{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T22:46:16Z","timestamp":1787957176602,"version":"build-2784847793"},"reference-count":28,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Neurol"],"published-print":{"date-parts":[[2024,3,1]]},"abstract":"\n Importance<\/jats:title>\n Antemortem infection is a risk factor for sudden infant death syndrome (SIDS)\u2014the leading postneonatal cause of infant mortality in the developed world. Manifestations of infection and inflammation are not always apparent in clinical settings or by standard autopsy; thus, enhanced resolution approaches are needed.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n To ascertain whether a subset of SIDS cases is associated with neuroinflammation and occult infection.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n In this case-control study, postmortem fluids from SIDS cases and controls collected between July 2011 and November 2018 were screened for elevated inflammatory markers, specifically cerebrospinal fluid (CSF) neopterin and CSF and serum cytokines. CSF, liver, and brain tissue from SIDS cases with elevated CSF neopterin were subjected to metagenomic next-generation sequencing (mNGS) to probe for infectious pathogens. Brainstem tissue from a subset of these cases was analyzed by single-nucleus RNA sequencing (snRNAseq) to measure cell type\u2013specific gene expression associated with neuroinflammation and infection. All tissue and fluid analyses were performed from April 2019 to January 2023 in a pathology research laboratory. Included was autopsy material from infants dying of SIDS and age-matched controls dying of known causes.<\/jats:p>\n <\/jats:sec>\n \n Exposures<\/jats:title>\n There were no interventions or exposures.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n CSF neopterin levels were measured by high-performance liquid chromatography. Cytokines were measured by multiplex fluorometric assay. mNGS was performed on liver, CSF, brain, and brainstem tissue. snRNAseq was performed on brainstem tissue.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n A cohort of 71 SIDS cases (mean [SD] age, 55.2 [11.4] postconceptional weeks; 42 male [59.2%]) and 20 controls (mean [SD] age, 63.2 [16.9] postconceptional weeks; 11 male [55.0%]) had CSF and\/or serum available. CSF neopterin was screened in 64 SIDS cases and 15 controls, with no exclusions. Tissues from 6 SIDS cases were further analyzed. For CSF neopterin measures, SIDS samples were from infants with mean (SD) age of 54.5\u2009(11.3) postconceptional weeks (38 male [59.4%]) and control samples were from infants with mean (SD) age of 61.5\u2009(17.4) postconceptional weeks (7 male [46.7%]). A total of 6 SIDS cases (9.3%) with high CSF neopterin were identified, suggestive of neuroinflammation. mNGS detected human parechovirus 3 (HPeV3) in tissue and CSF from 1 of these 6 cases. snRNAseq of HPeV3-positive brainstem tissue (medulla) revealed dramatic enrichment of transcripts for genes with predominately inflammatory functions compared with 3 age-matched SIDS cases with normal CSF neopterin levels.<\/jats:p>\n <\/jats:sec>\n \n Conclusions and Relevance<\/jats:title>\n Next-generation molecular tools in autopsy tissue provide novel insight into pathogens that go unrecognized by normal autopsy methodology, including in infants dying suddenly and unexpectedly.<\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jamaneurol.2023.5387","type":"journal-article","created":{"date-parts":[[2024,1,29]],"date-time":"2024-01-29T11:31:25Z","timestamp":1706527885000},"page":"240","source":"Crossref","is-referenced-by-count":21,"title":["Multiomic Analysis of Neuroinflammation and Occult Infection in Sudden Infant Death Syndrome"],"prefix":"10.1001","volume":"81","author":[{"given":"Prashanth S.","family":"Ramachandran","sequence":"first","affiliation":[{"name":"Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco"},{"name":"The Peter Doherty Institute for Immunity and Infection, University of Melbourne, Melbourne, Victoria, Australia"},{"name":"The Royal Melbourne Hospital, University of Melbourne, Melbourne, Victoria, Australia"},{"name":"Now with St Vincent\u2019s Hospital, University of Melbourne, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin W.","family":"Okaty","sequence":"additional","affiliation":[{"name":"Department of Genetics, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Molly","family":"Riehs","sequence":"additional","affiliation":[{"name":"Department of Pathology, Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Wapniarski","sequence":"additional","affiliation":[{"name":"Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Hershey","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Hospital Medicine, University of California San Diego, Rady Childrens Hospital, San Diego"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hani","family":"Harb","sequence":"additional","affiliation":[{"name":"Department of Immunology, Boston Children\u2019s Hospital, Boston, Massachusetts"},{"name":"Now with Institute for Medical Microbiology and Virology, Technical University Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maham","family":"Zia","sequence":"additional","affiliation":[{"name":"Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth A.","family":"Haas","sequence":"additional","affiliation":[{"name":"Department of Research, Rady Children\u2019s Hospital, San Diego, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanda","family":"Alexandrescu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lynn A.","family":"Sleeper","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Boston Children\u2019s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara O.","family":"Vargas","sequence":"additional","affiliation":[{"name":"Department of Pathology, Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark P.","family":"Gorman","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children\u2019s Hospital, Harvard Medical School, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Campman","sequence":"additional","affiliation":[{"name":"San Diego County Medical Examiner Office, San Diego, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Othon J.","family":"Mena","sequence":"additional","affiliation":[{"name":"San Diego County Medical Examiner Office, San Diego, California"},{"name":"Now with Ventura County Medical Examiner Office, Ventura, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Levert","sequence":"additional","affiliation":[{"name":"Medical Neurogenetics Laboratories, a Labcorp company, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Hyland","sequence":"additional","affiliation":[{"name":"Medical Neurogenetics Laboratories, a Labcorp company, Atlanta, Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard D.","family":"Goldstein","sequence":"additional","affiliation":[{"name":"Robert\u2019s Program on Sudden Unexpected Death in Pediatrics, Division of General Pediatrics, Department of Pediatrics, Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Weill Institute for Neurosciences, Department of Neurology, University of California San Francisco, San Francisco"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robin L.","family":"Haynes","sequence":"additional","affiliation":[{"name":"Department of Pathology, Boston Children\u2019s Hospital, Boston, Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"4","key":"noi230098r1","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1007\/s12024-019-00156-9","article-title":"Inconsistent classification of unexplained sudden deaths in infants and children hinders surveillance, prevention and research: recommendations from The 3rd International Congress on Sudden Infant and Child Death.","volume":"15","author":"Goldstein","year":"2019","journal-title":"Forensic Sci Med Pathol"},{"issue":"4","key":"noi230098r3","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1007\/s00401-009-0535-y","article-title":"Interleukin-6 and the serotonergic system of the medulla oblongata in the sudden infant death 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Recent reports of human parechovirus (PeV) in the US\u20142022. 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