Lipidome alterations in human prefrontal cortex during development, aging, and cognitive disorders

Abstract

Lipids are essential to brain functions, yet they remain largely unexplored. Here we investigated the lipidome composition of prefrontal cortex gray matter in 396 cognitively healthy individuals with ages spanning 100 years, as well as 67 adult individuals diagnosed with autism (ASD), schizophrenia (SZ), and Down syndrome (DS). Of the 5024 detected lipids, 95% showed significant age-dependent concentration differences clustering into four temporal stages, and resulting in a gradual increase in membrane fluidity in individuals ranging from newborn to nonagenarian. Aging affects 14% of the brain lipidome with late-life changes starting predominantly at 50-55 years of age-a period of general metabolic transition. All three diseases alter the brain lipidome composition, leading-among other things-to a concentration decrease in glycerophospholipid metabolism and endocannabinoid signaling pathways. Lipid concentration decreases in SZ were further linked to genetic variants associated with disease, indicating the relevance of the lipidome changes to disease progression.

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

“…In particular, reduced levels of glycerophosphoethanolamines along with reduced glycerophospholipid metabolism were observed in DS (Yu et al, 2018). Furthermore, the ratio of cholesterol to phospholipid concentration, phosphatidylcholine, and phosphatidylethanolamine levels were all reduced in DS frontal cortex (Yu et al, 2018). These alterations were suggested to result from an impaired endocannabinoid signaling pathway in DS (Yu et al, 2018).…”

“…Of 542 identified lipids, around 350 were reduced while the others were increased in DS frontal cortex (Yu et al, 2018). In particular, reduced levels of glycerophosphoethanolamines along with reduced glycerophospholipid metabolism were observed in DS (Yu et al, 2018). Furthermore, the ratio of cholesterol to phospholipid concentration, phosphatidylcholine, and phosphatidylethanolamine levels were all reduced in DS frontal cortex (Yu et al, 2018).…”

“…Furthermore, the ratio of cholesterol to phospholipid concentration, phosphatidylcholine, and phosphatidylethanolamine levels were all reduced in DS frontal cortex (Yu et al, 2018). These alterations were suggested to result from an impaired endocannabinoid signaling pathway in DS (Yu et al, 2018). In addition, in a very recent study, Hwang et al (2019) demonstrated that DS fibroblast were characterized by reduced levels of sphingosine derivatives called long chain bases (LCBs), which seem to be responsible for nuclear membrane alterations associated with accelerated aging process in DS.…”

“…In the brain, a lipidomic study performed by Yu et al (2018) reported altered lipid profile in prefrontal cortex samples collected from five DS (>60 years) individuals with respect to matched controls. Of 542 identified lipids, around 350 were reduced while the others were increased in DS frontal cortex (Yu et al, 2018). In particular, reduced levels of glycerophosphoethanolamines along with reduced glycerophospholipid metabolism were observed in DS (Yu et al, 2018).…”

Structural Alterations in Large-scale Brain Networks and Their Relationship with Sleep Disturbances in the Adolescent Population

“…FDR thresholding controls the expected proportion of false positives only among brain regions showing significance 78 . Although conservative levels of FDR (e.g., 0.01-0.05) can be used in neuroimaging studies, FDR control levels in the range of 0.1-0.2 are originally and practically known to be acceptable and have been applied in several neuroimaging studies 33,78,79,88,89 . FDR corrected p-values were calculated by using spm_P_FDR.m with all regional p-value inputs, which is a MATLAB code included in the SPM toolbox.…”