Serum Biomarkers and Neuroimaging Correlates in CT-Negative Mild Traumatic Brain Injury

Mild traumatic brain injury (mTBI) is a significant public health concern due to its high prevalence and potential for long-term cognitive adverse effects. Conventional neuroimaging techniques like computed tomography (CT) often fail to detect abnormalities in mTBI patients especially in those presenting with negative CT scans. The lack of detectable injury on imaging with persistent symptoms is still a challenge in accurate diagnosis and best management for mTBI. It is believed the pathophysiology of mTBI is complex and involves neuronal injury, neuroinflammation, and vascular dysfunction which also play a significant role in the long-term progression and potential neurodegeneration associated with mTBI. Previous studies suggested that blood-based biomarkers could provide valuable data into these underlying molecular mechanisms. Biomarkers such as neurofilament light (NfL), ubiquitin C-terminal hydrolase L1 (UCH-L1), and vascular endothelial growth factor (VEGF) have shown promise in reflecting axonal damage, neuronal cell body injury, and vascular changes, respectively. However, the temporal dynamics of these biomarkers and their precise relationship with neuroimaging findings and clinical outcomes in CT-negative mTBI patients remain unclear. To this account, new study published in Journal of Cerebral Cortex and conducted by PhD candidate Xiaoyan Jia, Xuan Li, Qiuyu Ji, Bo Yin, Yizhen Pan, Wenpu Zhao, Ming Zhang, Guanghui Bai, Jie Zhang, and led by Professor Lijun Bai from Xi’an Jiaotong University, the researchers performed comprehensive longitudinal study to investigate the potential of serum biomarkers in diagnosing and monitoring CT-negative mTBI. They focused on a cohort of mTBI patients with negative CT scans to elucidate the temporal profiles of key biomarkers and their association with neuroimaging abnormalities and cognitive function which enhanced our understanding of mTBI’s pathophysiology and provided guidelines for improved clinical management and therapeutic interventions.

To investigate the diagnostic and prognostic potential of serum biomarkers, the researchers measured levels of neurofilament light (NfL), UCH-L1, and VEGF, along with inflammatory cytokines (IL-1β, IL-6, IL-10). Blood samples were processed using a Luminex multiplex bead system and Simoa technology for NfL quantification. They observed NfL to be elevated in acute-stage mTBI patients compared to HCs which indicated axonal injury. These elevated NfL levels were associated with impaired white matter integrity and progressive brain atrophy which highlighted NfL’s potential as a marker for neurodegeneration. Another biomarker UCH-L1 which was also found to be elevated at both the acute and 3-month stages which reflects neuronal cell body injury and its levels correlated with cognitive flexibility impairment and highlighted the impact of neuronal injury on cognitive functions. Moreover, VEGF displayed the highest diagnostic potential with an AUC of 0.88 and was significantly elevated in acute-stage patients and also associated with post-traumatic symptoms which suggested its role in angiogenesis and brain recovery processes.

In their study, participants also underwent diffusion tensor imaging (DTI) and high-resolution T1-weighted MRI scans. DTI metrics, such as fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD), were analyzed to assess white matter integrity. The authors also evaluated brain volume changes using the Jacobian determinant (JD) metric to identify progressive atrophy. The authors found that acute mTBI patients have increased MD and RD in the corpus callosum which suggest cellular inflammation and potential demyelination while there were no significant differences found in chronic mTBI patients compared to HCs which indicated a resolution of some microstructural changes over time. They also showed using JD analysis progressive atrophy in both gray and white matter regions from the acute stage to 6-12 months post-injury with atrophy to be more significant in the frontal and temporal lobes which emphasizes the longitudinal impact of mTBI on brain structure. The research team assessed cognitive flexibility using the Digital Symbol Coding score from the Wechsler Adult Intelligence Scale III and found impairment was associated with elevated IL-1β and UCH-L1 levels from the acute to chronic stages highlighting the role of acute inflammatory responses and neuronal injury in long-term cognitive outcomes. Sleep disturbance was also evaluated using the Insomnia Severity Index. Post-concussive symptoms were assessed based on ICD-10 criteria and demonstrated it can be predicted by elevated VEGF levels at the acute stage which indicate the potential impact of angiogenesis-related processes on post-injury sleep quality.

In conclusion, the study by Professor Lijun Bai and her colleagues identified VEGF as a highly effective diagnostic biomarker for distinguishing CT-negative mTBI patients from healthy controls which demonstrates the potential for improved early diagnosis and this could lead to better management and treatment strategies for patients who might otherwise be overlooked due to negative CT scans. The findings and analysis that successfully linked specific biomarkers to neuronal injury, neuroinflammation, and vascular dysfunction advances our knowledge of mTBI’s complex pathophysiology which can be critical for developing better treatments. According to the authors measuring serum biomarkers such as NfL, UCH-L1, and VEGF in routine clinical practice can provide non-invasive and accessible method for diagnosing and monitoring mTBI and offer objective measures to complement traditional diagnostic tools. Moreover, the authors’ findings of biomarkers to be associated with specific pathological processes and outcomes allows for more personalized treatment strategies. For example, patients who have elevated inflammatory biomarkers might benefit from anti-inflammatory medications while those with high NfL levels could receive medications that axonal integrity. Finally, the authors recommended regular monitoring of biomarker levels because it could help clinicians track better disease progression and treatment efficacy over time which ultimately led to improved patient outcomes.

Acknowledgement

We  acknowledge Prof. Jie Zhang from the Department of Radiation Medicine, School of Preventive Medicine, Air Force Medical University, and Prof. Ming Zhang from the Department of Medical Imaging, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China, for their great contributions to this research work.