Post-acute Brain Injury Urinary Signature: A New Resource for Molecular Diagnostics

Heterogeneity within brain injury presents a challenge to the development of informative molecular diagnostics. Recent studies show progress particularly in cerebrospinal fluid with biomarker assays targeting one or a few structural proteins. Protein-based assays in peripheral fluids, however, have been more challenging to develop in part due to restricted and intermittent barrier access. Further, a greater number of molecular variables may be required to inform on patient status given the multifactorial nature of brain injury. Presented is an alternative approach profiling peripheral fluid for a class of small metabolic by-products rendered by ongoing brain pathobiology. Urine specimens were collected for head trauma subjects upon admission to acute brain injury rehabilitation and nontraumatized matched controls. An innovative data-independent mass spectrometry approach was employed for reproducible molecular quantification across osmolarity-normalized samples. The postacute human traumatic brain injury urinary signature encompassed 2,476 discriminant variables reproducibly measured in specimens for subject classification. Multiple sub-profiles were then discerned in correlation with injury severity per Glasgow Comma Scale and behavioral and neurocognitive function per Patient Competency Rating Scale and Frontal Systems Behavioral Scale. Identified peptide constituents were enriched for outgrowth and guidance, extracellular matrix and post-synaptic density proteins, which were reflective of ongoing post-acute neuroplastic processes demonstrating pathobiological relevance. Taken together, these findings support further development of diagnostics based on brain injury urinary signatures using either combinatorial quantitative models or patternrecognition methods. Particularly, these findings espouse assay development to address unmet diagnostic and theragnostic needs in brain injury rehabilitative medicine

Microglial priming through the lung-brain axis: the role of air pollution-induced circulating factors

Air pollution is implicated in neurodegenerative disease risk and progression and in microglial activation, but the mechanisms are unknown. In this study, microglia remained activated 24 h after ozone (O3) exposure in rats, suggesting a persistent signal from lung to brain. Ex vivo analysis of serum from O3-treated rats revealed an augmented microglial proinflammatory response and β-amyloid 42 (Aβ42) neurotoxicity independent of traditional circulating cytokines, where macrophage-1 antigen-mediated microglia proinflammatory priming. Aged mice exhibited reduced pulmonary immune profiles and the most pronounced neuroinflammation and microglial activation in response to mixed vehicle emissions. Consistent with this premise, cluster of differentiation 36 (CD36)(-/-) mice exhibited impaired pulmonary immune responses concurrent with augmented neuroinflammation and microglial activation in response to O3 Further, aging glia were more sensitive to the proinflammatory effects of O3 serum. Together, these findings outline the lung-brain axis, where air pollutant exposures result in circulating, cytokine-independent signals present in serum that elevate the brain proinflammatory milieu, which is linked to the pulmonary response and is further augmented with age