Lysophosphatidylcholines and Cognition (L-COG) Study

点击翻译按钮获取中文摘要

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.