A Quest for a Histaminergic or Orexinergic Biomarker for Sudden Infant Death Syndrome

Zhao, Y.; Cui, G.-F.; Plancoulaine, S.; Comajuan, M.; Bersault, M.; Inocente, C.; Hou, Y.-P.; Dauvilliers, Y.; Manuela, L.; Guyon, A.; Meyronet, D.; Jouvet, A.; Kugener, B.; Thieux, M.; Robert, P.; Lin, J.-S.; Franco, P.

doi:10.1101/2025.10.08.680830

bioRxiv · 10.1101/2025.10.08.680830

A Quest for a Histaminergic or Orexinergic Biomarker for Sudden Infant Death Syndrome

Zhao, Y.·Cui, G.-F.·Plancoulaine, S.·Comajuan, M.·Bersault, M.·Inocente, C.·Hou, Y.-P.·Dauvilliers, Y.·Manuela, L.·Guyon, A.·Meyronet, D.·Jouvet, A.·Kugener, B.·Thieux, M.·Robert, P.·Lin, J.-S.·Franco, P.

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Abstract

AimsThis study aimed to investigate the role of the Hypocretin/Orexin (Ox) and Histamine (HA) systems--two key regulators of wakefulness --in sudden infant death syndrome (SIDS), a condition characterized by impaired arousal responses during sleep. MethodsCerebrospinal fluid (CSF) Ox levels were measured in 61 healthy controls, 70 Sudden Unexpected Death Infants (SUDI) (38 SIDS cases and 32 explained deaths (ED). HA and its metabolite, tele-methylhistamine (t-MeHA), were analysed in an additional 46 SUDI (34 SIDS, 12 ED) and 42 controls. Immunocytochemistry was performed on hypothalamic tissue from 11 SIDS and 13 ED cases to assess the number of Ox and HA neurons, using markers for Orexin-A and histidine decarboxylase (HDC), respectively. ResultsOverall CSF Ox levels did not differ significantly between groups. However, while an age-related decline in Ox levels was observed in controls (0-2 vs. 2-6 months), this pattern was absent in deceased infants, resulting in relatively higher Ox concentrations in the 2-6 month age group. HA and t-MeHA levels were significantly elevated in both SIDS and ED cases, likely due to postmortem release. Immunohistochemical analysis revealed an increased number of Ox-immunoreactive neurons in the rostral and caudal dorsolateral hypothalamus in SIDS cases compared to EDs. No differences were observed in the number or morphology of HA neurons. ConclusionFindings suggest increased Ox activity in SIDS cases, potentially reflecting repeated exposure to stress or hypoxia prior to death. In contrast, HA neurons do not appear to play a role in the pathophysiology of SIDS. Further research is needed to identify more specific biomarkers for assessing SIDS risk.

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Zhao, Y., Cui, G.-F., Plancoulaine, S., Comajuan, M., Bersault, M., Inocente, C., Hou, Y.-P., Dauvilliers, Y., Manuela, L., Guyon, A., Meyronet, D., Jouvet, A., Kugener, B., Thieux, M., Robert, P., Lin, J.-S., Franco, P.. 2025-10-09. A Quest for a Histaminergic or Orexinergic Biomarker for Sudden Infant Death Syndrome. https://doi.org/10.1101/2025.10.08.680830

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