Lysophosphatidylcholines and Cognition (L-COG) Study

溶血磷脂酰胆碱与认知 (L-COG) 研究

• 批准号: 10040903
• 负责人: RICHARD D SEMBA
• 金额: $ 12.28万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10040903
• 关键词: Accounting; Address; Adult; Alzheimer' s Disease; Animals; Astrocytes; Biological Assay; Biological Process; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; C14 isotope; Cell membrane; Cholesterol; Clinical Trials; Cognition; Dementia; Diabetes Mellitus; Diet; Docosahexaenoic Acids; Elderly; Esterified Fatty Acids; Fatty Acids; General Population; Glycerol; Goals; Hippocampus (Brain); Human; Impaired cognition; Intake; Knockout Mice; Knowledge; Lesion; Link; Linoleic Acids; Linolenic Acids; Lipids; Lipoproteins; Liquid Chromatography; Lysophosphatidylcholines; Measurement; Memory; Microcephaly; Mutation; Myelin Sheath; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Oligodendroglia; Omega-3 Fatty Acids; Organ; Participant; Pathogenesis; Patients; Physiological; Play; Polyunsaturated Fatty Acids; Prospective Studies; Public Health; Risk; Risk Factors; Role; Serum; Sodium; Study of serum; Syndrome; Vascular Dementia; Vertebral column; Weight; Woman; aged; brain volume; cardiovascular risk factor; diabetic; docosahexaenoylascorbic acid; entorhinal cortex; fatty acid supplementation; fatty acid transport; frontal lobe; high risk; innovation; insight; lipid metabolism; long chain fatty acid; modifiable risk; neuron loss; non-diabetic; older women; receptor; symporter; tandem mass spectrometry; white matter

Adults with type 2 diabetes mellitus (T2DM) are at a higher risk of cognitive decline, vascular dementia, and Alzheimer’s disease (AD). The biological processes that account for the excess risk of cognitive impairment and dementia in patients with T2DM are largely unclear. Adults with T2DM have reduced brain volume, disruptions in white matter connectivity, and an increased burden of vascular lesions compared with controls. Altered lipid metabolism in the brain occurs in both vascular dementia and AD. Lower concentrations of long- chain polyunsaturated fatty acids (PUFA) have been described in the frontal cortex, entorhinal cortex, and hippocampus in the brain in dementia. The brain can synthesize only a few fatty acids, thus, most fatty acids must enter the brain from the blood. Higher dietary PUFA intake is associated with decreased risk of cognitive decline and dementia in observational studies, however, PUFA supplementation did not prevent cognitive decline in clinical trials. Recent animal studies show that long-chain fatty acids such as docosahexaenoic acid (DHA, 22:6) are transported across the blood-brain barrier (BBB) in the form of lysophosphatidylcholine (LPC) via a specific LPC receptor, the sodium-dependent LPC symporter 1 (MFSD2A). An insufficient pool of circulating LPC containing long-chain fatty acids could potentially limit the supply of long-chain fatty acids to the brain, including PUFA such as DHA, and play a role in the pathobiology of cognitive decline. Human trials of PUFA supplementation for cognition involved omega-3 PUFA that were not esterified in LPCs. Animal studies show LPC to be the preferred carrier to transport long-chain PUFA across the BBB via MFSD2A. The relationship of serum long-chain LPCs with cognitive decline has not been well characterized and remains an important major gap in knowledge. The specific aim of this project, the Lysophosphatidylcholines and Cognition (L-COG) Study, is to determine whether diabetic adults with low serum LPC concentrations are at an increased risk of cognitive decline. To address these aims, we will characterize the relationship of serum LPC concentrations with cognitive decline in participants in the ACCORDION-MIND Study, a prospective study in which cognition in adults with T2DM was assessed over an 80 month period. By the end of the study, we will determine whether low serum LPCs, which comprise a pool of long-chain PUFA for the brain, are an independent risk factor for cognitive decline in adults with T2DM. The findings from this study have high translational potential, as low serum LPCs may be a modifiable risk factor for cognitive decline.

患有2型糖尿病(T2 DM)的成年人患认知功能减退、血管性痴呆和 阿尔茨海默病(AD)。导致认知损害风险过高的生物过程 而T2 DM患者的痴呆症在很大程度上还不清楚。患有T2 DM的成年人大脑体积减少， 与对照组相比，脑白质连接中断，血管损伤负担增加。 脑部脂肪代谢的改变在血管性痴呆和AD中都会发生。较低浓度的长- 链多不饱和脂肪酸(PUFA)已被描述在额叶皮质、内嗅觉皮质和 痴呆症患者大脑中的海马体。大脑只能合成几种脂肪酸，因此，大多数脂肪酸 必须从血液进入大脑。饮食中多不饱和脂肪酸摄入量较高与认知风险降低相关 然而，在观察性研究中，补充多不饱和脂肪酸并没有阻止认知能力的下降和痴呆 临床试验的减少。最近的动物研究表明，长链脂肪酸，如二十二碳六烯酸 (DHA，22：6)以溶血磷脂酰胆碱(LPC)的形式通过血脑屏障(BBB)转运 通过一个特定的LPC受体，钠依赖的LPC转运蛋白1(MFSD2A)。不足的资金池 循环中含有长链脂肪酸的LPC可能会潜在地限制长链脂肪酸的供应 大脑，包括多不饱和脂肪酸，如DHA，在认知功能下降的病理生物学中起着作用。人体试验 补充多不饱和脂肪酸的认知功能涉及未在LPCS中酯化的omega-3多不饱和脂肪酸。动物 研究表明，LPC是通过MFSD2A跨BBB运输长链多不饱和脂肪酸的首选承运人。这个 血清长链LPCS与认知功能减退的关系尚未得到很好的描述，仍是一种 重要的重大知识差距。本项目的具体目标--溶血磷脂及其认知 (L-COG)的研究，是为了确定血清LPC浓度低的糖尿病成年人是否处于升高状态 认知能力下降的风险。为了达到这些目标，我们将描述血清LPC之间的关系 手风琴-心灵研究参与者的注意力与认知能力下降，这是一项前瞻性研究 对成年T2 DM患者的哪种认知进行了80个月的评估。在研究结束时，我们将 确定构成大脑长链多不饱和脂肪酸池的低血清LPCS是否是 成人2型糖尿病认知功能减退的独立危险因素。这项研究的发现有很高的 翻译潜能，因为低血清LPCS可能是认知能力下降的一个可改变的危险因素。