New biomarker stars for traumatic brain injury

There is a burning need for biomarkers for early diagnosis and long-term follow-up for several brain disorders, including traumatic brain injury (TBI). TBI is the consequence of a mechanical force applied to the head with a wide range of severities. TBI represents a major public health issue. ¹ The clinical assessment of TBI severity relies on the Glasgow Coma Scale (GCS) for the assessment of neurological function in combination with neuroimaging, such as computerized tomography (CT)-scan and magnetic resonance imaging (MRI). These approaches have been shown to be useful for severe and moderate TBI; however, these techniques show limitations for diagnosis and prognosis of mild TBI patients, which represent between 75 and 90% of all TBI cases. ² Better prognosis is important for repetitive head injuries, common in sports, because they have been associated with higher rate of chronic neurodegeneration. New diagnostic tools are needed for precise identification of at-risk patients in order to prevent disease progression.

Serum biomarkers present a great advantage to be a low-cost and non-invasive diagnostic tool that allows repeat sampling in time to mirror the disease course and the response to treatment. There has been increased research on TBI biomarkers in the last 10 years, with a recent interest in the astrocytic proteins S100ß and glial fibrillary acid proteins (GFAP) as potential TBI markers. However, these markers did not succeed to transfer in clinics for early diagnosis because both markers showed an absence of TBI specificity and a delayed appearance in serum after injury.

Halford et al.’s work ³ outlines new astrocytic biomarkers called astroglial injury-defined (AID) biomarkers found at early time-points (less than 3 h) in the serum of TBI-patients even after mild injury. The authors used proteomics on cerebrospinal fluid (CSF) from severe TBI patients to define specific proteins for TBI. Then, they compared these proteins with proteins released after stretch injury in mouse astrocyte culture ⁴ and identified four AID biomarkers: (1) aldolase C (ALDOC), (2) glutamine synthetase (GS), (3) brain lipid binding protein (BLBP) and (4) astrocytic phosphoprotein 15 (PEA15). Interestingly, energy metabolism and cerebral blood flow are frequently impaired after TBI even in mild TBI, ⁵ and the four selected proteins are essential for astrocytes metabolism. The markers exhibited kinetic diversity after severe TBI, with a persistent increase of ALDOC and GS for several days after injury, while BLBP and PEA15 were present early after the impact but fluctuated on the following days. The groundbreaking result is the presence of ALDOC, BLBP and PEA15 in the hyper acute period after mild TBI (1 h at earliest); however, the degraded product of GFAP, also new for the field, is rarely observed in the serum of mild TBI patients. It is important to highlight that AID biomarkers were present in blood before CSF questioning the role of the glymphatic system ⁶ for markers to reach blood compartment in pathophysiological conditions. The differential temporal increase of these proteins may reflect pathophysiological processes in astrocytes. The question is in part tackled in Halford et al.’s (2017) work using a control stretch injury model in human primary astrocyte culture. The AID biomarkers showed similar release pattern in vitro as in clinics, with a delayed release of GFAP-degraded products for the severe injury related to astrocyte death. These unique results suggest that AID biomarkers could be used as readout of astrocytes destiny (wounded or dead), to differentiate the severity of injury as well as to follow the disease progression over time. It is important to outline that AID biomarkers are present in severe and mild TBI suggesting that even mild injury alters astrocyte properties.

In summary, the AID biomarkers provide a new hope to define sub-categories in TBI and follow the evolution of TBI pathophysiology. The astromarkers could become the new stars of the biomarkers field of brain injuries.