{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T22:12:25Z","timestamp":1792188745916,"version":"4.4.0"},"reference-count":105,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T00:00:00Z","timestamp":1675209600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["272249"],"award-info":[{"award-number":["272249"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["273909"],"award-info":[{"award-number":["273909"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["2285733-9"],"award-info":[{"award-number":["2285733-9"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002341","name":"Academy of Finland","doi-asserted-by":"publisher","award":["602102"],"award-info":[{"award-number":["602102"]}],"id":[{"id":"10.13039\/501100002341","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Sigrid Jus\u00e9lius Foundation, and the European Union\u2019s Seventh Framework Programme (FP7\/2007-2013)","award":["272249"],"award-info":[{"award-number":["272249"]}]},{"name":"Sigrid Jus\u00e9lius Foundation, and the European Union\u2019s Seventh Framework Programme (FP7\/2007-2013)","award":["273909"],"award-info":[{"award-number":["273909"]}]},{"name":"Sigrid Jus\u00e9lius Foundation, and the European Union\u2019s Seventh Framework Programme (FP7\/2007-2013)","award":["2285733-9"],"award-info":[{"award-number":["2285733-9"]}]},{"name":"Sigrid Jus\u00e9lius Foundation, and the European Union\u2019s Seventh Framework Programme (FP7\/2007-2013)","award":["602102"],"award-info":[{"award-number":["602102"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Traumatic brain injury (TBI) causes 10\u201320% of structural epilepsies and 5% of all epilepsies. The lack of prognostic biomarkers for post-traumatic epilepsy (PTE) is a major obstacle to the development of anti-epileptogenic treatments. Previous studies revealed TBI-induced alterations in blood microRNA (miRNA) levels, and patients with epilepsy exhibit dysregulation of blood miRNAs. We hypothesized that acutely altered plasma miRNAs could serve as prognostic biomarkers for brain damage severity and the development of PTE. To investigate this, epileptogenesis was induced in adult male Sprague Dawley rats by lateral fluid-percussion-induced TBI. Epilepsy was defined as the occurrence of at least one unprovoked seizure during continuous 1-month video-electroencephalography monitoring in the sixth post-TBI month. Cortical pathology was analyzed by magnetic resonance imaging on day 2 (D2), D7, and D21, and by histology 6 months post-TBI. Small RNA sequencing was performed from tail-vein plasma samples on D2 and D9 after TBI (n = 16, 7 with and 9 without epilepsy) or sham operation (n = 4). The most promising miRNA biomarker candidates were validated by droplet digital polymerase chain reaction in a validation cohort of 115 rats (8 na\u00efve, 17 sham, and 90 TBI rats [21 with epilepsy]). These included 7 brain-enriched plasma miRNAs (miR-434-3p, miR-9a-3p, miR-136-3p, miR-323-3p, miR-124-3p, miR-212-3p, and miR-132-3p) that were upregulated on D2 post-TBI (p &lt; 0.001 for all compared with na\u00efve rats). The acute post-TBI plasma miRNA profile did not predict the subsequent development of PTE or PTE severity. Plasma miRNA levels, however, predicted the cortical pathology severity on D2 (Spearman \u03c1 = 0.345\u20130.582, p &lt; 0.001), D9 (\u03c1 = 0.287\u20130.522, p &lt; 0.001\u20130.01), D21 (\u03c1 = 0.269\u20130.581, p &lt; 0.001\u20130.05) and at 6 months post-TBI (\u03c1 = 0.230\u20130.433, p &lt; 0.001\u20130.05). We found that the levels of 6 of 7 miRNAs also reflected mild brain injury caused by the craniotomy during sham operation (ROC AUC 0.76\u20130.96, p &lt; 0.001\u20130.05). In conclusion, our findings revealed that increased levels of neuronally enriched miRNAs in the blood circulation after TBI reflect the extent of cortical injury in the brain but do not predict PTE development.<\/jats:p>","DOI":"10.3390\/ijms24032823","type":"journal-article","created":{"date-parts":[[2023,2,2]],"date-time":"2023-02-02T02:21:12Z","timestamp":1675304472000},"page":"2823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Discovery and Validation of Circulating microRNAs as Biomarkers for Epileptogenesis after Experimental Traumatic Brain Injury\u2013The EPITARGET Cohort"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1624-5240","authenticated-orcid":false,"given":"Mette","family":"Heiskanen","sequence":"first","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shalini","family":"Das Gupta","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James D.","family":"Mills","sequence":"additional","affiliation":[{"name":"Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London WC1N 3BG, UK"},{"name":"Chalfont Centre for Epilepsy, Buckinghamshire SL9 0RJ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5747-3202","authenticated-orcid":false,"given":"Erwin A.","family":"van Vliet","sequence":"additional","affiliation":[{"name":"Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Swammerdam Institute for Life Sciences, Center for Neuroscience, University of Amsterdam, 1098 XH Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9353-6079","authenticated-orcid":false,"given":"Eppu","family":"Manninen","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Ciszek","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9118-8341","authenticated-orcid":false,"given":"Pedro","family":"Andrade","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noora","family":"Puhakka","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3542-3770","authenticated-orcid":false,"given":"Eleonora","family":"Aronica","sequence":"additional","affiliation":[{"name":"Department of (Neuro)Pathology, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands"},{"name":"Stichting Epilepsie Instellingen Nederland, 2103 SW Heemstede, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8163-5416","authenticated-orcid":false,"given":"Asla","family":"Pitk\u00e4nen","sequence":"additional","affiliation":[{"name":"A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211 Kuopio, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"286","DOI":"10.1007\/s13311-014-0260-7","article-title":"Epilepsy Related to Traumatic Brain Injury","volume":"11","author":"Immonen","year":"2014","journal-title":"Neurotherapeutics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1637","DOI":"10.1016\/j.apmr.2010.05.017","article-title":"Position Statement: Definition of Traumatic Brain Injury","volume":"91","author":"Menon","year":"2010","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1056\/NEJM199801013380104","article-title":"A Population-Based Study of Seizures after Traumatic Brain Injuries","volume":"338","author":"Annegers","year":"1998","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"107762","DOI":"10.1016\/j.neuropharm.2019.107762","article-title":"No Prevention or Cure of Epilepsy as Yet","volume":"168","author":"Klein","year":"2020","journal-title":"Neuropharmacology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1007\/s13311-021-01119-1","article-title":"Novel Approaches to Prevent Epileptogenesis After Traumatic Brain Injury","volume":"18","author":"Dulla","year":"2021","journal-title":"Neurotherapeutics"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1111\/epi.12299","article-title":"Epilepsy Biomarkers","volume":"54","author":"Engel","year":"2013","journal-title":"Epilepsia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"843","DOI":"10.1016\/0092-8674(93)90529-Y","article-title":"The C. Elegans Heterochronic Gene Lin-4 Encodes Small RNAs with Antisense Complementarity to Lin-14","volume":"75","author":"Lee","year":"1993","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/S0092-8674(04)00045-5","article-title":"MicroRNAs: Genomics, Biogenesis, Mechanism, and Function","volume":"116","author":"Bartel","year":"2004","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1101\/gr.082701.108","article-title":"Most Mammalian MRNAs Are Conserved Targets of MicroRNAs","volume":"19","author":"Friedman","year":"2009","journal-title":"Genome Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/S0960-9822(02)00809-6","article-title":"Identification of Tissue-Specific MicroRNAs from Mouse","volume":"12","author":"Rauhut","year":"2002","journal-title":"Curr. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1401","DOI":"10.1016\/j.cell.2007.04.040","article-title":"A Mammalian MicroRNA Expression Atlas Based on Small RNA Library Sequencing","volume":"129","author":"Landgraf","year":"2007","journal-title":"Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"3865","DOI":"10.1093\/nar\/gkw116","article-title":"Distribution of MiRNA Expression across Human Tissues","volume":"44","author":"Ludwig","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"172","DOI":"10.3389\/fncel.2013.00172","article-title":"MicroRNA Regulation and Dysregulation in Epilepsy","volume":"7","author":"Dogini","year":"2013","journal-title":"Front. Cell Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1016\/S1474-4422(16)30246-0","article-title":"MicroRNAs in Epilepsy: Pathophysiology and Clinical Utility","volume":"15","author":"Henshall","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"107080","DOI":"10.1016\/j.yebeh.2020.107080","article-title":"Biomarkers for Posttraumatic Epilepsy","volume":"121","author":"Paananen","year":"2021","journal-title":"Epilepsy Behav."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.neuropharm.2018.08.028","article-title":"Circulating MicroRNAs as Biomarkers in Traumatic Brain Injury","volume":"145","author":"Toffolo","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2035","DOI":"10.1111\/epi.16632","article-title":"Postinjury Weight Rather than Cognitive or Behavioral Impairment Predicts Development of Posttraumatic Epilepsy after Lateral Fluid-Percussion Injury in Rats","volume":"61","author":"Lapinlampi","year":"2020","journal-title":"Epilepsia"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Das Gupta, S., Ciszek, R., Heiskanen, M., Lapinlampi, N., Kukkonen, J., Leinonen, V., Puhakka, N., and Pitk\u00e4nen, A. (2021). Plasma MiR-9-3p and MiR-136-3p as Potential Novel Diagnostic Biomarkers for Experimental and Human Mild Traumatic Brain Injury. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041563"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Bushel, P.R., Caiment, F., Wu, H., O\u2019Lone, R., Day, F., Calley, J., Smith, A., and Li, J. (2018). RATEmiRs: The Rat Atlas of Tissue-Specific and Enriched MiRNAs Database. BMC Genomics, 19.","DOI":"10.1186\/s12864-018-5220-x"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2580","DOI":"10.1089\/neu.2019.6796","article-title":"Early Increase in Cortical T(2) Relaxation Is a Prognostic Biomarker for the Evolution of Severe Cortical Damage, but Not for Epileptogenesis, after Experimental Traumatic Brain Injury","volume":"37","author":"Manninen","year":"2020","journal-title":"J. Neurotrauma"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R68","DOI":"10.1186\/gb-2004-5-9-r68","article-title":"Microarray Analysis of MicroRNA Expression in the Developing Mammalian Brain","volume":"5","author":"Miska","year":"2004","journal-title":"Genome Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"R13","DOI":"10.1186\/gb-2004-5-3-r13","article-title":"Expression Profiling of Mammalian MicroRNAs Uncovers a Subset of Brain-Expressed MicroRNAs with Possible Roles in Murine and Human Neuronal Differentiation","volume":"5","author":"Sempere","year":"2004","journal-title":"Genome Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1634\/stemcells.2005-0441","article-title":"Specific MicroRNAs Modulate Embryonic Stem Cell-Derived Neurogenesis","volume":"24","author":"Krichevsky","year":"2006","journal-title":"Stem Cells"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.molcel.2007.07.015","article-title":"The MicroRNA MiR-124 Promotes Neuronal Differentiation by Triggering Brain-Specific Alternative Pre-MRNA Splicing","volume":"27","author":"Makeyev","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.brainres.2006.11.035","article-title":"RT-PCR-Based Analysis of MicroRNA (MiR-1 and -124) Expression in Mouse CNS","volume":"1131","author":"Mishima","year":"2007","journal-title":"Brain Res."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Olsen, L., Klausen, M., Helboe, L., Nielsen, F.C., and Werge, T. (2009). MicroRNAs Show Mutually Exclusive Expression Patterns in the Brain of Adult Male Rats. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0007225"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Juhila, J., Sipil\u00e4, T., Icay, K., Nicorici, D., Ellonen, P., Kallio, A., Korpelainen, E., Greco, D., and Hovatta, I. (2011). MicroRNA Expression Profiling Reveals MiRNA Families Regulating Specific Biological Pathways in Mouse Frontal Cortex and Hippocampus. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0021495"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"5127","DOI":"10.1523\/JNEUROSCI.0600-12.2013","article-title":"Comprehensive Expression Analyses of Neural Cell-Type-Specific MiRNAs Identify New Determinants of the Specification and Maintenance of Neuronal Phenotypes","volume":"33","author":"Roshan","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.neuroscience.2020.02.045","article-title":"Elevated Acute Plasma MiR-124-3p Level Relates to Evolution of Larger Cortical Lesion Area after Traumatic Brain Injury","volume":"433","author":"Vuokila","year":"2020","journal-title":"Neuroscience"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"437","DOI":"10.7150\/ijms.39667","article-title":"Plasma Exosome-Derived MicroRNAs as Novel Biomarkers of Traumatic Brain Injury in Rats","volume":"17","author":"Wang","year":"2020","journal-title":"Int. J. Med. Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1080\/02699052.2020.1764102","article-title":"Bioinformatic Analysis of Brain-Specific MiRNAs for Identification of Candidate Traumatic Brain Injury Blood Biomarkers","volume":"34","author":"Smothers","year":"2020","journal-title":"Brain Inj."},{"key":"ref_32","first-page":"12","article-title":"Dynamic Changes in Peripheral Blood-Targeted MiRNA Expression Profiles in Patients with Severe Traumatic Brain Injury at High Altitude","volume":"6","author":"Ma","year":"2019","journal-title":"Mil. Med. Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Schindler, C.R., Woschek, M., Vollrath, J.T., Kontradowitz, K., Lustenberger, T., St\u00f6rmann, P., Marzi, I., and Henrich, D. (2020). MiR-142-3p Expression Is Predictive for Severe Traumatic Brain Injury (TBI) in Trauma Patients. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21155381"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1089\/neu.2010.1427","article-title":"Craniotomy: True Sham for Traumatic Brain Injury, or a Sham of a Sham?","volume":"28","author":"Cole","year":"2011","journal-title":"J. Neurotrauma"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Heiskanen, M., J\u00e4\u00e4skel\u00e4inen, O., Manninen, E., Das Gupta, S., Andrade, P., Ciszek, R., Gr\u00f6hn, O., Herukka, S.-K., Puhakka, N., and Pitk\u00e4nen, A. (2022). Plasma Neurofilament Light Chain (NF-L) Is a Prognostic Biomarker for Cortical Damage Evolution but Not for Cognitive Impairment or Epileptogenesis Following Experimental TBI. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232315208"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1002\/jcb.23168","article-title":"Altered Expression Levels of MiRNAs in Serum as Sensitive Biomarkers for Early Diagnosis of Traumatic Injury","volume":"112","author":"Zhang","year":"2011","journal-title":"J. Cell Biochem."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"220","DOI":"10.3389\/fncel.2013.00220","article-title":"MiR-9: A Versatile Regulator of Neurogenesis","volume":"7","author":"Coolen","year":"2013","journal-title":"Front. Cell Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"8641","DOI":"10.1523\/JNEUROSCI.0630-16.2016","article-title":"The Brain-Enriched MicroRNA MiR-9-3p Regulates Synaptic Plasticity and Memory","volume":"36","author":"Sim","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Ji, Q., Ji, Y., Peng, J., Zhou, X., Chen, X., Zhao, H., Xu, T., Chen, L., and Xu, Y. (2016). Increased Brain-Specific MiR-9 and MiR-124 in the Serum Exosomes of Acute Ischemic Stroke Patients. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163645"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s40364-017-0104-9","article-title":"Elevation of Brain-Enriched MiRNAs in Cerebrospinal Fluid of Patients with Acute Ischemic Stroke","volume":"5","author":"Nygaard","year":"2017","journal-title":"Biomark Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"874903","DOI":"10.3389\/fnmol.2022.874903","article-title":"Acute Cerebral Ischemia Increases a Set of Brain-Specific MiRNAs in Serum Small Extracellular Vesicles","volume":"15","author":"Zhou","year":"2022","journal-title":"Front. Mol. Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1093\/ehjacc\/zuac066","article-title":"MicroRNA-9-3p: A Novel Predictor of Neurological Outcome after Cardiac Arrest","volume":"11","author":"Beske","year":"2022","journal-title":"Eur. Heart J. Acute Cardiovasc. Care."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.cca.2014.03.007","article-title":"Comparison of MiR-124-3p and MiR-16 for Early Diagnosis of Hemorrhagic and Ischemic Stroke","volume":"433","author":"Leung","year":"2014","journal-title":"Clin. Chim. Acta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.jocn.2014.05.042","article-title":"Downregulation of Serum Brain Specific MicroRNA Is Associated with Inflammation and Infarct Volume in Acute Ischemic Stroke","volume":"22","author":"Liu","year":"2015","journal-title":"J. Clin. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"925","DOI":"10.18632\/aging.100624","article-title":"Plasma MicroRNA Biomarkers for Detection of Mild Cognitive Impairment: Biomarker Validation Study","volume":"5","author":"Sheinerman","year":"2013","journal-title":"Aging"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/mds.27928","article-title":"Circulating Brain-Enriched MicroRNAs for Detection and Discrimination of Idiopathic and Genetic Parkinson\u2019s Disease","volume":"35","author":"Ravanidis","year":"2020","journal-title":"Mov. Disord."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1594","DOI":"10.1002\/acn3.51146","article-title":"Validation of Differentially Expressed Brain-Enriched MicroRNAs in the Plasma of PD Patients","volume":"7","author":"Ravanidis","year":"2020","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"5348","DOI":"10.1096\/fj.201902463RR","article-title":"MiR-136-3p Targets PTEN to Regulate Vascularization and Bone Formation and Ameliorates Alcohol-Induced Osteopenia","volume":"34","author":"Chen","year":"2020","journal-title":"FASEB J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1095\/biolreprod.113.109207","article-title":"Role of MicroRNA-136-3p on the Expression of Luteinizing Hormone-Human Chorionic Gonadotropin Receptor MRNA in Rat Ovaries","volume":"89","author":"Kitahara","year":"2013","journal-title":"Biol. Reprod."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"37043","DOI":"10.18632\/oncotarget.6158","article-title":"Altered MicroRNA Profiles in Cerebrospinal Fluid Exosome in Parkinson Disease and Alzheimer Disease","volume":"6","author":"Gui","year":"2015","journal-title":"Oncotarget"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"22884","DOI":"10.1038\/srep22884","article-title":"MiR-434-3p and DNA Hypomethylation Co-Regulate EIF5A1 to Increase AChRs and to Improve Plasticity in SCT Rat Skeletal Muscle","volume":"6","author":"Shang","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1483","DOI":"10.1093\/gerona\/glx025","article-title":"Comprehensive MiRNA Profiling of Skeletal Muscle and Serum in Induced and Normal Mouse Muscle Atrophy During Aging","volume":"72","author":"Jung","year":"2017","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.18632\/aging.101207","article-title":"MicroRNA-434-3p Regulates Age-Related Apoptosis through EIF5A1 in the Skeletal Muscle","volume":"9","author":"Pardo","year":"2017","journal-title":"Aging"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"156","DOI":"10.3389\/fnins.2012.00156","article-title":"A Neuronal Transcriptome Response Involving Stress Pathways Is Buffered by Neuronal MicroRNAs","volume":"6","author":"Manakov","year":"2012","journal-title":"Front. Neurosci."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Sharma, A., Chandran, R., Barry, E.S., Bhomia, M., Hutchison, M.A., Balakathiresan, N.S., Grunberg, N.E., and Maheshwari, R.K. (2014). Identification of Serum MicroRNA Signatures for Diagnosis of Mild Traumatic Brain Injury in a Closed Head Injury Model. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0112019"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4742","DOI":"10.1093\/nar\/gks151","article-title":"MiR-212\/132 Expression and Functions: Within and beyond the Neuronal Compartment","volume":"40","author":"Wanet","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"16426","DOI":"10.1073\/pnas.0508448102","article-title":"A CAMP-Response Element Binding Protein-Induced MicroRNA Regulates Neuronal Morphogenesis","volume":"102","author":"Vo","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"R101","DOI":"10.1186\/ar2493","article-title":"Upregulated MiR-146a Expression in Peripheral Blood Mononuclear Cells from Rheumatoid Arthritis Patients","volume":"10","author":"Pauley","year":"2008","journal-title":"Arthritis Res. Ther."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1084\/jem.20150489","article-title":"The MicroRNA-212\/132 Cluster Regulates B Cell Development by Targeting Sox4","volume":"212","author":"Mehta","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"15672","DOI":"10.1074\/jbc.M111.322669","article-title":"Small RNA Sequencing Reveals MicroRNAs That Modulate Angiotensin II Effects in Vascular Smooth Muscle Cells","volume":"287","author":"Jin","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.mce.2016.01.010","article-title":"Transcriptional Regulation of the MiR-212\/MiR-132 Cluster in Insulin-Secreting \u03b2-Cells by CAMP-Regulated Transcriptional Co-Activator 1 and Salt-Inducible Kinases","volume":"424","author":"Malm","year":"2016","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1002\/glia.23700","article-title":"MicroRNA-132 Is Overexpressed in Glia in Temporal Lobe Epilepsy and Reduces the Expression of pro-Epileptogenic Factors in Human Cultured Astrocytes","volume":"68","author":"Korotkov","year":"2020","journal-title":"Glia"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"9093","DOI":"10.1073\/pnas.0803072105","article-title":"An Activity-Regulated MicroRNA Controls Dendritic Plasticity by down-Regulating P250GAP","volume":"105","author":"Wayman","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"20382","DOI":"10.1073\/pnas.1015691107","article-title":"MicroRNA-132 Regulates Dendritic Growth and Arborization of Newborn Neurons in the Adult Hippocampus","volume":"107","author":"Magill","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Luikart, B.W., Bensen, A.L., Washburn, E.K., Perederiy, J.V., Su, K.G., Li, Y., Kernie, S.G., Parada, L.F., and Westbrook, G.L. (2011). MiR-132 Mediates the Integration of Newborn Neurons into the Adult Dentate Gyrus. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019077"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Remenyi, J., van den Bosch, M.W.M., Palygin, O., Mistry, R.B., McKenzie, C., Macdonald, A., Hutvagner, G., Arthur, J.S.C., Frenguelli, B.G., and Pankratov, Y. (2013). MiR-132\/212 Knockout Mice Reveal Roles for These MiRNAs in Regulating Cortical Synaptic Transmission and Plasticity. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0062509"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/j.bbr.2015.03.032","article-title":"Memory Formation and Retention Are Affected in Adult MiR-132\/212 Knockout Mice","volume":"287","author":"Smith","year":"2015","journal-title":"Behav. Brain Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1101\/lm.039578.115","article-title":"Targeted Deletion of MiR-132\/-212 Impairs Memory and Alters the Hippocampal Transcriptome","volume":"23","author":"Hansen","year":"2016","journal-title":"Learn. Mem."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.neuron.2007.05.017","article-title":"MicroRNA Modulation of Circadian-Clock Period and Entrainment","volume":"54","author":"Cheng","year":"2007","journal-title":"Neuron"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"e1","DOI":"10.1016\/j.neurobiolaging.2016.09.019","article-title":"The MiRNome of Alzheimer\u2019s Disease: Consistent Downregulation of the MiR-132\/212 Cluster","volume":"50","author":"Pichler","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.3389\/fnins.2019.01208","article-title":"MiR-212 and MiR-132 Are Downregulated in Neurally Derived Plasma Exosomes of Alzheimer\u2019s Patients","volume":"13","author":"Cha","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"427","DOI":"10.1002\/epi4.12275","article-title":"Discovery and Validation of Blood MicroRNAs as Molecular Biomarkers of Epilepsy: Ways to Close Current Knowledge Gaps","volume":"3","author":"Enright","year":"2018","journal-title":"Epilepsia Open"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1038\/s41582-021-00461-4","article-title":"Identification of Clinically Relevant Biomarkers of Epileptogenesis\u2014A Strategic Roadmap","volume":"17","author":"Simonato","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1002\/hipo.20646","article-title":"Neuronal Activity Rapidly Induces Transcription of the CREB-Regulated MicroRNA-132, In Vivo","volume":"20","author":"Nudelman","year":"2010","journal-title":"Hippocampus"},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Bot, A.M., D\u0119bski, K.J., and Lukasiuk, K. (2013). Alterations in MiRNA Levels in the Dentate Gyrus in Epileptic Rats. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0076051"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"508","DOI":"10.1016\/j.nbd.2013.10.026","article-title":"Hippocampal Subregion-Specific MicroRNA Expression during Epileptogenesis in Experimental Temporal Lobe Epilepsy","volume":"62","author":"Gorter","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_77","first-page":"1297","article-title":"Expression of P-CREB and Activity-Dependent MiR-132 in Temporal Lobe Epilepsy","volume":"7","author":"Guo","year":"2014","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"9649","DOI":"10.1038\/s41598-021-89084-9","article-title":"Dynamic MiRNA Changes during the Process of Epileptogenesis in an Infantile and Adult-Onset Model","volume":"11","author":"Bencurova","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"15977","DOI":"10.1073\/pnas.1919313117","article-title":"A Systems Approach Delivers a Functional MicroRNA Catalog and Expanded Targets for Seizure Suppression in Temporal Lobe Epilepsy","volume":"117","author":"Reschke","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"2519","DOI":"10.1016\/j.ajpath.2011.07.036","article-title":"MiRNA Expression Profile after Status Epilepticus and Hippocampal Neuroprotection by Targeting MiR-132","volume":"179","author":"Bray","year":"2011","journal-title":"Am. J. Pathol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1007\/s12031-013-9953-3","article-title":"Expression Patterns of MiR-124, MiR-134, MiR-132, and MiR-21 in an Immature Rat Model and Children with Mesial Temporal Lobe Epilepsy","volume":"50","author":"Peng","year":"2013","journal-title":"J. Mol. Neurosci."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1080\/21655979.2021.2015528","article-title":"Relationships between Plasma Expression Levels of MicroRNA-146a and MicroRNA-132 in Epileptic Patients and Their Cognitive, Mental and Psychological Disorders","volume":"13","author":"Huang","year":"2022","journal-title":"Bioengineered"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.nbd.2015.02.025","article-title":"SOX11 Identified by Target Gene Evaluation of MiRNAs Differentially Expressed in Focal and Non-Focal Brain Tissue of Therapy-Resistant Epilepsy Patients","volume":"77","author":"Haenisch","year":"2015","journal-title":"Neurobiol. Dis."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"8413","DOI":"10.18632\/aging.103148","article-title":"LncRNA ILF3-AS1 Mediated the Occurrence of Epilepsy through Suppressing Hippocampal MiR-212 Expression","volume":"12","author":"Cai","year":"2020","journal-title":"Aging"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"4557","DOI":"10.1007\/s00018-018-2911-z","article-title":"MiR-124-3p Is a Chronic Regulator of Gene Expression after Brain Injury","volume":"75","author":"Vuokila","year":"2018","journal-title":"Cell Mol. Life Sci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"7822","DOI":"10.1007\/s12035-018-0946-7","article-title":"Neurobiological Correlates of Alpha-Tocopherol Antiepileptogenic Effects and MicroRNA Expression Modulation in a Rat Model of Kainate-Induced Seizures","volume":"55","author":"Ambrogini","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2402","DOI":"10.1016\/j.celrep.2016.02.042","article-title":"Dual and Opposing Roles of MicroRNA-124 in Epilepsy Are Mediated through Inflammatory and NRSF-Dependent Gene Networks","volume":"14","author":"Brennan","year":"2016","journal-title":"Cell Rep."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.neulet.2010.11.040","article-title":"Expression Profile of MicroRNAs in Rat Hippocampus Following Lithium-Pilocarpine-Induced Status Epilepticus","volume":"488","author":"Hu","year":"2011","journal-title":"Neurosci. Lett."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"106400","DOI":"10.1016\/j.eplepsyres.2020.106400","article-title":"Genome-Wide MicroRNA Profiling in Brain and Blood Samples in a Mouse Model of Epileptogenesis","volume":"166","author":"Chen","year":"2020","journal-title":"Epilepsy Res."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1938205","DOI":"10.1155\/2022\/1938205","article-title":"The Neuroprotective Effect of MiR-136 on Pilocarpine-Induced Temporal Lobe Epilepsy Rats by Inhibiting Wnt\/\u03b2-Catenin Signaling Pathway","volume":"2022","author":"Cui","year":"2022","journal-title":"Comput. Math Methods Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1016\/j.clinbiochem.2016.02.016","article-title":"Plasma MiR-124-3p and MiR-16 Concentrations as Prognostic Markers in Acute Stroke","volume":"49","author":"Rainer","year":"2016","journal-title":"Clin. Biochem."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"2013","DOI":"10.1111\/epi.13915","article-title":"Standardization Procedure for Plasma Biomarker Analysis in Rat Models of Epileptogenesis: Focus on Circulating MicroRNAs","volume":"58","author":"Puhakka","year":"2017","journal-title":"Epilepsia"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1016\/j.neuroscience.2006.03.012","article-title":"A Model of Posttraumatic Epilepsy Induced by Lateral Fluid-Percussion Brain Injury in Rats","volume":"140","author":"Kharatishvili","year":"2006","journal-title":"Neuroscience"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1089\/neu.2016.4404","article-title":"Unfolded Maps for Quantitative Analysis of Cortical Lesion Location and Extent after Traumatic Brain Injury","volume":"34","author":"Kharatishvili","year":"2017","journal-title":"J. Neurotrauma"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.jneumeth.2018.08.028","article-title":"A Web-Based Application for Generating 2D-Unfolded Cortical Maps to Analyze the Location and Extent of Cortical Lesions Following Traumatic Brain Injury in Adult Rats","volume":"308","author":"Andrade","year":"2018","journal-title":"J. Neurosci. Methods"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"2114","DOI":"10.1093\/bioinformatics\/btu170","article-title":"Trimmomatic: A Flexible Trimmer for Illumina Sequence Data","volume":"30","author":"Bolger","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"D68","DOI":"10.1093\/nar\/gkt1181","article-title":"MiRBase: Annotating High Confidence MicroRNAs Using Deep Sequencing Data","volume":"42","author":"Kozomara","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"923","DOI":"10.1093\/bioinformatics\/btt656","article-title":"FeatureCounts: An Efficient General Purpose Program for Assigning Sequence Reads to Genomic Features","volume":"30","author":"Liao","year":"2014","journal-title":"Bioinformatics"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/j.1467-9868.2005.00503.x","article-title":"Regularization and Variable Selection via the Elastic Net","volume":"67","author":"Zou","year":"2005","journal-title":"J. R Stat. Soc. Ser. B Stat. Methodol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"1","DOI":"10.18637\/jss.v033.i01","article-title":"Regularization Paths for Generalized Linear Models via Coordinate Descent","volume":"33","author":"Friedman","year":"2010","journal-title":"J. Stat. Softw."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1007\/s12021-015-9292-3","article-title":"Comparison of Feature Selection Techniques in Machine Learning for Anatomical Brain MRI in Dementia","volume":"14","author":"Tohka","year":"2016","journal-title":"Neuroinformatics"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"6562","DOI":"10.1073\/pnas.102102699","article-title":"Selection Bias in Gene Extraction on the Basis of Microarray Gene-Expression Data","volume":"99","author":"Ambroise","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"104324","DOI":"10.1016\/j.compbiomed.2021.104324","article-title":"Evaluation of Machine Learning Algorithms for Health and Wellness Applications: A Tutorial","volume":"132","author":"Tohka","year":"2021","journal-title":"Comput. Biol. Med."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.neuroimage.2018.02.050","article-title":"T1 White\/Gray Contrast as a Predictor of Chronological Age, and an Index of Cognitive Performance","volume":"173","author":"Lewis","year":"2018","journal-title":"Neuroimage"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1016\/S0031-3203(96)00142-2","article-title":"The Use of the Area under the ROC Curve in the Evaluation of Machine Learning Algorithms","volume":"30","author":"Bradley","year":"1997","journal-title":"Pattern Recognit."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2823\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:21:27Z","timestamp":1760120487000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/3\/2823"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,1]]},"references-count":105,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24032823"],"URL":"https:\/\/doi.org\/10.3390\/ijms24032823","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,1]]}}}