Review on the Role of Salivary Biomarkers in the Diagnosis of Mild Traumatic Brain Injury and Post-Concussion Syndrome

Abstract

(1) Background: While mild traumatic brain injuries (TBIs) are a major public health issue, post-concussion syndrome (PCS) remains a controversial entity. In both cases, the clinical diagnosis is mainly based on the symptoms and brain imaging evaluation. The current molecular biomarkers were described from blood and cerebrospinal fluid (CSF), yet both fluid collection methods are invasive. Saliva could be preferred in molecular diagnosis due to its non-invasive and non-expensive methods of acquisition, transport, and samples processing. (2) Objectives: In the present study, we aimed to review the latest developments in salivary biomarkers and their potential role in diagnosing mild TBIs, and PCS. (3) Results: In TBIs and PCS, a few novel studies focusing on salivary biomarkers have emphasized their importance in diagnosis. The previous studies mainly focused on micro RNAs, and only a few on extracellular vesicles, neurofilament light chain, and S100B. (4) Conclusions: The combination between salivary biomarkers, clinical history and examination, self-reported symptoms, and cognitive/balance testing can provide a non-invasive alternative diagnostic methodology, as compared to the currently approved plasma and cerebrospinal fluid biomarkers.

Assessment of salivary microRNA by RT-qPCR: Challenges in data interpretation for clinical diagnosis

“…Salivary miRNA biomarkers have become recently relevant to the medical diagnostic community due to their easiness in sample collection and their expression signatures in diverse diseases [4,6,7]. However, the lack of standardized approaches in experimental design, method of analysis and data interpretation coupled with inter-individual variability has led to the generation of considerable study-dependent and controversial data [37,39].…”

“…Relying on already established potential miRNA biomarkers for the diagnostic of brain concussion [6,[16][17][18], we quantified a representative panel of six miRNA (hsa-Let-7a-5p, hsa-Let-7f-5p, has-mir-148a-3p, has-miR-26b-5p, hsa-miR-103a-3p and hsa-miR-107) in saliva from ten participants at four sampling points. Interestingly, we firstly noted that although no significant difference among the average concentrations of the extracted small RNA was observed throughout the four samplings of the study (Figure S1), upon standardization to 50 ng, a significant fluctuation of miRNA detection signal across time was obtained (Figure 2B).…”

“…Altogether, this makes the quantification of salivary biomarkers highly challenging, requiring exceedingly robust assays [3]. Nevertheless, the concentration levels of salivary biomarkers of different natures including DNA, miRNA, RNA, protein and metabolite have been identified to be associated to a broad range of diseases [4][5][6][7] via numerous clinical studies, demonstrating the significant clinical interest of precisely quantifying these biomarkers.…”

“…The relationships of their regulation with the disease onsets [8,9] and their presence in the extracellular circulation [11][12][13] make them available for various liquid biopsies enabling non-invasive medical assessment [14,15]. For instance, signatures of salivary miRNAs have been recently associated with the diagnosis of mild traumatic brain injury (mTBI) [6,[16][17][18], cancers [12,19,20] , endometriosis [21,22], neurodegenerative [23], metabolic [24] or systemic diseases [7] along with many others [25][26][27][28][29]. However, due to their small size (19-25 nucleotides), their high sequence similarity and their complex gene regulation process [10], the correlation between their expression levels and disease stages is often non-linear, causing it an issue of constant debate [8,15,30].…”

“…Different classes of salivary biomarkers (DNA, RNA, proteins and metabolites) have been identified via numerous clinical studies across a broad range of diseases 9,10,11 , demonstrating its potential for early detection of diseases 1 . In particular, human microRNA (miRNA) have emerged as an attractive biomarker due to its involvement in RNA silencing and post-transcriptional regulation of gene expression, hence associating their dysregulation with diverse diseases, 3 and their extracellular circulation for cell-cell communication.…”