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Updated: May 28, 2026
Systems Analysis of the Neuroinflammatory and Hemodynamic Response to Traumatic Brain Injury
Published on: May 27, 2022
Extracellular Vesicle and Plasma miRNAs as Candidate Biomarkers of Traumatic Brain Injury in the Context of
Cora Rebecca Schindler1, Dirk Henrich1, Lena Krämer1
1Department of Trauma Surgery and Orthopedics, University Hospital of Goethe University Frankfurt, 60323 Frankfurt am Main, Germany.
Insights
Circulating microRNAs (miRNAs) in plasma reflect general trauma severity, while extracellular vesicle (EV)-associated miRNAs, like miR-1469, may offer specific signals for traumatic brain injury (TBI) in polytrauma patients.
Area of Science:
- Biomarkers and Diagnostics
- Molecular Biology
- Trauma and Critical Care
Background:
- Severe traumatic brain injury (TBI) poses significant mortality and disability risks in polytrauma (PT) patients.
- Predicting clinical outcomes in TBI/PT is challenging due to heterogeneity and secondary injuries.
- Current diagnostic/prognostic methods are limited, especially when neurological evaluation is impaired.
Purpose of the Study:
- To compare plasma- and extracellular vesicle (EV)-associated microRNA (miRNA) signatures in severe TBI patients versus controls.
- To identify minimally invasive miRNA biomarkers for TBI.
- To enhance understanding of molecular responses following severe TBI.
Main Methods:
- Blood samples collected at ≤3 h and 48 h post-admission from TBI patients and healthy controls.
- Next-generation sequencing (NGS) for miRNA screening in pooled plasma samples.
- Reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) for validating candidate miRNAs in individual plasma and EV samples.
Main Results:
- NGS identified more differentially expressed miRNAs in plasma (103 at ≤3h, 65 at 48h) than in EVs (14 at ≤3h, 32 at 48h).
- Validation confirmed differential expression for 12/16 plasma and 10/15 EV-miRNAs; 3 plasma and 4 EV-miRNAs differed between TBI and PT groups.
- Plasma miRNAs correlated with systemic injury severity; EV miR-1469 showed association with TBI group status and Glasgow Coma Scale (GCS).
Conclusions:
- Circulating miRNA profiles are primarily influenced by systemic trauma severity, not solely TBI-specific effects.
- Plasma miRNAs reflect general injury burden, while EV-associated miRNAs show more heterogeneous, potentially TBI-specific patterns.
- EV-derived miR-1469 is a promising candidate biomarker for TBI, warranting further investigation.
Abstract:
Severe traumatic brain injury (TBI) is a leading cause of mortality and long-term disability in polytrauma (PT) patients, and its clinical outcome remains difficult to predict due to clinical heterogeneity and secondary injury mechanisms. Current diagnostic and prognostic approaches based on clinical assessment and imaging are limited, particularly in PT where neurological evaluation is often impaired. This study aimed to compare plasma- and extracellular vesicle (EV)-associated microRNA (miRNA) signatures in patients with severe TBI and healthy controls to identify their potential as minimally invasive biomarkers and to improve understanding of molecular responses. For profiling circulating miRNAs, blood samples were collected at ≤3 h and at 48 h after admission. In the screening phase, plasma samples of n = 15 patients with severe isolated TBI (Abbreviated Injury Scale [AIS]Head ≥ 4, all other AIS ≤ 1) and n = 15 age- and sex-matched healthy controls were pooled (n = 5/pool) and subjected to next-generation sequencing (NGS). In the following validation phase, n = 25 severely injured trauma patients (Injury Severity Score [ISS] ≥ 16) were enrolled and stratified into PT without TBI (PT; AISHead = 0; n = 13) and isolated TBI (n = 12). Differentially expressed candidate miRNAs identified in the screening phase were validated in individual plasma and EV samples using reverse transcription droplet digital polymerase chain reaction (RT-ddPCR). Functional enrichment and pathway analyses were performed using miRNet. NGS identified more differentially expressed miRNAs in plasma (ER: 103; 48 h: 65) than in EVs (Emergency Room [ER]: 14; 48 h: 32). Functional enrichment analysis indicated associations with pathways related to cellular stress, senescence, growth factor signaling, transcriptional regulation, and apoptosis. In validation, 12 of 16 plasma and 10 of 15 EV-miRNAs were confirmed as differentially expressed in TBI patients; among these, three plasma and four EV miRNAs differed between TBI and PT. After adjustment, most plasma miRNAs were associated with injury severity rather than group status. EV miRNA profiles showed heterogeneous patterns, with miR-1469 associated with TBI group status in adjusted analysis, while miR-1237-5p was linked to injury severity and other EV miRNAs showed no consistent group-specific effects. Plasma miRNAs mainly correlated with systemic injury markers, whereas EV miR-1469 showed a moderate association with the Glasgow Coma Scale (GCS). Overall, circulating miRNA profiles after injury appear to be predominantly influenced by systemic trauma severity rather than TBI-specific effects. Plasma miRNAs mainly reflected general injury burden, whereas EV-associated miRNAs showed more heterogeneous patterns, with miR-1469 emerging as a candidate associated with TBI after adjustment for clinical covariates. These findings suggest that EV-derived miRNAs, particularly miR-1469, may provide more targeted signals related to brain injury and warrant further investigation.
