Gray and white matter metabolite differences in Alzheimer’s disease and normal human brain tissue

Abstract

AbstractBackgroundGray matter atrophy and white matter alteration are key neurological features of Alzheimer’s disease (AD), but very little has been reported about the biochemical profile of the gray and white matter in AD. Here we measure the metabolites of AD brains and control brains in the gray and white matter to understand what differences are present.MethodThe global biochemical profiles of post‐mortem human brain tissue from Brodmann area 9 was determined using mass spectroscopy. Brain tissue from 53 subjects with AD and 46 cognitively normal subjects were analyzed. Metabolites in gray and white matter were compared. Metabolites were quantified using global untargeted metabolomics (HD4) and compared between cohorts using Welch’s two‐sample t‐test and random Forest.ResultGray and white matter metabolites differed in both the AD and the control brains. The gray matter had more metabolites associated with anaerobic metabolism including increased glycine, serine and threonine metabolism, alanine and aspartate metabolism, dipeptides, glycolysis, gluconeogenesis, and pyruvate metabolism, pentose metabolism, BCAA metabolism, phosphatidylcholine, phosphatidylethanolamine, sphingolipid synthesis, ceramides, nicotinate and nicotinamide metabolism, and vitamin B6 metabolism. The white matter had more metabolites associated with aerobic metabolism including oxidative phosphorylation, fatty acid metabolism, long chain monounsaturated fatty acid, Acyl Carnitine Fatty Acid Metabolism, Glycerolipid Metabolism, Monoacylglycerol, Hexosylceramides (HCER), Sterols, and Pantothenate and CoA Metabolism in the white matter vs the gray matter. White and gray matter differences were dependent on disease status for the following metabolites: N‐acetylserine – part of serine metabolism, 1‐arachidonoyl‐GPA (20:4) – a lysophospholipid, Valylleucine – a dipeptide, and octadecenedioate (C18:1‐DC) and oleoylcarnitine (C18:1) – both fatty acids.ConclusionIn our cohort, gray matter showed more metabolite differences dependent on anaerobic metabolism and white matter showed more metabolite differences dependent on aerobic metabolism. Some metabolite differences were dependent on disease status. Researchers using brain metabolomics data should be aware of these gray and white matter differences so that their results aren’t due simply to differences in concentration of gray and white matter between samples. An understanding of how the brain metabolites differ depending on AD disease status can give important insights into disease pathology.