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Neuronal exosome proteins: novel biomarkers for predicting neonatal response to therapeutic hypothermia
  1. Beth Pineles1,
  2. Arunmani Mani1,
  3. Livia Sura2,
  4. Candace Rossignol2,
  5. Mehmet Albayram3,
  6. Michael David Weiss2,
  7. Laura Goetzl1
  1. 1 Department of Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, USA
  2. 2 Department of Pediatrics, University of Florida Health Science Center, Gainesville, Florida, USA
  3. 3 Department of Radiology, University of Florida Health Science Center, Gainesville, Florida, USA
  1. Correspondence to Dr Laura Goetzl, Obstetrics, Gynecology and Reproductive Sciences, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston TX, 77030, USA; laura.goetzl{at}uth.tmc.edu

Abstract

Objective Central nervous system (CNS) derived exosomes can be purified from peripheral blood and have been used widely in adult neurological disease. Application to neonatal neurological disease deserves investigation in the setting of hypoxic–ischaemic encephalopathy (HIE).

Design Observational cohort.

Setting Level III neonatal intensive care unit.

Participants Term/near-term neonates undergoing therapeutic hypothermia (TH) for HIE.

Interventions Blood samples were collected at 0–6, 12, 24, 48 and 96 hours of life.

Main outcomes and measures CNS exosomes were purified from serum using previously described methods. Biomarker protein levels were quantified using standard ELISA methods and normalised to exosome marker CD-81. The slope of change for biomarker levels was calculated for each time interval. Our primary outcome was MRI basal ganglia/watershed score of ≥3.

Results 26 subjects were included (umbilical artery pH range 6.6–7.29; 35% seizures). An increasing MRI injury score was significantly associated with decreasing levels of synaptopodin between 0–6 and 12 hours (p=0.03) and increasing levels of lipocalin-2 (NGAL) between 12 and 48 hours (p<0.0001). Neuronal pentraxin was not significant. The negative predictive values for increasing synaptopodin and decreasing NGAL was 70.0% and 90.9%, respectively.

Conclusions and relevance Our results indicate that CNS exosome cargo has the potential to act as biomarkers of the severity of brain injury and response to TH as well as quantify pharmacological response to neuroactive therapeutic/adjuvant agents. Rigorous prospective trials are critical to evaluate potential clinical use of exosome biomarkers.

  • neonatology
  • neurology

Data availability statement

Data are available on reasonable request. All study data are available on reasonable request. Please contact Laura Goetzl at laura.goetzl@uth.tmc.edu. Data reuse is permitted on agreement from all authors.

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Data availability statement

Data are available on reasonable request. All study data are available on reasonable request. Please contact Laura Goetzl at laura.goetzl@uth.tmc.edu. Data reuse is permitted on agreement from all authors.

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Footnotes

  • Contributors LG, BP and MDW conceived of this research plan and designed the experiments. All three contributed to the analysis and interpretation. All three drafted the original manuscript together. AM performed the bench experiments and contributed to the analysis and interpretation of the data. MA performed the MRI data acquisition and contributed to the analysis and interpretation of the data. LS and CR contributed to the conception, design and execution of the clinical study. They collected biological samples and all clinical data. They aided in the analysis and interpretation of the data.

  • Funding This work was supported by the Thrasher Foundation grant number 12919.

  • Competing interests LG has a patent for isolating fetal/neonatal neural exosomes using Contactin-2, but there is no current commercial use.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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