microRNA Biomarkers of Cumulative Blast-Mild Traumatic Brain Injury (Micro BCB)
Abstract
Slowly resolving disease processes can be initiated by mild traumatic brain injury (mTBI). There is increasing evidence that repetitive, subinjurious, head impact/blast exposures can provoke similar pathology. Training military units may sustain multiple injurious and subinjurious mTBI insults throughout their careers. For example, our published analyses estimate a typical Special Operations Forces (SOF) team experiences 54+ blasts per training week (>251 psi/week); equaling 648 subinjurious blasts/quarterly (>3,000 psi/quarter/Soldier). Science is only now exploring these traumatic events’ long-term effects, with definitive studies demonstrating repeated mTBI exposures increase the risk of Alzheimer’s disease and related dementias. During the chronic phase of the injury/recovery process, mTBI is largely diagnosed based on retrospectively recalling acute symptoms following the event, as well as behavioral and cognitive assessments. Similarly, diagnostics and prognostics for cumulative mTBI exposures are also lacking. Therefore, objective biomarkers enabling accurate diagnoses for identifying and managing individuals with probable mTBI would be useful. Although there has been progress in identifying acute mTBI biomarkers, few studies have identified candidate biomarkers for chronic mTBI resulting from significant cumulative blast exposure. Testing previously identified molecules for their diagnostic and prognostic performance in additional populations will help validate and establish their use in guiding medical care decisions, monitoring aggravation of previous mTBIs and will help support disability claims based on a history of TBI. Our project aims to validate previously identified objective blood miRNA biomarker candidates. We will determine their performance for diagnosis, prognosis, or monitoring of chronic repetitive mTBI across the blast injury spectrum—ranging from repetitive low-intensity blast (LIB) training exposure to mild- intensity blast (MIB) typically encountered during combat. miRNAs are a class of small, stable ribonucleic acid molecules carried in the blood, allowing these biomarkers to be easily attained. The fact that they are easily measured by polymerase chain reaction (PCR)-based techniques additionally allows them to be inexpensive, highly accurate and deployable both within civilian and far forward operational settings. miRNAs bind to cognate sequences in messenger RNA, preventing its expression as protein and thereby limiting the role of that protein in the function of the cell. miRNAs can therefore not only have profound effects on the trajectory of disease and injury recovery processes, but also knowing which miRNAs are differentially expressed along the injury and recovery process can indicate which molecular mechanisms may be beneficial to treat. We have previously identified a group of blood miRNAs with altered expression in Veterans with chronic repetitive blast-mTBI. Importantly, we identified altered disease pathways related to their expression levels reflecting the value of this powerful approach. Our recent work in support of this application has determined several of these miRNAs may serve as high performance diagnostics discriminating persons with and without blast-mTBI. We have performed additional studies in mice identifying novel miRNAs that reflect cumulative LIB exposure, as well as additional miRNAs related to chronic MIB exposures. In both cases, our preliminary work indicates the miRNAs relate to behavioral impairments and with diffusion tensor imaging (DTI) measures of hindbrain injuries in the superior cerebellar peduncle and medulla. Importantly, changes in DTI metrics may precede both neuronal loss and symptoms onset. Taken together, identifying blood biomarkers correlated with both symptom burden and neurodegenerative structural changes may help guide the neuroimaging-based monitoring of traumatic brain injury resolution as an essential part of pe
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310755
Entities
People
- James Meabon
Organizations
- United States Army
- VA Puget Sound Health Care System