Exploratory Brain Metabolomics: Sudden Infant Death Syndrome

Abstract

Sudden Infant Death Syndrome (SIDS) is the sudden, unexplained passing of an infant during sleep within the first year of life. The diagnosis of SIDS is one of exclusion, with no plausible explanation following autopsy and investigation of the death scene. Most of our present understanding of SIDS comes from epidemiological studies, and much is less known about molecular etiology. One candidate mechanism is that abnormalities in brainstem biochemistry cause altered neural control of breathing, leading to rousing defect and apparent SIDS. The objective of this study was to identify novel brain biochemicals associated with SIDS. Postmortem human infant brain tissue specimens from 28 decedents underwent comprehensive metabolomic profiling (SIDS, n=15; non‐SIDS, n=13). A total of 87 brain specimens were collected from 4 different regions of the brain associated with learning and memory, including the auditory cortex (AC, n=11), frontal cortex (FC, n=27), hippocampus (HC, n=22), and occipital cortex (OC, n=27). The contributions of both SIDS status and age to differential abundance of biochemicals were determined using Wilcoxon rank sum and Spearman correlation tests. A total of 247 known biochemicals were detected. Between SIDS and non‐SIDS specimens, 2 biochemicals in the AC, 12 in the FC, 9 in the HC and 10 in the OC were detected at significantly different levels (p<0.05). The most striking metabolomic pattern in SIDS vs. non‐SIDS specimens was attributed to changes in the urea cycle. Urea levels were 34% and 45% lower in the OC and HC, respectively, from SIDS brains, suggesting hyperammonemia. Also related to urea cycle, SIDS specimens showed changes in spermidine (−29% in OC), citrulline (+94% in HC), aspartate (+49% in FC and +35% in HC), arginine (+17% in FC) and 4‐guanidobutanoate (+31% in HC), relative to non‐SIDS specimens. Carbohydrate metabolism was altered, as glucose, fructose and sorbitol levels trended downward in all 4 SIDS brain specimens. Changes in both fructose (−70% in OC) and sorbitol (−59% in FC) achieved significance. Protein metabolism was also altered. The tryptophan metabolite kynurenine and the valine metabolite α‐hydoxyisovalerate were 37% and 74% lower in SIDS OC, while cysteine (+2.1‐fold) and cysteine‐glutathione disulfide (+2.2‐fold) increased in SIDS FC. Pseudouridine was ~30% decreased in each of FC, HC and OC from SIDS brains, suggesting differences in tRNA metabolism. Additionally, correlation analysis of biochemical levels vs. age of infant showed remarkable differences between SIDS and non‐SIDS. For example, non‐SIDS HC and OC age correlated with 7 and 22 biochemicals, respectively, while SIDS HC and OC age correlated with 29 and 49 biochemicals. In sum, we have identified several new candidate brain biochemicals and pathways, such as the urea cycle, associated with SIDS.Support or Funding InformationFunding for this study was provided by Abbott Nutrition.