Lysophosphatidylcholines and Cognition (L-COG) Study

溶血磷脂酰胆碱与认知 (L-COG) 研究

基本信息

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
项目类别：
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&apos 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

项目摘要

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 (T2DM) 的成人患认知能力下降、血管性痴呆和阿尔茨海默病 (AD) 是导致认知障碍风险过高的生物过程。成人 T2DM 患者的脑容量是否减少，目前还不清楚。与对照组相比，白质连接中断，血管病变负担增加。血管性痴呆和 AD 中都会发生大脑中脂质代谢的改变。链状多不饱和脂肪酸 (PUFA) 已在额叶皮层、内嗅皮层和痴呆症患者大脑中的海马体只能合成少量脂肪酸，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越高，认知风险就会降低。然而，在观察性研究中，PUFA 补充剂并没有阻止认知能力下降和痴呆。最近的动物研究表明，二十二碳六烯酸等长链脂肪酸的含量有所下降。（DHA，22:6）以溶血磷脂酰胆碱（LPC）的形式穿过血脑屏障（BBB）通过特定的 LPC 受体，即钠依赖性 LPC 同向转运蛋白 1 (MFSD2A)。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 DHA 等 PUFA，并在认知能力下降的病理生物学中发挥作用。用于认知的 PUFA 补充涉及在 LPC 动物中未酯化的 omega-3 PUFA。研究表明，LPC 是通过 MFSD2A 跨 BBB 运输长链 PUFA 的首选载体。血清长链 LPC 与认知能力下降的关系尚未得到很好的表征，并且仍然是一个该项目的具体目标是溶血磷脂酰胆碱和认知。 (L-COG) 研究旨在确定血清 LPC 浓度低的糖尿病成人是否处于升高状态为了解决这些目标，我们将描述血清 LPC 的关系。 Accordion-MIND 研究中参与者认知能力下降的浓度，这是一项前瞻性研究我们将在 80 个月的时间内对患有 T2DM 的成人进行认知评估。确定低血清 LPC（包含大脑的长链 PUFA 池）是否是一种这项研究的结果表明，T2DM 成人认知能力下降的独立危险因素。转化潜力，因为低血清 LPC 可能是认知能力下降的一个可改变的危险因素。