{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T09:06:02Z","timestamp":1789549562671,"version":"build-2803163510"},"reference-count":57,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T00:00:00Z","timestamp":1789516800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["5R21AA019580-02"],"award-info":[{"award-number":["5R21AA019580-02"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R33AA019580-03"],"award-info":[{"award-number":["1R33AA019580-03"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R01AA024123-05"],"award-info":[{"award-number":["1R01AA024123-05"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1R56AA024123-03"],"award-info":[{"award-number":["1R56AA024123-03"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"award":["5R21AA019580-02"],"award-info":[{"award-number":["5R21AA019580-02"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1R33AA019580-03"],"award-info":[{"award-number":["1R33AA019580-03"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1R01AA024123-05"],"award-info":[{"award-number":["1R01AA024123-05"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["1R56AA024123-03"],"award-info":[{"award-number":["1R56AA024123-03"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Masonic Institute for the Developing Brain","award":["NA"],"award-info":[{"award-number":["NA"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Postnatal choline supplementation improves memory, non-verbal IQ, executive function, and white-matter microstructure in children with fetal alcohol spectrum disorder (FASD) across randomized controlled trials; however, peripheral and brain biomarkers of these effects are uncharacterized. Methods: We measured eight immune and neurotrophic biomarkers (TNF\u03b1, transferrin receptor 1 [TfR1], BDNF, ferritin, MCP-1, RANTES, CRP, and Eotaxin) in plasma and brain-derived extracellular vesicles (BDEVs) from 24 children with FASD randomized to choline (n = 13; 7 male, 6 female) or placebo (n = 11; 7 male, 4 female), before and approximately nine months after treatment (23 with paired pre\/post samples). Values were log10-transformed to correct for non-normal distribution. We modeled Group \u00d7 Time effects with linear mixed models, adjusted for age, sex, and sample storage duration, cross-checked with cluster-robust ordinary least squares, and tested plasma-to-BDEV concordance for each analyte with linear regression adjusted for age and sex. Multiplicity was corrected by Benjamini\u2013Hochberg FDR. Results: Plasma MCP-1 showed a nominally significant Group \u00d7 Time interaction (p = 0.035, q = 0.28), rising over time in the placebo but not the choline group. Ferritin and CRP showed similar patterns that did not reach significance (interaction p = 0.099 and p = 0.118; q = 0.31 for both). RANTES and BDNF rose significantly in BDEVs over time, without evidence of a differential change by treatment group, and survived FDR correction (both q \u2264 0.02); ferritin also rose significantly (p = 0.021) but its Time effect did not survive FDR correction (q = 0.06). BDEV TfR1 was nominally lower in the choline group than placebo at both timepoints (p = 0.023; q = 0.13). Plasma levels were associated with BDEV levels for five markers (ferritin, TfR1, TNF\u03b1, Eotaxin, RANTES; all p &lt; 0.05), independent of age, sex, time, and group; all five associations survived FDR correction (q \u2264 0.01). The plasma-BDEV association for MCP-1 became non-significant when adjusted for time and group (p = 0.134, q = 0.13). CRP and BDNF showed a between-person, but not within-person, plasma-BDEV association. Conclusions: In this small, exploratory sample of children with FASD, a condition characterized by brain iron deficiency and inflammation, choline was associated with an attenuated rise in pro-inflammatory plasma MCP-1 relative to placebo, generating a new hypothesized candidate biomarker for further study. Most BDEV markers changed over time (Pre-to-Post), not with treatment. Plasma and BDEV BDNF were not significantly associated overall, although a between-person association was present without a corresponding within-person signal, suggesting that inferring central nervous system function from plasma BDNF should proceed with caution. These hypothesis-generating findings support further, larger-scale investigation of BDEV content analysis as a candidate complement to this trial program\u2019s cognitive and neuroimaging outcomes. Replication and expansion of the BDEV panel of analytes in a larger sample are needed. Trial registration: ClinicalTrials.Gov [NCT02735473]; registered 2 April 2016.<\/jats:p>","DOI":"10.3390\/nu18183022","type":"journal-article","created":{"date-parts":[[2026,9,16]],"date-time":"2026-09-16T07:58:59Z","timestamp":1789545539000},"page":"3022","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma and Brain-Derived Extracellular Vesicle Biomarkers Following a Randomized Controlled Trial of Choline for Neurodevelopment in Fetal Alcohol Spectrum Disorder: A Pilot Analysis"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4301-941X","authenticated-orcid":false,"given":"Phu V.","family":"Tran","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4401-3110","authenticated-orcid":false,"given":"Zia L.","family":"Maxim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith K.","family":"Eckerle","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven H.","family":"Zeisel","sequence":"additional","affiliation":[{"name":"Nutrition Research Institute, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0844-6907","authenticated-orcid":false,"given":"Michael K.","family":"Georgieff","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7132-8519","authenticated-orcid":false,"given":"Jeffrey R.","family":"Wozniak","sequence":"additional","affiliation":[{"name":"Masonic Institute for the Developing Brain, University of Minnesota, Minneapolis, MN 55455, USA"},{"name":"Department of Psychiatry & Behavioral Sciences, University of Minnesota, Minneapolis, MN 55455, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/0892-0362(95)00005-C","article-title":"An update on incidence of FAS: FAS is not an equal opportunity birth defect","volume":"17","author":"Abel","year":"1995","journal-title":"Neurotoxicol. 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