From Brain to Blood to Skin: Compartment Biology, Interstitial Fluid Dynamics, and Microneedle Sampling of Neurological Biomarkers

Proteins released after brain injury can be measured in blood, but a blood result does not directly measure the concentration at the site of injury. Between brain tissue and a peripheral sample, proteins may enter brain interstitial fluid (ISF), exchange with cerebrospinal fluid (CSF), leave through several drainage or barrier pathways, and undergo dilution and clearance. This narrative review examines those steps for glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase-L1 (UCH-L1), neurofilament light chain (NfL), S100B, neuron-specific enolase (NSE), tau proteoforms, and amyloid-beta. It also evaluates whether microneedle sampling of dermal ISF (dISF) could support repeated, low-burden measurement. The evidence indicates that gradients and time lags differ by analyte; a single blood-to-skin conversion is unlikely to work. Human dISF studies demonstrate broad molecular overlap with plasma, including similar N-glycan profiles despite lower total protein, and a human aptamer-patch trial demonstrates frequent drug monitoring. These findings do not yet validate a neurological protein assay in skin: no paired clinical study has established quantitative dISF concordance for GFAP, UCH-L1, NfL, tau, or amyloid-beta. The immediate priorities are analyte-specific recovery testing, paired blood–dISF time courses, paired CSF measurements where clinically feasible, and careful accounting for local skin and device effects.