TY - JOUR
T1 - Plasma microRNAs as prognostic biomarkers for development of severe epilepsy after experimental traumatic brain injury—EpiBioS4Rx Project 1 study
AU - Heiskanen, Mette
AU - Ndode-Ekane, Xavier Ekolle
AU - Ali, Idrish
AU - Santana-Gomez, Cesar
AU - Puhakka, Noora
AU - Gupta, Shalini Das
AU - Andrade, Pedro
AU - Immonen, Riikka
AU - Casillas-Espinosa, Pablo
AU - Manninen, Eppu
AU - Smith, Gregory
AU - Brady, Rhys D.
AU - Silva, Juliana
AU - Braine, Emma
AU - Hudson, Matt
AU - Yamakawa, Glen R.
AU - Jones, Nigel C.
AU - Shultz, Sandy R.
AU - Harris, Neil G.
AU - Wright, David K.
AU - Gröhn, Olli
AU - Staba, Richard J.
AU - O'Brien, Terence J.
AU - Pitkänen, Asla
N1 - Publisher Copyright:
© 2024 The Author(s). Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.
PY - 2025/3
Y1 - 2025/3
N2 - Objective: To test a hypothesis that acutely regulated plasma microRNAs (miRNAs) can serve as prognostic biomarkers for the development of post-traumatic epilepsy (PTE). Methods: Adult male Sprague–Dawley rats (n = 245) were randomized to lateral fluid-percussion–induced traumatic brain injury (TBI) or sham operation at three study sites (Finland, Australia, United States). Video-electroencephalography (vEEG) was performed on the seventh post-injury month to detect spontaneous seizures. Tail vein plasma collected 48 h after TBI for miRNA analysis was available from 209 vEEG monitored animals (45 sham, 164 TBI [32 with epilepsy]). Based on small RNA sequencing and previous data, the seven most promising brain enriched miRNAs (miR-183-5p, miR-323-3p, miR-434-3p, miR-9a-3p, miR-124-3p, miR-132-3p, and miR-212-3p) were validated by droplet digital polymerase chain reaction (ddPCR). Results: All seven plasma miRNAs differentiated between TBI and sham-operated rats. None of the seven miRNAs differentiated TBI rats that did and did not develop epilepsy (p >.05), or rats with ≥3 vs <3 seizures in a month (p >.05). However, miR-212-3p differentiated rats that developed epilepsy with seizure clusters (i.e., ≥3 seizures within 24 h) from those without seizure clusters (.34 ±.14 vs.60 ±.34, adj. p <.05) with an area under the curve (AUC) of.81 (95% confidence interval [CI].65–.97, p <.01, 64% sensitivity, 95% specificity). Lack of elevation in miR-212-3p also differentiated rats that developed epilepsy with seizure clusters from all other TBI rats (n = 146,.34 ±.14 vs.55 ±.31, p <.01) with an AUC of.74 (95% CI.61–.87, p <.01, 82% sensitivity, 62% specificity). Glmnet analysis identified a combination of miR-212-3p and miR-132-3p as an optimal set to differentiate TBI rats with vs without seizure clusters (cross-validated AUC.75, 95% CI.47–.92, p <.05). Significance: miR-212-3p alone or in combination with miR-132-3p shows promise as a translational prognostic biomarker for the development of severe PTE with seizure clusters.
AB - Objective: To test a hypothesis that acutely regulated plasma microRNAs (miRNAs) can serve as prognostic biomarkers for the development of post-traumatic epilepsy (PTE). Methods: Adult male Sprague–Dawley rats (n = 245) were randomized to lateral fluid-percussion–induced traumatic brain injury (TBI) or sham operation at three study sites (Finland, Australia, United States). Video-electroencephalography (vEEG) was performed on the seventh post-injury month to detect spontaneous seizures. Tail vein plasma collected 48 h after TBI for miRNA analysis was available from 209 vEEG monitored animals (45 sham, 164 TBI [32 with epilepsy]). Based on small RNA sequencing and previous data, the seven most promising brain enriched miRNAs (miR-183-5p, miR-323-3p, miR-434-3p, miR-9a-3p, miR-124-3p, miR-132-3p, and miR-212-3p) were validated by droplet digital polymerase chain reaction (ddPCR). Results: All seven plasma miRNAs differentiated between TBI and sham-operated rats. None of the seven miRNAs differentiated TBI rats that did and did not develop epilepsy (p >.05), or rats with ≥3 vs <3 seizures in a month (p >.05). However, miR-212-3p differentiated rats that developed epilepsy with seizure clusters (i.e., ≥3 seizures within 24 h) from those without seizure clusters (.34 ±.14 vs.60 ±.34, adj. p <.05) with an area under the curve (AUC) of.81 (95% confidence interval [CI].65–.97, p <.01, 64% sensitivity, 95% specificity). Lack of elevation in miR-212-3p also differentiated rats that developed epilepsy with seizure clusters from all other TBI rats (n = 146,.34 ±.14 vs.55 ±.31, p <.01) with an AUC of.74 (95% CI.61–.87, p <.01, 82% sensitivity, 62% specificity). Glmnet analysis identified a combination of miR-212-3p and miR-132-3p as an optimal set to differentiate TBI rats with vs without seizure clusters (cross-validated AUC.75, 95% CI.47–.92, p <.05). Significance: miR-212-3p alone or in combination with miR-132-3p shows promise as a translational prognostic biomarker for the development of severe PTE with seizure clusters.
KW - harmonization
KW - lateral fluid-percussion
KW - post-traumatic epilepsy
KW - preclinical
KW - receiver-operating characteristic analysis
KW - video-EEG monitoring
UR - https://www.scopus.com/pages/publications/85211458118
U2 - 10.1111/epi.18219
DO - 10.1111/epi.18219
M3 - Article
C2 - 39661396
AN - SCOPUS:85211458118
SN - 0013-9580
VL - 205
SP - 870
EP - 885
JO - Epilepsia
JF - Epilepsia
ER -