{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T19:19:49Z","timestamp":1789586389348,"version":"build-2803163510"},"posted":{"date-parts":[[2025,4,20]]},"group-title":"Physiology","reference-count":68,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,20]],"date-time":"2025-04-20T00:00:00Z","timestamp":1745107200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH","award":["P01-046925"],"award-info":[{"award-number":["P01-046925"]}]},{"name":"NIH","award":["P20GM103620"],"award-info":[{"award-number":["P20GM103620"]}]},{"name":"NIH","award":["R01HL160980"],"award-info":[{"award-number":["R01HL160980"]}]},{"name":"NIH","award":["P30GM154633"],"award-info":[{"award-number":["P30GM154633"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,10,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Non-infectious neuroinflammation (NINI) in early life and neonatal neural iron deficiency (nID) have been proposed to contribute to neurodevelopmental dysfunction and disorders, including autism, through toxic effects on neural cells and impaired molecular signaling. Early detection of NINI and nID may enable interventions to restore neurodevelopmental homeostasis and reduce long-term impact. However, such diagnoses are impossible due to ethical reason to access to the central nervous system (e.g., lumbar puncture) when there is no suspicion of brain infection (e.g., meningitis).<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We refined a methodology to isolate and quantify inflammatory and iron-regulatory proteins in high-quality brain-derived extracellular vesicles (BDEVs) from human umbilical cord blood. A preclinical model was used to validate that BDEV contents reflect the brain microenvironment. We then applied this approach to evaluate biomarkers of NINI and nID in BDEVs isolated from cord plasma of newborns of mothers with obesity, a non-infectious pro-inflammatory gestational condition and a risk factor for nID.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>Plasma BDEV analytes correlated more strongly with brain analytes and showed stronger associations among functionally related molecules compared with whole plasma analytes. Maternal obesity induced an anti-inflammatory response in the brain compartment, a pro-inflammatory response in the periphery, and functional nID.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>BDEVs may provide a more sensitive representation of the brain microenvironment than blood-based measures (e.g., plasma), enabling non-invasive, early detection of infants with NINI and neonatal nID.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding<\/jats:title>\n                  <jats:p>Supported by NIH, the Masonic Institute for Developing Brain, Hennepin Healthcare Research Institute, UnityPoint Health Meriter Foundation, and American Academy of Pediatrics Resident Research Grant.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Research in Context<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Evidence before this study<\/jats:title>\n                    <jats:p>Previous studies hypothesized that gestational inflammatory environments (e.g., maternal obesity) increase risk of neonatal neural iron deficiency (nID), neuroinflammation, and neurodevelopmental disorders. However, assessing non-infectious neuroinflammation (NINI) in infants from these high-risk groups is not feasible or clinically justifiable using invasive methods (e.g., cerebrospinal fluid collection), and analytes from whole blood or plasma may not accurately reflect brain physiological status.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Added value of this study<\/jats:title>\n                    <jats:p>We refined a protocol to isolate brain-derived extracellular vesicles (BDEVs) from a small amount of plasma sample (100 \u00b5L) and characterized their contents to approximate brain physiology. We demonstrated that BDEVs more accurately reflect brain status compared with whole plasma. In newborns of mothers with obesity during pregnancy, we found evidence of a low-grade peripheral inflammation accompanied by a protective anti-inflammatory response in the brain. Maternal obesity was also found to induce neonatal nID.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Implications of all the available evidence<\/jats:title>\n                    <jats:p>BDEVs can serve as an accurate, non-invasive tool to assess brain condition. In clinical settings, this approach may be used for early diagnosis, monitoring disease progression, and evaluating treatment effects.<\/jats:p>\n                  <\/jats:sec>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphical Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"648967v2_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>","DOI":"10.1101\/2025.04.15.648967","type":"posted-content","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T12:14:49Z","timestamp":1745410489000},"source":"Crossref","is-referenced-by-count":2,"title":["Utility of brain-derived extracellular vesicles from human umbilical cord blood to measure non-infectious neuroinflammation and functional iron deficiency"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4301-941X","authenticated-orcid":false,"given":"Phu V.","family":"Tran","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shirelle X.","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew C.","family":"Harris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zia L.","family":"Maxim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manjula","family":"Munirathinam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Muelken","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narmin","family":"Javadova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sowmya","family":"Kruttiventi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela J.","family":"Kling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle L.","family":"Baack","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael K.","family":"Georgieff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025101705450634000_2025.04.15.648967v2.1","doi-asserted-by":"crossref","unstructured":"Au NPB , Ma CHE. Neuroinflammation, Microglia and Implications for Retinal Ganglion Cell Survival and Axon Regeneration in Traumatic Optic Neuropathy. Front Immunol. 2022;13.","DOI":"10.3389\/fimmu.2022.860070"},{"key":"2025101705450634000_2025.04.15.648967v2.2","doi-asserted-by":"crossref","unstructured":"Ramos-Gonz\u00e1lez EJ , Bitzer-Quintero OK , Ortiz G , Hern\u00e1ndez-Cruz JJ , Ram\u00edrez-Jirano LJ . Relationship between inflammation and oxidative stress and its effect on multiple sclerosis. Neurologia. 2024;39(3).","DOI":"10.1016\/j.nrl.2021.10.003"},{"key":"2025101705450634000_2025.04.15.648967v2.3","doi-asserted-by":"crossref","unstructured":"Ward RJ , Dexter DT , Crichton RR. Iron, Neuroinflammation and Neurodegeneration. Int J Mol Sci. 2022;23(13).","DOI":"10.3390\/ijms23137267"},{"key":"2025101705450634000_2025.04.15.648967v2.4","doi-asserted-by":"crossref","unstructured":"You LH , Yu PP , Dong TY , Guo WH , Chang SY , Zheng BJ , et al. Astrocyte-derived hepcidin controls iron traffic at the blood-brain-barrier via regulating ferroportin 1 of microvascular endothelial cells. Cell Death Dis. 2022;13(8).","DOI":"10.1038\/s41419-022-05043-w"},{"key":"2025101705450634000_2025.04.15.648967v2.5","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2206758120"},{"key":"2025101705450634000_2025.04.15.648967v2.6","doi-asserted-by":"publisher","DOI":"10.1002\/aur.2284"},{"issue":"1","key":"2025101705450634000_2025.04.15.648967v2.7","doi-asserted-by":"crossref","first-page":"166854","DOI":"10.1016\/j.bbadis.2023.166854","article-title":"Neuroinflammation in fetal alcohol spectrum disorders and related novel therapeutic approaches","volume":"1870","year":"2024","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"key":"2025101705450634000_2025.04.15.648967v2.8","doi-asserted-by":"publisher","DOI":"10.1038\/srep25881"},{"key":"2025101705450634000_2025.04.15.648967v2.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2022.12.001"},{"key":"2025101705450634000_2025.04.15.648967v2.10","doi-asserted-by":"publisher","DOI":"10.1176\/appi.ajp.2016.16020138"},{"key":"2025101705450634000_2025.04.15.648967v2.11","doi-asserted-by":"crossref","unstructured":"Qin LY , He J , Hanes RN , Pluzarev O , Hong JS , Crews FT . Increased systemic and brain cytokine production and neuroinflammation by endotoxin following ethanol treatment. J Neuroinflamm. 2008;5.","DOI":"10.1186\/1742-2094-5-10"},{"key":"2025101705450634000_2025.04.15.648967v2.12","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1016\/j.neubiorev.2021.11.036","article-title":"Blood-based biomarkers of inflammation in mild traumatic brain injury: A systematic review","volume":"132","year":"2022","journal-title":"Neurosci Biobehav R"},{"key":"2025101705450634000_2025.04.15.648967v2.13","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/657086"},{"key":"2025101705450634000_2025.04.15.648967v2.14","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-016-0366-z"},{"key":"2025101705450634000_2025.04.15.648967v2.15","doi-asserted-by":"publisher","DOI":"10.1007\/s00406-022-01497-3"},{"key":"2025101705450634000_2025.04.15.648967v2.16","doi-asserted-by":"crossref","unstructured":"Banks WA , Sharma P , Bullock KM , Hansen KM , Ludwig N , Whiteside TL . Transport of Extracellular Vesicles across the Blood-Brain Barrier: Brain Pharmacokinetics and Effects of Inflammation. Int J Mol Sci. 2020;21(12).","DOI":"10.3390\/ijms21124407"},{"key":"2025101705450634000_2025.04.15.648967v2.17","doi-asserted-by":"crossref","unstructured":"Denizli M , Capitano ML , Kua KL . Maternal obesity and the impact of associated early-life inflammation on long-term health of offspring. Front Cell Infect Mi. 2022;12.","DOI":"10.3389\/fcimb.2022.940937"},{"key":"2025101705450634000_2025.04.15.648967v2.18","doi-asserted-by":"crossref","unstructured":"Urbonaite G , Knyzeliene A , Bunn FS , Smalskys A , Neniskyte U . The impact of maternal high-fat diet on offspring neurodevelopment. Front Neurosci-Switz. 2022;16.","DOI":"10.3389\/fnins.2022.909762"},{"key":"2025101705450634000_2025.04.15.648967v2.19","doi-asserted-by":"crossref","unstructured":"Vuong B , Odero G , Rozbacher S , Stevenson M , Kereliuk SM , Pereira TJ , et al. Exposure to gestational diabetes mellitus induces neuroinflammation, derangement of hippocampal neurons, and cognitive changes in rat offspring. J Neuroinflamm. 2017;14.","DOI":"10.1186\/s12974-017-0859-9"},{"key":"2025101705450634000_2025.04.15.648967v2.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2017.07.002"},{"key":"2025101705450634000_2025.04.15.648967v2.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2016.11.020"},{"key":"2025101705450634000_2025.04.15.648967v2.22","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-021-00530-8"},{"key":"2025101705450634000_2025.04.15.648967v2.23","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-024-03106-7"},{"key":"2025101705450634000_2025.04.15.648967v2.24","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1186\/s12974-014-0156-9","article-title":"Dietary intervention rescues maternal obesity induced behavior deficits and neuroinflammation in offspring","volume":"11","year":"2014","journal-title":"J Neuroinflammation"},{"key":"2025101705450634000_2025.04.15.648967v2.25","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2022.02.024"},{"key":"2025101705450634000_2025.04.15.648967v2.26","doi-asserted-by":"publisher","DOI":"10.1007\/s11695-024-07081-z"},{"key":"2025101705450634000_2025.04.15.648967v2.27","doi-asserted-by":"publisher","DOI":"10.1016\/j.soard.2014.09.028"},{"key":"2025101705450634000_2025.04.15.648967v2.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2016.08.005"},{"key":"2025101705450634000_2025.04.15.648967v2.29","doi-asserted-by":"crossref","unstructured":"Hasebe K , Kendig MD , Morris MJ . Mechanisms Underlying the Cognitive and Behavioural Effects of Maternal Obesity. Nutrients. 2021;13(1).","DOI":"10.3390\/nu13010240"},{"issue":"1","key":"2025101705450634000_2025.04.15.648967v2.30","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/s41398-023-02701-1","article-title":"Bdnf-Nrf-2 crosstalk and emotional behavior are disrupted in a sex-dependent fashion in adolescent mice exposed to maternal stress or maternal obesity","volume":"13","year":"2023","journal-title":"Transl Psychiatry"},{"key":"2025101705450634000_2025.04.15.648967v2.31","doi-asserted-by":"crossref","unstructured":"Marell PS , Blohowiak SE , Evans MD , Georgieff MK , Kling PJ , Tran PV . Cord Blood-Derived Exosomal CNTN2 and BDNF: Potential Molecular Markers for Brain Health of Neonates at Risk for Iron Deficiency. Nutrients. 2019;11(10).","DOI":"10.3390\/nu11102478"},{"key":"2025101705450634000_2025.04.15.648967v2.32","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.5746-12.2013"},{"key":"2025101705450634000_2025.04.15.648967v2.33","doi-asserted-by":"publisher","DOI":"10.3389\/fnana.2017.00104"},{"key":"2025101705450634000_2025.04.15.648967v2.34","doi-asserted-by":"publisher","DOI":"10.1002\/cne.901590202"},{"key":"2025101705450634000_2025.04.15.648967v2.35","doi-asserted-by":"publisher","DOI":"10.1097\/01.AOG.0000425668.87506.4c"},{"key":"2025101705450634000_2025.04.15.648967v2.36","doi-asserted-by":"crossref","unstructured":"Sheller-Miller S , Trivedi J , Yellon SM , Menon R . Exosomes Cause Preterm Birth in Mice: Evidence for Paracrine Signaling in Pregnancy. Sci Rep-Uk. 2019;9.","DOI":"10.1038\/s41598-018-37002-x"},{"key":"2025101705450634000_2025.04.15.648967v2.37","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.neuroscience.2024.03.014","article-title":"Neonatal Hypoxia-Ischemia alters Brain-Derived Contactin-2-Positive Extracellular Vesicles in the Mouse Plasma","volume":"545","year":"2024","journal-title":"Neuroscience"},{"key":"2025101705450634000_2025.04.15.648967v2.38","doi-asserted-by":"publisher","DOI":"10.1002\/jev2.12404"},{"key":"2025101705450634000_2025.04.15.648967v2.39","doi-asserted-by":"publisher","DOI":"10.7861\/clinmed.2020-0582"},{"key":"2025101705450634000_2025.04.15.648967v2.40","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.117.155846"},{"key":"2025101705450634000_2025.04.15.648967v2.41","doi-asserted-by":"publisher","DOI":"10.1203\/01.pdr.0000127021.38207.62"},{"key":"2025101705450634000_2025.04.15.648967v2.42","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3667-11.2011"},{"key":"2025101705450634000_2025.04.15.648967v2.43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.18.10896"},{"key":"2025101705450634000_2025.04.15.648967v2.44","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1387808"},{"issue":"1","key":"2025101705450634000_2025.04.15.648967v2.45","doi-asserted-by":"crossref","first-page":"24154","DOI":"10.1038\/s41598-025-08632-9","article-title":"Central nervous system and systemic inflammatory networks associated with acute neurological outcomes in COVID-19","volume":"15","year":"2025","journal-title":"Sci Rep"},{"key":"2025101705450634000_2025.04.15.648967v2.46","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.2002.01880.x"},{"key":"2025101705450634000_2025.04.15.648967v2.47","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2017.144"},{"key":"2025101705450634000_2025.04.15.648967v2.48","doi-asserted-by":"crossref","unstructured":"Nociti V , Romozzi M . The Role of BDNF in Multiple Sclerosis Neuroinflammation. Int J Mol Sci. 2023;24(9).","DOI":"10.3390\/ijms24098447"},{"issue":"5","key":"2025101705450634000_2025.04.15.648967v2.49","doi-asserted-by":"crossref","first-page":"589","DOI":"10.1038\/s42255-022-00576-y","article-title":"PARK7\/DJ-1 promotes pyruvate dehydrogenase activity and maintains T(reg) homeostasis during ageing","volume":"4","year":"2022","journal-title":"Nat Metab"},{"key":"2025101705450634000_2025.04.15.648967v2.50","doi-asserted-by":"crossref","unstructured":"Heremans IP , Caligiore F , Gerin I , Bury M , Lutz M , Graff J , et al. Parkinson\u2019s disease protein PARK7 prevents metabolite and protein damage caused by a glycolytic metabolite. Proc Natl Acad Sci U S A. 2022;119(4).","DOI":"10.1073\/pnas.2111338119"},{"key":"2025101705450634000_2025.04.15.648967v2.51","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14574"},{"key":"2025101705450634000_2025.04.15.648967v2.52","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.169342"},{"key":"2025101705450634000_2025.04.15.648967v2.53","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2016.02.023"},{"key":"2025101705450634000_2025.04.15.648967v2.54","doi-asserted-by":"crossref","first-page":"940937","DOI":"10.3389\/fcimb.2022.940937","article-title":"Maternal obesity and the impact of associated early-life inflammation on long-term health of offspring","volume":"12","year":"2022","journal-title":"Front Cell Infect Microbiol"},{"key":"2025101705450634000_2025.04.15.648967v2.55","doi-asserted-by":"publisher","DOI":"10.1504\/IJDS.2024.135946"},{"key":"2025101705450634000_2025.04.15.648967v2.56","doi-asserted-by":"publisher","DOI":"10.1002\/pd.4932"},{"key":"2025101705450634000_2025.04.15.648967v2.57","doi-asserted-by":"publisher","DOI":"10.1002\/oby.24017"},{"key":"2025101705450634000_2025.04.15.648967v2.58","doi-asserted-by":"publisher","DOI":"10.1111\/1471-0528.13795"},{"key":"2025101705450634000_2025.04.15.648967v2.59","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-043021-032816"},{"key":"2025101705450634000_2025.04.15.648967v2.60","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.254268"},{"key":"2025101705450634000_2025.04.15.648967v2.61","doi-asserted-by":"publisher","DOI":"10.1038\/nn0706-859"},{"key":"2025101705450634000_2025.04.15.648967v2.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2008.11.009"},{"key":"2025101705450634000_2025.04.15.648967v2.63","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201207-1265OC"},{"key":"2025101705450634000_2025.04.15.648967v2.64","doi-asserted-by":"publisher","DOI":"10.1038\/s41372-021-00951-9"},{"key":"2025101705450634000_2025.04.15.648967v2.65","doi-asserted-by":"crossref","unstructured":"Fleming MD . The regulation of hepcidin and its effects on systemic and cellular iron metabolism. Hematology Am Soc Hematol Educ Program. 2008:151\u20138.","DOI":"10.1182\/asheducation-2008.1.151"},{"key":"2025101705450634000_2025.04.15.648967v2.66","doi-asserted-by":"publisher","DOI":"10.1007\/s00109-008-0349-8"},{"key":"2025101705450634000_2025.04.15.648967v2.67","doi-asserted-by":"publisher","DOI":"10.1007\/s10571-019-00694-4"},{"issue":"7","key":"2025101705450634000_2025.04.15.648967v2.68","doi-asserted-by":"crossref","first-page":"1092","DOI":"10.3390\/nu16071092","article-title":"Biomarkers of Brain Dysfunction in Perinatal Iron Deficiency","volume":"16","year":"2024","journal-title":"Nutrients"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.04.15.648967","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T08:31:30Z","timestamp":1768465890000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.04.15.648967"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,20]]},"references-count":68,"URL":"https:\/\/doi.org\/10.1101\/2025.04.15.648967","relation":{},"subject":[],"published":{"date-parts":[[2025,4,20]]},"subtype":"preprint"}}