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

Within the neurovascular unit (NVU), the blood–brain barrier (BBB) operates as a key cerebrovascular interface, dynamically insulating the brain parenchyma from peripheral blood and compartments. Increased BBB permeability is clinically relevant for at least two reasons: it actively participates to the etiology of central nervous system (CNS) diseases, and it enables the diagnosis of neurological disorders based on the detection of CNS molecules in peripheral body fluids. In pathological conditions, a suite of glial, neuronal, and pericyte biomarkers can exit the brain reaching the peripheral blood and, after a process of filtration, may also appear in saliva or urine according to varying temporal trajectories. Here, we specifically examine the evidence in favor of or against the use of protein biomarkers of NVU damage and BBB permeability in traumatic head injury, including sport (sub)concussive impacts, seizure disorders, and neurodegenerative processes such as Alzheimer's disease. We further extend this analysis by focusing on the correlates of human extreme physiology applied to the NVU and its biomarkers. To this end, we report NVU changes after prolonged exercise, freediving, and gravitational stress, focusing on the presence of peripheral biomarkers in these conditions. The development of a biomarker toolkit will enable minimally invasive routines for the assessment of brain health in a broad spectrum of clinical, emergency, and sport settings.