore, targeting brain energy usage by providing ketones could be one strategy for improving sleep quality in aged animals. In addition, the aged population is more susceptible to general anesthesia. Less anesthesia is needed to anesthetize older people and they are more likely to develop post-operative cognitive dysfunction. The energy substrate and anti-inflammatory effects of ketones could be neuroprotective during anesthesia in the aged brain. Taken together, these ideas give rise to novel strategies that address the dysfunctional neuronal metabolic-immune interactions in the aged brain by increasing ketones that could lead to improved sleep quality (AIM 1) and safer delivery of general anesthesia (AIM 2) to the elderly. These innovative strategies to improve brain health in the aged population have the potential for broad impact as many brain diseases have components of metabolic dysregulation including epilepsy, Alzheimer's disease, Parkinson's disease, autism, anxiety, depression and glioblastoma.

摘要 这项研究的目标是开发代谢干预措施，以改善睡眠质量和 麻醉在老年人中的安全性，并最终用于治疗阿尔茨海默病等神经退行性疾病。 衰老的大脑有许多变化，包括线粒体功能障碍，胰岛素抵抗和减少 神经递质的释放会导致睡眠质量变差和全身麻醉的更多并发症。这个 大脑利用葡萄糖的能力随着年龄的增长而下降，但大脑使用酮作为燃料的能力仍然存在。酮 身体是由脂肪酸分解而自然产生的，并成为大脑的主要燃料来源 在饥饿时期，锻炼和高脂肪、低碳水化合物饮食。酮体乙酰乙酸酯和 β-羟基丁酸酯不仅为大脑提供能量，而且还具有强大的信号和抗炎作用 效果。炎症途径的激活，如核因子kappa B，被认为是 睡眠障碍和痴呆症的联系机制以及手术后精神错乱和 术后认知功能障碍。炎症反应也与疾病的发生和发展密切相关 阿尔茨海默病的临床病程和睡眠障碍是阿尔茨海默病的早期生物标志。 睡眠质量在正常年龄时也会下降，失去恢复性的缓慢和三角洲力量，并变得更 支离破碎。因此，通过提供酮来瞄准大脑能量的使用可能是一种改善的策略 老年动物的睡眠质量。此外，老年人更容易受到全身麻醉的影响。较少 麻醉老年人需要麻醉，他们更有可能在术后发展认知能力 功能障碍。酮类物质的能量底物和抗炎作用可能具有神经保护作用 老年人大脑中的麻醉剂。综上所述，这些想法催生了解决 老年脑内神经元代谢免疫功能障碍的相互作用可能通过增加酮而导致 改善睡眠质量(AIM 1)和更安全地为老年人提供全身麻醉(AIM 2)。这些创新之处 改善老年人大脑健康的策略可能会产生广泛的影响，因为许多大脑 疾病有代谢失调的成分，包括癫痫、阿尔茨海默病、帕金森氏症 疾病、自闭症、焦虑、抑郁和胶质母细胞瘤。