Plasma extracellular vesicles as a source of biomarkers in traumatic brain injury

View More View Less
  • 1 Departments of Neurological Surgery and
  • | 2 Immunology, Mayo Clinic, Rochester;
  • | 3 Mayo Clinic Graduate School of Biomedical Sciences, Rochester, Minnesota; and
  • | 4 Department of Neurosurgery, University of Pittsburgh, Pennsylvania
Restricted access

Purchase Now

USD  $45.00

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00
Print or Print + Online

OBJECTIVE

The objective of this study was to isolate extracellular vesicles (EVs) from plasma in a cohort of patients with traumatic brain injury (TBI) and analyze their contents for novel biomarkers that could prove useful for rapid diagnosis and classification of brain injury during initial evaluation.

METHODS

Plasma EVs were isolated by serial ultracentrifugation from patients with TBI (n = 15) and healthy controls (n = 5). Samples were obtained from the TRACK-TBI biorepository (2010–present). Size and concentration were determined by nanoparticle tracking. Glial fibrillary acidic protein (GFAP) concentration was determined in EV protein. EV RNA was isolated and deep sequencing of short noncoding RNA was performed.

RESULTS

Plasma EVs are physically similar but contained approximately 10 times more GFAP in TBI patients with altered consciousness than patients and controls with normal consciousness. Eleven highly differentially expressed microRNAs (miRNAs) were identified between these groups. Genes targeted by these miRNAs are highly associated with biologically relevant cellular pathways, including organismal injury, cellular development, and organismal development. Multiple additional coding and noncoding RNA species with potential biomarker utility were identified.

CONCLUSIONS

Isolating plasma EVs in patients with TBI is feasible. Increased GFAP concentration—a validated plasma TBI marker—in EVs from TBI patients with altered consciousness, along with differential expression of multiple miRNAs targeting TBI-relevant pathways, suggests that EVs may be a useful source of TBI biomarkers. Additional evaluation in larger patient cohorts is indicated.

ABBREVIATIONS

EV = extracellular vesicle; GCS = Glasgow Coma Scale; GFAP = glial fibrillary acidic protein; lincRNA = long intervening noncoding RNA; miRNA = microRNA; mRNA = messenger RNA; rRNA = ribosomal RNA; snoRNA = small nucleolar RNA; snRNA = small nuclear RNA; TBI = traumatic brain injury; TRACK-TBI = Transforming Research and Clinical Knowledge in Traumatic Brain Injury; UCH-L1 = ubiquitin carboxy-terminal hydrolase L1.

JNS + Pediatrics - 1 year subscription bundle (Individuals Only)

USD  $505.00

JNS + Pediatrics + Spine - 1 year subscription bundle (Individuals Only)

USD  $600.00

Contributor Notes

Correspondence Ian F. Parney: Mayo Clinic, Rochester, MN. parney.ian@mayo.edu.

INCLUDE WHEN CITING Published online July 24, 2020; DOI: 10.3171/2020.4.JNS20305.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

  • 1

    Heijnen HF , Schiel AE , Fijnheer R , et al. Activated platelets release two types of membrane vesicles: microvesicles by surface shedding and exosomes derived from exocytosis of multivesicular bodies and alpha-granules . Blood . 1999 ;94 (11 ):3791 3799 .

    • Search Google Scholar
    • Export Citation
  • 2

    Kowal J , Tkach M , Théry C . Biogenesis and secretion of exosomes . Curr Opin Cell Biol . 2014 ;29 :116 125 .

  • 3

    Li CC , Eaton SA , Young PE , et al. Glioma microvesicles carry selectively packaged coding and non-coding RNAs which alter gene expression in recipient cells . RNA Biol . 2013 ;10 (8 ):1333 1344 .

    • Search Google Scholar
    • Export Citation
  • 4

    Proia P , Schiera G , Mineo M , et al. Astrocytes shed extracellular vesicles that contain fibroblast growth factor-2 and vascular endothelial growth factor . Int J Mol Med . 2008 ;21 (1 ):63 67 .

    • Search Google Scholar
    • Export Citation
  • 5

    Schiera G , Proia P , Alberti C , et al. Neurons produce FGF2 and VEGF and secrete them at least in part by shedding extracellular vesicles . J Cell Mol Med . 2007 ;11 (6 ):1384 1394 .

    • Search Google Scholar
    • Export Citation
  • 6

    Mathivanan S , Lim JW , Tauro BJ , et al. Proteomics analysis of A33 immunoaffinity-purified exosomes released from the human colon tumor cell line LIM1215 reveals a tissue-specific protein signature . Mol Cell Proteomics . 2010 ;9 (2 ):197 208 .

    • Search Google Scholar
    • Export Citation
  • 7

    Korley FK , Kelen GD , Jones CM , Diaz-Arrastia R . Emergency department evaluation of traumatic brain injury in the United States, 2009–2010 . J Head Trauma Rehabil . 2016 ;31 (6 ):379 387 .

    • Search Google Scholar
    • Export Citation
  • 8

    McMahon P , Hricik A , Yue JK , et al. Symptomatology and functional outcome in mild traumatic brain injury: results from the prospective TRACK-TBI study . J Neurotrauma . 2014 ;31 (1 ):26 33 .

    • Search Google Scholar
    • Export Citation
  • 9

    Seabury SA , Gaudette É , Goldman DP , et al. Assessment of follow-up care after emergency department presentation for mild traumatic brain injury and concussion: results from the TRACK-TBI study . JAMA Netw Open . 2018 ;1 (1 ):e180210 .

    • Search Google Scholar
    • Export Citation
  • 10

    Korley FK , Yue JK , Wilson DH , et al. Performance evaluation of a multiplex assay for simultaneous detection of four clinically relevant traumatic brain injury biomarkers . J Neurotrauma . 2018 ;36 (1 ):182 187 .

    • Search Google Scholar
    • Export Citation
  • 11

    Manek R , Moghieb A , Yang Z , et al. Protein biomarkers and neuroproteomics characterization of microvesicles/exosomes from human cerebrospinal fluid following traumatic brain injury . Mol Neurobiol . 2018 ;55 (7 ):6112 6128 .

    • Search Google Scholar
    • Export Citation
  • 12

    Okonkwo DO , Yue JK , Puccio AM , et al. GFAP-BDP as an acute diagnostic marker in traumatic brain injury: results from the prospective transforming research and clinical knowledge in traumatic brain injury study . J Neurotrauma . 2013 ;30 (17 ):1490 1497 .

    • Search Google Scholar
    • Export Citation
  • 13

    Cumba Garcia LM , Peterson TE , Cepeda MA , et al. Isolation and analysis of plasma-derived exosomes in patients with glioma . Front Oncol . 2019 ;9 :651 .

    • Search Google Scholar
    • Export Citation
  • 14

    Pitt JM , Kroemer G , Zitvogel L . Extracellular vesicles: masters of intercellular communication and potential clinical interventions . J Clin Invest . 2016 ;126 (4 ):1139 1143 .

    • Search Google Scholar
    • Export Citation
  • 15

    Chang CY , Lui TN , Lin JW , et al. Roles of microRNA-1 in hypoxia-induced apoptotic insults to neuronal cells . Arch Toxicol . 2016 ;90 (1 ):191 202 .

    • Search Google Scholar
    • Export Citation
  • 16

    Zeng X , Liu N , Zhang J , et al. Inhibition of miR-143 during ischemia cerebral injury protects neurones through recovery of the hexokinase 2-mediated glucose uptake . Biosci Rep . 2017 ;37 (4 ):BSR20170216 .

    • Search Google Scholar
    • Export Citation
  • 17

    Ko J , Hemphill M , Yang Z , et al. Multi-dimensional mapping of brain-derived extracellular vesicle microRNA biomarker for traumatic brain injury diagnostics . J Neurotrauma . Published online May 6, 2019. doi:10.1089/neu.2018.6220

    • Search Google Scholar
    • Export Citation

Metrics

All Time Past Year Past 30 Days
Abstract Views 200 200 200
Full Text Views 42 42 42
PDF Downloads 54 54 54
EPUB Downloads 0 0 0