Peripheral Blood and Salivary Biomarkers of Blood–Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts

Janigro, Damir; Bailey, Damian Miles; Lehmann, Sylvain; Badaut, Jérôme; O’flynn, Robin; Hirtz, Christophe; Marchi, Nicola

doi:10.3389/fneur.2020.577312

Cited by 41 publications

(51 citation statements)

References 246 publications

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“…Biomarkers in traumatic brain injury may be sampled from blood, cerebrospinal fluid, brain interstitial fluid collected during brain microdialysis and most recently, saliva. Preliminary studies have shown that there is a correlation between salivary and serum S100B (14,15). The greatest contribution to the peripheral signal most likely comes from those brain cell biomarkers derived from the brain interstitial fluid and cerebrospinal fluid.…”

Section: Biomarkersmentioning

confidence: 99%

“…Traumatic brain injury is the commonest cause of death and disability amongst children greater than one year of age (1) and continues to present complex management and prediction challenges for the clinician. Traumatic brain injury is commonly classified into mild [Glasgow Coma Score (GCS) [13][14][15], moderate (GCS 9-12) or severe (GCS 3-8) based on the GCS. TBI should not be viewed as a single pathophysiological event, but a cascade that involves two separate injury phases, primary and secondary (2).…”

Section: Introductionmentioning

confidence: 99%

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Serum biomarkers in severe paediatric traumatic brain injury—a narrative review

Ganeshalingham¹,

Beca²

2021

Transl Pediatr

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Severe traumatic brain injury continues to present complex management and prediction challenges for the clinician. While there is some evidence that better systems of care can improve outcome, multiple multi-centre randomised controlled trials of specific therapies have consistently failed to show benefit. In addition, clinicians are challenged in attempting to accurately predict which children will recover well and which children will have severe and persisting neurocognitive deficits. Traumatic brain injury is vastly heterogeneous and so it is not surprising that one therapy or approach, when applied to a mixed cohort of children in a clinical trial setting, has yielded disappointing results. Children with severe traumatic brain injury have vastly different brain injury pathologies of widely varying severity, in any number of anatomical locations at what may be disparate stages of brain development. This heterogeneity may also explain why clinicians are unable to accurately predict outcome. Biomarkers are objective molecular signatures of injury that are released following traumatic brain injury and may represent a way of unifying the heterogeneity of traumatic brain injury into a single biosignature. Biomarkers hold promise to diagnose brain injury severity, guide intervention selection for clinical trials, or provide vital prognostic information so that early intervention and rehabilitation can be planned much earlier in the course of a child's recovery. Serum S100B and serum NSE levels show promise as a diagnostic tool with biomarker levels significantly higher in children with severe TBI including children with inflicted and non-inflicted head injury. Serum S100B and serum NSE also show promise as a predictor of neurodevelopmental outcome. The role of biomarkers in traumatic brain injury is an evolving field with the potential for clinical application within the next few years.

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Section: Biomarkersmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Serum biomarkers in severe paediatric traumatic brain injury—a narrative review

Ganeshalingham¹,

Beca²

2021

Transl Pediatr

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“…Other studies have shown that S100B is increased by exercise alone (13,25,26), while others found no effect of strenuous exercise on S100B levels (27)(28)(29)(30)). An explanation of these contrasting ndings points to BBB damage induced by extreme exercise (31). According to this hypothesis, strenuous exercise or performance in extreme sports results in BBB "opening," possibly due to a mechanism involving free radical formation, as suggested by ref.…”

Section: Introductionmentioning

confidence: 97%

“…(32). In any case, it is not known how different sources of S100B contribute to the peripheral signal in blood (or saliva) (26,31,33,34). Lastly, a common motif in S100B diagnostics is that S100B is not speci c for any neurological disease (2).…”

Section: Introductionmentioning

confidence: 99%

Diagnostic Pharmacokinetics: how brain-derived biomarkers distribute through the human body, and how this affects their diagnostic significance - the case of S100B

Murcko¹,

Marchi

Bailey

et al. 2022

Preprint

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Blood biomarkers of neurological diseases are often employed to rule out or confirm the presence of significant intracranial or cerebrovascular pathology or for the differential diagnosis of conditions with similar presentations (e.g., hemorrhagic vs. embolic stroke). More widespread utilization of biomarkers related to brain health is hampered by our incomplete understanding of the kinetic properties, release patterns, and excretion of molecules derived from the brain. This is, in particular, true for S100B, an astrocyte-derived protein released across the blood-brain barrier (BBB). We developed an open-source pharmacokinetic computer model that allows investigations of a biomarker’s movement across the body, the sources of a biomarker’s release, and its elimination. This model was derived from a general in silico model of drug pharmacokinetics adapted for protein biomarkers. We improved the model's predictive value by adding realistic blood flow values, organ levels of S100B, lymphatic and glymphatic circulation, and glomerular filtration for excretion in urine. Three key variables control biomarker levels in blood or saliva: blood-brain barrier permeability, the S100B partition into peripheral organs, and the cellular levels of S100B in astrocytes. A small contribution to steady-state levels of glymphatic drainage was also observed; this mechanism contributed to the uptake of organs of circulating S100B. Additionally, this open-source model can also mimic the kinetic behavior of other markers, such as GFAP or NF-L. Our results show that S100B, after uptake by various organs from the systemic circulation, can be released back into systemic fluids at levels that do not significantly affect the clinical significance of venous blood or salivary levels after an episode of BBB disruption.

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“…Generally, fluids [8], such as blood [9], saliva [9], urine [10], and cerebrospinal fluid (CSF) [11] and brain imaging techniques, such as structural MRI [12] and PET [13] have been used to establish a disease diagnosis and predict disease outcomes. Although CSF analysis is key in AD diagnosis, the moderately invasive nature of CSF collection limits its widespread use in routine primary clinical care practice, as the procedure is rarely performed by general practitioners [14].…”

Section: Introductionmentioning

confidence: 99%

Brain-Derived Exosomal Proteins as Effective Biomarkers for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

2021

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Alzheimer’s disease (AD), a progressive neurodegenerative disease, affects approximately 50 million people worldwide, which warrants the search for reliable new biomarkers for early diagnosis of AD. Brain-derived exosomal (BDE) proteins, which are extracellular nanovesicles released by all cell lineages of the central nervous system, have been focused as biomarkers for diagnosis, screening, prognosis prediction, and monitoring in AD. This review focused on the possibility of BDE proteins as AD biomarkers. The articles published prior to 26 January 2021 were searched in PubMed, EMBASE, Web of Science, and Cochrane Library to identify all relevant studies that reported exosome biomarkers in blood samples of patients with AD. From 342 articles, 20 studies were selected for analysis. We conducted a meta-analysis of six BDE proteins and found that levels of amyloid-β42 (standardized mean difference (SMD) = 1.534, 95% confidence interval [CI]: 0.595–2.474), total-tau (SMD = 1.224, 95% CI: 0.534–1.915), tau phosphorylated at threonine 181 (SMD = 4.038, 95% CI: 2.312-5.764), and tau phosphorylated at serine 396 (SMD = 2.511, 95% CI: 0.795–4.227) were significantly different in patients with AD compared to those in control. Whereas, those of p-tyrosine-insulin receptor substrate-1 and heat shock protein 70 did not show significant differences. This review suggested that Aβ42, t-tau, p-T181-tau, and p-S396-tau could be effective in diagnosing AD as blood biomarkers, despite the limitation in the meta-analysis based on the availability of data. Therefore, certain BDE proteins could be used as effective biomarkers for AD.

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Peripheral Blood and Salivary Biomarkers of Blood–Brain Barrier Permeability and Neuronal Damage: Clinical and Applied Concepts

Cited by 41 publications

References 246 publications

Serum biomarkers in severe paediatric traumatic brain injury—a narrative review

Serum biomarkers in severe paediatric traumatic brain injury—a narrative review

Diagnostic Pharmacokinetics: how brain-derived biomarkers distribute through the human body, and how this affects their diagnostic significance - the case of S100B

Brain-Derived Exosomal Proteins as Effective Biomarkers for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

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