Application and prospect of liquid biopsy in diagnosis and prognostic evaluation of neonatal brain injury

doi:10.3877/cma.j.issn.1673-5250.2022.02.001

Liquid biopsies (LB), a technique using human body fluids to obtain disease information, has been widely carried out in multiple fields and made breakthrough progress, especially in tumor diagnosis and treatment. The application of LB has been developed in the diagnosis of neonatal brain injury, such as intracranial hemorrhage, neonatal hypoxic-ischemic brain damage (HIBD), and brain white matter injury in preterm infants. We intend to describe the latest research progresses of advantages and current application statuses of LB in diagnosis and prognosis evaluation of neonatal brain injury, in order to provide reference for clinical diagnosis and prognosis evaluation of neonatal brain injury.

Key words: Brain injuries, neonate, Hypoxia-ischemia, brain, Liquid biopsy, Biological markers, Blood markers, Exosomes, Early diagnosis, Infant, newborn

表1 外泌体生物标志物与神经系统疾病诊断的关系

外泌体生物标志物	相关神经系统疾病
GFAP	HIV感染及烟、酒所致相关脑损伤^[19]、运动相关急性期脑震荡^[20]、中至重度创伤性脑损伤^[21]
MBP	多发性硬化症^[22]、运动相关急性期脑震荡^[20]
突触足蛋白	急性期创伤性脑损伤^[11]
miRNA	创伤性脑损伤、脑卒中^{[7,23,24,25,26]}

表1 外泌体生物标志物与神经系统疾病诊断的关系

外泌体生物标志物	相关神经系统疾病
GFAP	HIV感染及烟、酒所致相关脑损伤^[19]、运动相关急性期脑震荡^[20]、中至重度创伤性脑损伤^[21]
MBP	多发性硬化症^[22]、运动相关急性期脑震荡^[20]
突触足蛋白	急性期创伤性脑损伤^[11]
miRNA	创伤性脑损伤、脑卒中^{[7,23,24,25,26]}

表2 目前临床用于新生儿脑损伤诊断中，主要涉及的相关游离血液生物标志物

血液生物标志物	来源	可用于诊断的新生儿脑损伤
GFAP	星形胶质细胞	脑室周围白质软化、脑室周围-脑室内出血、新生儿HIBD^[27,28,29]
MBP	少突胶质细胞	脑室周围白质软化、脑室周围-脑室内出血、新生儿HIBD、新生儿脑外伤、脱髓鞘病变^[5,30]
突触足蛋白	神经突触	HIBD^[11]
miRNA	神经元	HIBD^[31]

表2 目前临床用于新生儿脑损伤诊断中，主要涉及的相关游离血液生物标志物

血液生物标志物	来源	可用于诊断的新生儿脑损伤
GFAP	星形胶质细胞	脑室周围白质软化、脑室周围-脑室内出血、新生儿HIBD^[27,28,29]
MBP	少突胶质细胞	脑室周围白质软化、脑室周围-脑室内出血、新生儿HIBD、新生儿脑外伤、脱髓鞘病变^[5,30]
突触足蛋白	神经突触	HIBD^[11]
miRNA	神经元	HIBD^[31]

[1]	Sorrells RB. Synovioanalysis (" liquid biopsy" )[J]. J Ark Med Soc, 1974, 71(1): 59-62.
[2]	Cheung AH, Chow C, To KF. Latest development of liquid biopsy[J]. J Thorac Dis, 2018, 10(Suppl 14): S1645-S1651. DOI: 10.21037/jtd.2018.04.68.
[3]	Graham EM, Burd I, Everett AD, et al. Blood biomarkers for evaluation of perinatal encephalopathy[J]. Front Pharmacol, 2016, 7: 196. DOI: 10.3389/fphar.2016.00196.
[4]	Massaro AN, Wu YW, Bammler TK, et al. Plasma biomarkers of brain injury in neonatal hypoxic-ischemic encephalopathy[J]. J Pediatr, 2018, 194: 67.e1-75.e1. DOI: 10.1016/j.jpeds.2017.10.060.
[5]	Lv H, Wang Q, Wu S, et al. Neonatal hypoxic ischemic encephalopathy-related biomarkers in serum and cerebrospinal fluid[J]. Clin Chim Acta, 2015, 450: 282-297. DOI: 10.1016/j.cca.2015.08.021.
[6]	Graham EM, Everett AD, Delpech JC, et al. Blood biomarkers for evaluation of perinatal encephalopathy: state of the art[J]. Curr Opin Pediatr, 2018, 30(2): 199-203. DOI: 10.1097/MOP.0000000000000591.
[7]	Chen Y, Song Y, Huang J, et al. Increased circulating exosomal miRNA-223 is associated with acute ischemic stroke[J]. Front Neurol, 2017, 8: 57. DOI: 10.3389/fneur.2017.00057.
[8]	陈小娜，姜毅. 2018昆士兰临床指南：缺氧缺血性脑病介绍[J]. 中华新生儿科杂志，2019, 34(1): 77-78. DOI: 10.3760/cma.j.issn.2096-2932.2019.01.019.
[9]	Greco P, Nencini G, Piva I, et al. Pathophysiology of hypoxic-ischemic encephalopathy: a review of the past and a view on the future[J]. Acta Neurol Belg, 2020, 120(2): 277-288. DOI: 10.1007/s13760-020-01308-3.
[10]	Bano S, Chaudhary V, Garga UC. Neonatal hypoxic-ischemic encephalopathy: a radiological review[J]. J Pediatr Neurosci, 2017, 12(1): 1-6. DOI: 10.4103/1817-1745.205646.
[11]	Goetzl L, Merabova N, Darbinian N, et al. Diagnostic potential of neural exosome cargo as biomarkers for acute brain injury[J]. Ann Clin Transl Neurol, 2018, 5(1): 4-10. DOI: 10.1002/acn3.499.
[12]	Gardiner C, Di Vizio D, Sahoo S, et al. Techniques used for the isolation and characterization of extracellular vesicles: results of a worldwide survey[J]. J Extracell Vesicles, 2016, 5(1): 32945. DOI: 10.3402/jev.v5.32945.
[13]	Graner MW, Epple LM, Dusto NL, et al. Circulating exosomes as new biomarkers for brain disease and injury[C]// Conference on sensing technologies for global health, military medicine, and environmental monitoring Ⅲ，2013. DOI: 10.1117/12.2027435.
[14]	Jia L, Qiu Q, Zhang H, et al. Concordance between the assessment of Abeta42, T-tau, and P-T181-tau in peripheral blood neuronal-derived exosomes and cerebrospinal fluid[J]. Alzheimers Dement, 2019, 15(8): 1071-1080. DOI: 10.1016/j.jalz.2019.05.002.
[15]	Muller L, Hong CS, Stolz DB, et al. Isolation of biologically-active exosomes from human plasma[J]. J Immunol Methods, 2014, 411: 55-65. DOI: 10.1016/j.jim.2014.06.007.
[16]	Devoto C, Arcurio L, Fetta J, et al. Inflammation relates to chronic behavioral and neurological symptoms in military personnel with traumatic brain injuries[J]. Cell Transplant, 2017, 26(7): 1169-1177. DOI: 10.1177/0963689717714098.
[17]	Gurunathan S, Kang MH, Kim JH. A comprehensive review on factors influences biogenesis, functions, therapeutic and clinical implications of exosomes[J]. Int J Nanomedicine, 2021, 16: 1281-1312. DOI: 10.2147/IJN.S291956.
[18]	Dinkins MB, Wang G, Bieberich E. Sphingolipid-enriched extracellular vesicles and Alzheimer′s disease: a decade of research[J]. J Alzheimers Dis, 2017, 60(3): 757-768. DOI: 10.3233/JAD-160567.
[19]	Kodidela S, Gerth K, Sinha N, et al. Circulatory astrocyte and neuronal EVs as potential biomarkers of neurological dysfunction in HIV-infected subjects and alcohol/tobacco users[J]. Diagnostics (Basel), 2020, 10(6): 349. DOI: 10.3390/diagnostics10060349.
[20]	Kawata K, Mitsuhashi M, Aldret R. A preliminary report on brain-derived extracellular vesicle as novel blood biomarkers for sport-related concussions[J]. Front Neurol, 2018, 9: 239. DOI: 10.3389/fneur.2018.00239.
[21]	Mondello S, Guedes VA, Lai C, et al. Circulating brain injury exosomal proteins following moderate-to-severe traumatic brain injury: temporal profile, outcome prediction and therapy implications[J]. Cells, 2020, 9(4): 977. DOI: 10.3390/cells9040977.
[22]	Galazka G, Mycko MP, Selmaj I, et al. Multiple sclerosis: serum-derived exosomes express myelin proteins[J]. Mult Scler, 2018, 24(4): 449-458. DOI: 10.1177/1352458517696597.
[23]	Kumar A, Stoica BA, Loane DJ, et al. Microglial-derived microparticles mediate neuroinflammation after traumatic brain injury[J]. J Neuroinflammation, 2017, 14(1): 47. DOI: 10.1186/s12974-017-0819-4.
[24]	Ji Q, Ji Y, Peng J, et al. Increased brain-specific MiR-9 and MiR-124 in the serum exosomes of acute ischemic stroke patients[J]. PLoS One, 2016, 11(9): e0163645. DOI: 10.1371/journal.pone.0163645.
[25]	Li DB, Liu JL, Wang W, et al. Plasma exosomal miR-422a and miR-125b-2-3p serve as biomarkers for ischemic stroke[J]. Curr Neurovasc Res, 2017, 14(4): 330-337. DOI: 10.2174/1567202614666171005153434.
[26]	Wang W, Li DB, Li RY, et al. Diagnosis of hyperacute and acute ischaemic stroke: the potential utility of exosomal microRNA-21-5p and microRNA-30a-5p[J]. Cerebrovasc Dis, 2018, 45(5-6): 204-212. DOI: 10.1159/000488365.
[27]	Papa L, Ramia MM, Edwards D, et al. Systematic review of clinical studies examining biomarkers of brain injury in athletes after sports-related concussion[J]. J Neurotrauma, 2015, 32(10): 661-673. DOI: 10.1089/neu.2014.3655.
[28]	Maggiotto LV, Sondhi M, Shin BC, et al. Circulating blood cellular glucose transporters-surrogate biomarkers for neonatal hypoxic-ischemic encephalopathy assessed by novel scoring systems[J]. Mol Genet Metab, 2019, 127(2): 166-173. DOI: 10.1016/j.ymgme.2019.05.013.
[29]	Daverey A, Agrawal SK. Neuroprotective effects of riluzole and curcumin in human astrocytes and spinal cord white matter hypoxia[J]. Neurosci Lett, 2020, 738: 135351. DOI: 10.1016/j.neulet.2020.135351.
[30]	Beers SR, Berger RP, Adelson PD. Neurocognitive outcome and serum biomarkers in inflicted versus non-inflicted traumatic brain injury in young children[J]. J Neurotrauma, 2007, 24(1): 97-105. DOI: 10.1089/neu.2006.0055.
[31]	Jeyaseelan K, Lim KY, Armugam A. MicroRNA expression in the blood and brain of rats subjected to transient focal ischemia by middle cerebral artery occlusion[J]. Stroke, 2008, 39(3): 959-966. DOI: 10.1161/STROKEAHA.107.500736.
[32]	Douglas-Escobar MV, Heaton SC, Bennett J, et al. UCH-L1 and GFAP serum levels in neonates with hypoxic-ischemic encephalopathy: a single center pilot study[J]. Front Neurol, 2014, 5: 273. DOI: 10.3389/fneur.2014.00273.
[33]	Cho KHT, Wassink G, Galinsky R, et al. Protective effects of delayed intraventricular TLR7 agonist administration on cerebral white and gray matter following asphyxia in the preterm fetal sheep[J]. Sci Rep, 2019, 9(1): 9562. DOI: 10.1038/s41598-019-45872-y.
[34]	Papa L, Silvestri S, Brophy GM, et al. GFAP out-performs S100beta in detecting traumatic intracranial lesions on computed tomography in trauma patients with mild traumatic brain injury and those with extracranial lesions[J]. J Neurotrauma, 2014, 31(22): 1815-1822. DOI: 10.1089/neu.2013.3245.
[35]	Ennen CS, Huisman TA, Savage WJ, et al. Glial fibrillary acidic protein as a biomarker for neonatal hypoxic-ischemic encephalopathy treated with whole-body cooling[J]. Am J Obstet Gynecol, 2011, 205(3): 251.e1-251.e7. DOI: 10.1016/j.ajog.2011.06.025.
[36]	McMahon PJ, Panczykowski DM, Yue JK, et al. Measurement of the glial fibrillary acidic protein and its breakdown products GFAP-BDP biomarker for the detection of traumatic brain injury compared to computed tomography and magnetic resonance imaging[J]. J Neurotrauma, 2015, 32(8): 527-533. DOI: 10.1089/neu.2014.3635.
[37]	Rangon CM, Schang AL, Van Steenwinckel J, et al. Myelination induction by a histamine H3 receptor antagonist in a mouse model of preterm white matter injury[J]. Brain Behav Immun, 2018, 74: 265-276. DOI: 10.1016/j.bbi.2018.09.017.
[38]	Zhou W, Li W, Qu LH, et al. Relationship of plasma S100B and MBP with brain damage in preterm infants[J]. Int J Clin Exp Med, 2015, 8(9): 16445-16453.
[39]	Goetzl L, Darbinian N, Merabova N. Noninvasive assessment of fetal central nervous system insult: potential application to prenatal diagnosis[J]. Prenat Diagn, 2019, 39(8): 609-615. DOI: 10.1002/pd.5474.
[40]	Ma Q, Dasgupta C, Li Y, et al. Inhibition of microRNA-210 provides neuroprotection in hypoxic-ischemic brain injury in neonatal rats[J]. Neurobiol Dis, 2016, 89: 202-212. DOI: 10.1016/j.nbd.2016.02.011.
[41]	Laterza OF, Lim L, Garrett-Engele PW, et al. Plasma microRNAs as sensitive and specific biomarkers of tissue injury[J]. Clin Chem, 2009, 55(11): 1977-1983. DOI: 10.1373/clinchem.2009.131797.
[42]	Weng H, Shen C, Hirokawa G, et al. Plasma miR-124 as a biomarker for cerebral infarction[J]. Biomed Res, 2011, 32(2): 135-141. DOI: 10.2220/biomedres.32.135.
[43]	Sun Y, Luo ZM, Guo XM, et al. An updated role of microRNA-124 in central nervous system disorders: a review[J]. Front Cell Neurosci, 2015, 9: 193. DOI: 10.3389/fncel.2015.00193.
[44]	Huang SH, Wang L, Chi F, et al. Circulating brain microvascular endothelial cells (cBMECs) as potential biomarkers of the blood-brain barrier disorders caused by microbial and non-microbial factors[J]. PLoS One, 2013, 8(4): e62164. DOI: 10.1371/journal.pone.0062164.
[45]	李妍，杜蕾，袁霖，等. 外周血中血脑屏障损伤新型标记物脑微血管内皮细胞检测方法的建立[J]. 南方医科大学学报，2014, 34(12): 1733-1737. DOI: 10.3969/j.issn.1673-4254.2014.12.05.
[46]	甘浪舸，李祥攀，阮林，等. 循环内皮细胞和放射性脑损伤的关系[J]. 中华肿瘤防治杂志，2007, 14(5): 352-354. DOI: 10.3969/j.issn.1673-5269.2007.05.010.
[47]	Pourcyrous M, Basuroy S, Tcheranova D, et al. Brain-derived circulating endothelial cells in peripheral blood of newborn infants with seizures: a potential biomarker for cerebrovascular injury[J]. Physiol Rep, 2015, 3(3): e12345. DOI: 10.14814/phy2.12345.
[48]	Rainer TH, Wong LK, Lam W, et al. Prognostic use of circulating plasma nucleic acid concentrations in patients with acute stroke[J]. Clin Chem, 2003, 49(4): 562-569. DOI: 10.1373/49.4.562.
[49]	Regner A, Meirelles LDS, Ikuta N, et al. Prognostic utility of circulating nucleic acids in acute brain injuries[J]. Expert Rev Mol Diagn, 2018, 18(11): 925-938. DOI: 10.1080/14737159.2018.1535904.
[50]	Lehmann-Werman R, Neiman D, Zemmour H, et al. Identification of tissue-specific cell death using methylation patterns of circulating DNA[J]. Proc Natl Acad Sci USA, 2016, 113(13)：1826-1834. DOI: 10.1073/pnas.1519286113.

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