Serum metabolomic biomarkers of perceptual speed in cognitively normal and mildly impaired subjects with fasting state stratification

Kamil Borkowski,John W Newman,Matthias Arnold,Ameer Y Taha,Philip L De Jager,Rima Kaddurah-Daouk,David A Bennett,Theresa L Pedersen

doi:10.1038/s41598-021-98640-2

Abstract

Cognitive decline is associated with both normal aging and early pathologies leading to dementia. Here we used quantitative profiling of metabolites involved in the regulation of inflammation, vascular function, neuronal function and energy metabolism, including oxylipins, endocannabinoids, bile acids, and steroid hormones to identify metabolic biomarkers of mild cognitive impairment (MCI). Serum samples (n = 212) were obtained from subjects with or without MCI opportunistically collected with incomplete fasting state information. To maximize power and stratify the analysis of metabolite associations with MCI by the fasting state, we developed an algorithm to predict subject fasting state when unknown (n = 73). In non-fasted subjects, linoleic acid and palmitoleoyl ethanolamide levels were positively associated with perceptual speed. In fasted subjects, soluble epoxide hydrolase activity and tauro-alpha-muricholic acid levels were negatively associated with perceptual speed. Other cognitive domains showed associations with bile acid metabolism, but only in the non-fasted state. Importantly, this study shows unique associations between serum metabolites and cognitive function in the fasted and non-fasted states and provides a fasting state prediction algorithm based on measurable metabolites.

Highlights

Cognitive decline is associated with both normal aging and early pathologies leading to dementia
We describe an exploration of circulating oxylipin, endocannabinoids, bile acids, and steroids for biomarkers of cognitive impairment, providing insights into unique associations in basal and postprandial metabolism
A high probability of the fasted state was described by low levels of the linoleic acid (LA)-derived cytochrome P450 (CYP) metabolite [12(13)-EpOME], low levels of the primary conjugated bile acid glycochenodeoxycholic acid (GCDCA) and elevated levels of the glycine-conjugated oleic acid (NO-Gly; Fig. 1A,B)

Summary

Introduction

Cognitive decline is associated with both normal aging and early pathologies leading to dementia. Soluble epoxide hydrolase activity and tauro-alpha-muricholic acid levels were negatively associated with perceptual speed. Other cognitive domains showed associations with bile acid metabolism, but only in the non-fasted state. Biochemical markers of altered cognitive capacity may provide diagnostic and prognostic biomarkers of these diseases and their associated metabolic trajectories before clinical symptoms manifest. Such biomarkers could provide new insights into the mechanisms of cognitive decline. It has recently become clear that cardiometabolic disorders and associated low-grade systemic inflammation and altered lipid and energy metabolism, are risk factors for cognitive impairment[3,4,5]. Four important families of such lipid mediators readily detected in the circulation are the oxygenated polyunsaturated fatty acids (i.e. oxylipins), the endogenous cannabinoid receptor activators and their structural equivalents (i.e. endocannabinoids), bile acids and steroids

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