New astroglial injury-defined biomarkers for neurotrauma assessment

Abstract

Traumatic brain injury (TBI) is an expanding public health epidemic with pathophysiology that is difficult to diagnose and thus treat. TBI biomarkers should assess patients across severities and reveal pathophysiology, but currently, their kinetics and specificity are unclear. No single ideal TBI biomarker exists. We identified new candidates from a TBI CSF proteome by selecting trauma-released, astrocyte-enriched proteins including aldolase C (ALDOC), its 38kD breakdown product (BDP), brain lipid binding protein (BLBP), astrocytic phosphoprotein (PEA15), glutamine synthetase (GS) and new 18-25kD-GFAP-BDPs. Their levels increased over four orders of magnitude in severe TBI CSF. First post-injury week, ALDOC levels were markedly high and stable. Short-lived BLBP and PEA15 related to injury progression. ALDOC, BLBP and PEA15 appeared hyper-acutely and were similarly robust in severe and mild TBI blood; 25kD-GFAP-BDP appeared overnight after TBI and was rarely present after mild TBI. Using a human culture trauma model, we investigated biomarker kinetics. Wounded (mechanoporated) astrocytes released ALDOC, BLBP and PEA15 acutely. Delayed cell death corresponded with GFAP release and proteolysis into small GFAP-BDPs. Associating biomarkers with cellular injury stages produced astroglial injury-defined (AID) biomarkers that facilitate TBI assessment, as neurological deficits are rooted not only in death of CNS cells, but also in their functional compromise.

Circulating Brain Injury Exosomal Proteins following Moderate-to-Severe Traumatic Brain Injury: Temporal Profile, Outcome Prediction and Therapy Implications

“…In our study population, correlations between free-circulating and exosomal concentration in serum were strong and improved over time for the two cytoskeletal proteins NFL and GFAP, in contrast to t-tau and especially UCH-L1, which showed weaker correlations that appreciably worsened at the late stages of injury. The most likely interpretation of these findings is that acute glial and neuroaxonal injury results in structural damage leading to (1) ensuing direct leakage of NFL and GFAP into the extracellular space and biofluids through mechanoporation, or altered plasmalemma permeability of injured cells [23][24][25], and (2) intracellular accumulation of aggregated proteins [26] that, in turn, are secreted through an exosome-mediated pathway to reduce toxicity and maintain intracellular proteostasis [21]. Taken together, these observations support the idea that free-circulating and exosomal concentrations of cytoskeletal proteins in serum are products of a common disease-induced damage that follows two distinct parallel pathways.…”

Questions and (some) answers on reactive astrocytes

“…Last, some astrocyte proteins like GFAP or their break‐down products may also end up in the cerebrospinal fluid of patients subject to traumatic brain injury [TBI, (Halford et al, )], but also in more progressive diseases like Creutzfeldt‐Jakob disease or AD [for review, see (Carter et al, ; Perez‐Nievas & Serrano‐Pozo, )].…”

“…Such improvements will be facilitated by basic studies that establish the molecular and functional profile of reactive astrocytes (see Section 6) but also of their microglia or neuronal neighbors, allowing the identification of new and specific astrocyte targets. Last, some astrocyte proteins like GFAP or their break-down products may also end up in the cerebrospinal fluid of patients subject to traumatic brain injury [TBI, (Halford et al, 2017)], but also in more progressive diseases like Creutzfeldt-Jakob disease or AD [for review, see (Carter et al, 2019;Perez-Nievas & Serrano-Pozo, 2018)].…”

Early Levels of Glial Fibrillary Acidic Protein and Neurofilament Light Protein in Predicting the Outcome of Mild Traumatic Brain Injury

“…The results from the present study are thus consistent with the aforementioned studies, with an AUC of 0.755 (95%CI 0.628-0.882). It has been suggested that combining several astroglia-derived markers may improve the predictive ability 44 . NF-L has been reported to be a highly sensitive blood-based protein biomarker for severe TBI.…”