Geroscience metabolites beta-hydroxybutyrate and NAD+ linking inflammation and neuroenergetic failure in delirium

项目总结 妄想是一种波动的混乱的老年综合征，是手术和治疗的常见并发症。 老年人住院，并与死亡、残疾和痴呆症风险增加有关。人民 患有阿尔茨海默氏症和相关痴呆症(ADRD)的人患精神错乱的风险特别高。这个 精神错乱的病理生理学还不是很清楚，但被认为包括神经炎症和大脑。 充满活力的颠覆。这些特征也将精神错乱与ADRD联系在一起。大脑葡萄糖代谢受损是一种 ADRD的慢性特征，以及精神错乱的急性特征。同样，慢性神经炎被认为是 是ADRD的重要因素，急性炎症与精神错乱有关。在这个翻译版本中 我们计划测试慢性急性脑炎和慢性脑炎之间的创新分子联系。 代谢功能障碍，使用细胞系统、小鼠模型和来自人类精神错乱队列的生物标本。 酮体在空腹时为大脑提供非葡萄糖能量来源，而酮体 即使在糖代谢受损的情况下，ADRD的代谢仍然完好无损。我们最近发现这一点被破坏了 葡萄糖代谢是导致精神错乱小鼠行为改变的重要因素。我们也 最近发现，生酮饮食改善了衰老小鼠和ADRD小鼠模型的记忆力。我们 开发了一套创新的化合物和遗传模型工具包，用于对酮体进行机械研究 试验性的。我们推测，来自酮体的能量支持可能有助于补偿 炎症诱导的葡萄糖代谢中的神经元损伤。我们还阐明了一种新的机制 将炎症与新陈代谢联系起来，表明外周巨噬细胞的激活诱导了 降解关键代谢调节因子NAD。炎症驱动的NAD耗竭慢性发生在衰老和 ADRD，并可急性发生在精神错乱中。 我们将使用正常小鼠的致幻性发炎模型和两个ADRD模型来测试酮 躯体或NAD可抢救急性妄想样行为改变，并确定相关机制(目的 1)。我们将使用培养的细胞和体内的脑炎症模型来确定激活的小胶质细胞 与巨噬细胞类似地消耗NAD，以及阻止这一过程是否也能挽救神志不清的行为(AIM 2)。最后，我们将使用来自术后精神障碍的大型临床研究的脑脊液样本来 确定患有和不伴有妄想症患者的内源性酮体和NAD水平有何不同 (目标3)。这个合作项目将酮体和NAD生物学方面的基础科学专业知识联系起来 ADRD，拥有对精神错乱的基础和临床研究专长。这将开辟一个新的力学研究领域。 发炎导致的精神错乱的代谢缺陷，指导翻译干预的发展。

PROJECT SUMMARY Delirium is a geriatric syndrome of fluctuating confusion that is a common complication of surgery and hospitalization in older adults, and is associated with increased risk of death, disability, and dementia. People with Alzheimer's Disease and Related Dementias (ADRD) are at especially high risk for delirium. The pathophysiology of delirium is not well understood, but is thought to include neuroinflammation and brain energetic disruption. These features also link delirium to ADRD. Impaired cerebral glucose metabolism is a chronic feature of ADRD, and an acute feature of delirium. Similarly, chronic neuroinflammation is thought to be an important contributor to ADRD, and acute inflammation is associated with delirium. In this translational project we propose to test an innovative molecular link between acute-on-chronic brain inflammation and metabolic dysfunction, using cell systems, mouse models, and biospecimens from a human delirium cohort. Ketone bodies provide a non-glucose energy source for the brain during fasting, and ketone body metabolism remains intact in ADRD even with impaired glucose metabolism. We recently found that disrupted glucose metabolism is an important driver of behavioral changes in mouse models of delirium. We also recently showed that a ketogenic diet improves memory in both aging mice and an ADRD mouse model. We developed an innovative toolkit of compounds and genetic models to mechanistically study ketone bodies experimentally. We hypothesize that energetic support from ketone bodies might help compensate for inflammation-induced neuronal impairments in glucose metabolism. We also elucidated a new mechanism linking inflammation to metabolism, showing that activation of peripheral macrophages induces enzymes that degrade the key metabolic mediator NAD+. Inflammation-driven NAD+ depletion occurs chronically in aging and ADRD, and may occur acutely in delirium. We will use an inflammation model of delirium with normal mice and two ADRD models to test if ketone bodies or NAD+ can rescue acute delirium-like behavioral changes, and identify the relevant mechanisms (Aim 1). We will use cultured cells and an in vivo brain inflammation model to determine if activated microglia deplete NAD+ similarly to macrophages, and whether preventing this also rescues delirium-like behaviors (Aim 2). Finally, we will use cerebrospinal fluid samples from a large clinical study of postoperative delirium to determine how endogenous ketone body and NAD+ levels differ between patients with vs. without delirium (Aim 3). This collaborative project links basic science expertise in ketone body and NAD+ biology relevant to ADRD, with basic and clinical research expertise in delirium. It will open a new area of mechanistic study on inflammation-induced metabolic deficits in delirium, guiding development of translational interventions.