Table 1.
Literature survey of human TBI and EV studies
| References | Populations | EV sources | Key findings |
|---|---|---|---|
| Kawata et al., 2018 | Sports related concussion | Plasma, neuron, astrocyte, microglia-derived EVs | Non-significant increases in NfL, tau, TNF-a, IL8, GFAP and MBP. |
| Mondello et al., 2020 | Moderate-to-severe TBI | Serum exosomes | Diffuse injury was associated with higher acute NfL and GFAP compared to focal lesions. An acute rise followed by a secondary steep rise of EV UCH-L1 was associated with early mortality. |
| Goetzl et al., 2019 | Sports related concussion | Plasma, neuron-derived exosomes | EV levels of a range of functional proteins were abnormal in acute mTBI. Chronic mTBI showed elevated EV Ab-42, P-T181-tau, P-S396-tau, IL-6, prion cellular protein. |
| Winston et al., 2019 | Military-related mTBI | Neuronal- and astrocyte- derived exosomes | Aβ42 higher in neuronal and astrocytic EVs. Lower Neurogranin levels |
| Kenney et al., 2018 | Military-related chronic mTBI | Plasma exosomes | EV tau and p-tau was elevated in repetitive TBI compared to those who had two or fewer mTBIs or were TBI-negative. Increases correlated with post-concussive symptoms. |
| Gill et al., 2018 | Military-related chronic mTBI | Blood neuron-derived exosomes | EV tau, Aβ42 and IL-10 were elevated in mTBI group compared to controls. EV tau concentrations correlated with post-concussive symptoms while EV IL-10 levels correlated with PTSD symptoms. |
| Stern et al., 2016 | Sports related concussion | Plasma exosomes | NFL players had higher EV tau than the control group. |
| Muraoka et al., 2019 | Sports-related TBI | CSF, EVs | T-tau and p-tau181 levels of EVs correlated with t-tau and p-tau181 levels of total CSF in former NFL players. |
| Goetzl et al., 2018 | Acute TBI | Plasma and serum neuron-derived exosomes | Slope change of neuronal EV synaptopodin between 8 and 14 hours correlated with clinical outcomes in acute brain injury. |
| Ghai et al., 2020 | Blast related chronic military TBI | Plasma EVs | 45 significantly changed miRNAs in EVs were identified in the in chronic mTBI cohort compared with the control groups. |
| Flynn et al., 2021 | 1 year post injury | Serum EVs | Elevated EV GFAP and NfL levels correlated with lower one year Glasgow Outcome Scale-Extended score. |
| Manek et al., 2018 | Severe blunt head trauma, 12 hours post injury | CSF EVs | Following severe TBI the brain increased number of EVs released into the CSF. |
| Matuk et al., 2021 | Pre- and post-fight MMA fighters vs. control | Salivary EVs | A correlation was found between absolute gene information signals and fight related markers of head injury severity. |
| Kuharić et al., 2019 | Severe TBI, up to 7 days | CSF EVs | Flotillin-1 was only detected in CSF from approximately one third of TBI patients. Unfavorable outcomes were associated with decreasing Arf6 and a delayed Rab7a increase. Arf6 and Rab7a were negatively correlated. |
| Beard et al., 2021 | mTBI patients | Plasma EVs, plasma and brain derived | GluR2+ EVs have distinct biomarker profiles compared to plasma profiles. |
| Guedes et al., 2022 | Major TBI requiring intensive care (within 6–12 hours of injury) | Plasma EVs, plasma | Total body EVs with GFAP, UCH-L1, and NfL were elevated in multiple injuries. |
| Guedes et al., 2021 | Military-related chronic mTBI | Plasma EVs, plasma | EV NfL levels were increased in participants with more severe PTSD symptoms. |
| Ko et al., 2020 | Non-acute penetrating TBI, enrolled < 24 hours after injury | Plasma EVs | Four miRNAs (miR-203b-5p, miR-203a-3p, miR-206, and miR-185-5p) identified as potential biomarkers for TBI patients. |
| Kerr et al., 2019 | Severe TBI, start < 24 hours after injury and collected in intervals up to 5 days after TBI | Serum EVs | TBI patients had increased serum-derived EVs and levels of apoptosis-associated speck-like protein containing a caspase-recruiting domain. |
| Ko et al., 2018 | TBI (0.4–120 hours after injury) and healthy controls | Plasma EVs | Developed and tested a microchip diagnostic for characterizing TBI using RNA in brain derived EVs. |
| Meier et al., 2022 | Concussion in high school/collegiate football players | Serum EVs, EV-depleted serum | EV IL-6 increased acutely following concussion. |
| After injury: 6, 24–48 hours, 8, 15, and 45 days | Acute EV IL-6 correlated with symptoms post injury. | ||
| Edwards et al., 2022 | Experienced breachers from law enforcement or military (repeated blast exposure) | Serum, neuronal EVs (CD171+) from serum | TNFα and IL-6 in neuronal-derived EVs were increased in breachers and IL-10 levels were decreased in breachers relative to controls. IL-6/IL-10 ratio in neuronal-derived EVs was elevated in breachers compared to controls and correlated with higher total Rivermead Post-concussion Questionnaire scores. |
| Li et al., 2023 | TBI patients after 6 hours (no previous TBI or other neurological diseases) | Plasma EVs | The number of HMGB1+ EVs correlated with injury severity. |
| Huang et al., 2023 | Mild and severe TBI patients | Serum EVs | 245 exosomal microRNAs detected with significant differences between TBI and control groups (136 up-regulated and 109 down-regulated). |
| Seršić et al., 2023 | Severe TBI | CSF EVs | MiR-142-3p, miR-204-5p, and miR-223-3p were identified as cargo of CD81-enriched EVs. |
Table 1 outlines the literature survey of studies assessing human samples of EVs post TBI considered in the preparation of this manuscript. Articles were sourced from PubMed and published between the years 2016–2023. Aβ: Amyloid-beta; CSF: cerebrospinal fluid; EV: extracellular vesicle; GFAP: glial fibrillary acidic protein; HMGB1: high mobility group box 1 protein; IL: interleukin; MBP: myelin basic protein; MMA: mixed martial arts; mTBI: mild TBI; NfL: neurofilament light chain; PTSD: post-traumatic stress disorder; TBI: traumatic brain injury; TNF: tumor necrosis factor; UCH-L1: ubiquitin C-terminal hydrolase L1.