Lysophosphatidylcholines and Cognition (L-COG) Study

溶血磷脂酰胆碱与认知 (L-COG) 研究

• 批准号: 10242168
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242168
• 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; 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; dietary; 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.

2型糖尿病（T2DM）的成年人的认知能力下降，血管性痴呆和 阿尔茨海默氏病（AD）。解释了认知障碍的过多风险的生物过程 T2DM患者的痴呆在很大程度上不清楚。 T2DM的成年人的大脑体积减少， 与对照组相比，白质连通性的破坏以及血管病变的燃烧增加。 大脑中脂质代谢的改变发生在血管痴呆和AD中。较低的长度 在额叶皮层，内嗅皮层和 痴呆症大脑中的海马。大脑只能合成几个脂肪酸，因此，大多数脂肪酸 必须从血液中进入大脑。更高的饮食PUFA摄入量与认知风险降低有关 然而，在观察性研究中，PUFA补充并不能阻止认知 临床试验的下降。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）的形式在血脑屏障（BBB）上运输 通过特定的LPC接收器，依赖钠的LPC分类器1（MFSD2A）。池不足 循环LPC含有长链脂肪酸可能会限制长链脂肪酸的供应 包括DHA等PUFA在内的大脑，并在认知能力下降的病理学中发挥作用。人类试验 补充认知的PUFA涉及在LPC中未酯化的Omega-3 PUFA。动物 研究表明，LPC是通过MFSD2A在BBB上运输长链PUFA的首选载体。这 血清长链LPC与认知下降的关系尚未得到很好的特征，并且仍然是 知识的重要差距。该项目的具体目的，溶物磷脂酰胆碱和认知 （L-COG）研究是为了确定血清LPC浓度低的糖尿病成年人是否在增加 认知能力下降的风险。为了解决这些目标，我们将表征血清LPC的关系 手风琴研究参与者认知能力下降的浓度，这是一项前瞻性研究 在80个月内评估了T2DM成年人的认知。在研究结束时，我们将 确定低血清LPC是否包括大脑的长链PUFA池 T2DM成人认知能力下降的独立危险因素。这项研究的发现很高 转化潜力，因为低血清LPC可能是认知能力下降的可修改风险因素。