Blood proteome of acute intracranial hemorrhage in infant victims of abusive head trauma

Abstract

Abusive head trauma (AHT) is a leading cause of mortality and morbidity in infants.While the reported incidence is close to 40 cases per 100′000 births/year, misdiagnoses are commonly observed in cases with atypical, subacute, or chronic presentation.Currently, standard clinical evaluation of inflicted intracranial hemorrhagic injury (ICH) in infants urgently requires a screening test able to identify infants who need additional investigations. Blood biomarkers characteristic of AHT may assist in detecting these infants, improving prognosis through early medical care. To date, the application of innovative omics technologies in retrospective studies of AHT in infants is rare, due also to the blood serum and cerebrospinal fluid of AHT cases being scarce and not systematically accessible. Here, we explored the circulating blood proteomes of infants with severe AHT and their atraumatic controls. We discovered 165 circulating serum proteins that display differential changes in AHT cases compared with atraumatic controls. The peripheral blood proteomes of pediatric AHT commonly reflect:(i) potentially secreted proteome from injured brain, and (ii) proteome dysregulated in the system's circulation by successive biological events following acute ICH. This study opens up a novel opportunity for research efforts in clinical screening of AHT cases.

Activity based proteome profiling of serum serine hydrolases: application in pediatric abusive head trauma

“…We focused on the five complement proteases (e.g. C1S, C1R, C2, C1RL, MASP1, Figure S2A ) that were significantly elevated in sera from severe AHT cases and for which expression levels were measured in our previous study[19]. We observed that proteolytic activities of five complement proteases did not follow their high circulating levels or correlate with markers of neuronal damage (i.e.…”

“…We then focused in the activity of serine proteases of complement cascade involved in neuroinflammation [7] and metabolic serine lipases highly expressed in brain [13]. As biochemical reactions occur at controlled stoichiometric proportions, we hypothesized that after the blood has clotted, the native serum liquid, that is free of additives, potentially contains the active proteases of complement if the latter were present in excess in the bloodstream, as we previously demonstrated in infants with intracranial bleeding induced by AHT [19]. We focused on the five complement proteases (e.g.…”

“…LCAT esterifies free cholesterol on nascent APOE-containing lipoproteins secreted from glia and influences CSF APOE-and APOA1 levels [21]. Interestingly, several Apolipoproteins were elevated in the serum of AHT cases [19]. Glycerophospholipids are the major component of biological membranes in the brain [44], and it has been shown that an increase in CSF glycerophospholipids and lipoproteins modulates LCAT enzyme activity to maintain cholesterol homeostasis in the brain of patients with neurodegenerative diseases.…”

“…AHT is one of the most severe forms of TBI in young children, with higher mortality and morbidity than accidental injury [16][17][18][19]. Our recent study demonstrated that the SHs of complement cascades and those involved in neurodevelopment, such as Lecithin-cholesterol acyltransferase (LCAT) with their substrate lipoproteins (e.g., APOE, CLU) [20][21][22] known to modulate TBI [22] , were highly elevated enzymes in infant victims of AHT with severe ICH compared with atraumatic cases [19].…”

Post‐translational modification and phenotype

“…A total of 1684 differential phosphosites together with 25 phosphorylation motifs were identified, indicating a role of Akt1 in TRAIL signaling. While the four articles above interrogated the proteomic and phosphoproteomic regulations in a defined clinical phenotype or a clarified drug response, the fifth article in this category by Wiskott et al [17], very interestingly, was set to identify blood biomarkers for the acute intracranial hemorrhage in infant victims of abusive head trauma (AHT), a status that is difficult to be effectively diagnosed in current hospital practice. The authors measured the matched postmortem and antemortem blood specimens of AHT cases, together with controls of sudden infant death syndrome using DIA‐MS.…”