Proteomic differences in hippocampus and cortex of sudden unexplained death in childhood

Abstract

Sudden unexplained death in childhood (SUDC) is death of a child over 1 year of age that is unexplained after review of clinical history, circumstances of death, and complete autopsy with ancillary testing. Multiple etiologies may cause SUDC. SUDC and sudden unexpected death in epilepsy (SUDEP) share clinical and pathological features, suggesting some similarities in mechanism of death and possible abnormalities in hippocampus and cortex. To identify molecular signaling pathways, we performed label-free quantitative mass spectrometry on microdissected frontal cortex, hippocampal dentate gyrus (DG), and cornu ammonis (CA1-3) in SUDC (n = 19) and pediatric control cases (n = 19) with an explained cause of death. At a 5% false discovery rate (FDR), we found differential expression of 660 proteins in frontal cortex, 170 in DG, and 57 in CA1-3. Pathway analysis of altered proteins identified top signaling pathways associated with activated oxidative phosphorylation (p = 6.3 × 10–15, z = 4.08) and inhibited EIF2 signaling (p = 2.0 × 10–21, z = − 2.56) in frontal cortex, and activated acute phase response in DG (p = 8.5 × 10–6, z = 2.65) and CA1-3 (p = 4.7 × 10–6, z = 2.00). Weighted gene correlation network analysis (WGCNA) of clinical history indicated that SUDC-positive post-mortem virology (n = 4/17) had the most significant module in each brain region, with the top most significant associated with decreased mRNA metabolic processes (p = 2.8 × 10–5) in frontal cortex. Additional modules were associated with clinical history, including fever within 24 h of death (top: increased mitochondrial fission in DG, p = 1.8 × 10–3) and febrile seizure history (top: decreased small molecule metabolic processes in frontal cortex, p = 8.8 × 10–5) in all brain regions, neuropathological hippocampal findings in the DG (top: decreased focal adhesion, p = 1.9 × 10–3). Overall, cortical and hippocampal protein changes were present in SUDC cases and some correlated with clinical features. Our studies support that proteomic studies of SUDC cohorts can advance our understanding of the pathogenesis of these tragedies and may inform the development of preventive strategies.

Metabolomic, proteomic, and transcriptomic changes in adults with epilepsy on modified Atkins diet

“…Pathways were considered enriched at p ‐value of overlap < .05 and activated/inhibited as a result of combined protein fold changes in the pathway as reflected by | z score| ≥ 2. Brain cell type annotation was performed as reported previously 4,5,26–28 …”

Are brief febrile seizures benign? A systematic review and narrative synthesis

“…We only reported one. 39 Three studies (Leitner et al 35,41 and McGuone et al 37 ) reported unique outcomes from the same case series with some known overlap. We included these studies by our group, relative to their unique methodology and outcome results, but ensured the accuracy of mortality incidence by measuring each unique case once.…”

“…35 The highest frequency of altered protein were expressed in the frontal cortex, with some altered proteins correlating with fever before death and febrile seizure history. 35 The risk of bias was medium.…”

“…The systematic review included 26 studies (Table S1) between 1978 and 2022 . 5,6,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40 All reported ≥1 cases within inclusion criteria and data related to our primary mortality outcome (11), or secondary outcomes of neurodevelopment (11) or neuropathology (13). Two studies (Krous et al 5 and Kinney et al 39 ) reported mortality data from the same case registry with undefined case redundancy that could not be clarified after contact with the author.…”

Sudden unexpected death in epilepsy

“…Considerable work has been done recently to evaluate anatomical and pathological changes in patients who died from SUDEP compared with cohorts with or without epilepsy. This has included examining 5-HT receptor subtypes in hippocampus and temporal cortex [95], 5-HT transporter in brainstem and amygdala [96], evaluating proteomic changes [97,98] and evaluating for anatomical changes in central autonomic regions [99,100,101 ▪ ]. Changes in 5-HT and serotonergic nuclei in brainstem have been evaluated previously [102].…”