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.

成人2型糖尿病（T2 DM）患者发生认知能力下降、血管性痴呆和 阿尔茨海默病（AD）。解释认知障碍过度风险的生物学过程 和痴呆的发病率尚不清楚。患有T2 DM的成年人脑容量减少， 与对照组相比，白色物质连接性中断，血管病变负担增加。 血管性痴呆和AD患者脑内脂质代谢均发生改变。低浓度的长- 链多不饱和脂肪酸（PUFA）已被描述在额叶皮层，内嗅皮层， 大脑中的海马体大脑只能合成少数脂肪酸，因此，大多数脂肪酸 必须从血液进入大脑较高的膳食PUFA摄入量与认知风险降低相关 然而，在观察性研究中，PUFA补充剂并不能预防认知功能下降和痴呆。 临床试验下降。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）的形式转运穿过血脑屏障（BBB） 通过一个特定的LPC受体，钠依赖性LPC同向转运体1（MFSD 2A）。缺乏足够的 含有长链脂肪酸的循环LPC可能会限制长链脂肪酸的供应， 大脑，包括PUFA如DHA，并在认知能力下降的病理生物学中发挥作用。人体试验 补充PUFA对认知的影响涉及在LPC中未酯化的ω-3 PUFA。动物 研究表明LPC是通过MFSD 2A运输长链PUFA穿过BBB的优选载体。的 血清长链LPCs与认知功能下降的关系尚未得到很好的表征， 知识上的重大差距。这个项目的具体目标，溶血磷脂酰胆碱和认知 （L-COG）研究的目的是确定低血清LPC浓度的糖尿病成人是否处于增加的 认知能力下降的风险。为了实现这些目标，我们将描述血清LPC的关系 ACCORDION-MIND研究（一项前瞻性研究， 在80个月的时间内评估了T2 DM成人的认知。在研究结束时，我们将 确定低血清LPCs（其包含脑的长链PUFA库）是否是一种 T2 DM成人认知功能下降的独立危险因素。这项研究的结果具有很高的 翻译潜力，因为低血清LPCs可能是认知能力下降的一个可改变的风险因素。