Plasma brain-derived tau: analytical and clinical validation of the first commercial immunoassay

BackgroundBrain-derived tau (BD-tau) is a promising blood-based biomarker for neurodegeneration/brain injury in neurodegenerative and acute neurological disorders. However, widespread use is hampered by lack of commercial assays. MethodsUsing the Simoa(R) HD-X analyzer, we evaluated the first commercial research-use only BD-tau Advantage PLUS assays robustness, precision, dilution linearity, spike recovery, specificity, and limits of detection. Matrix effect was examined by comparing BD-tau levels in n=48 plasma/serum and n=20 plasma/CSF sample pairs. Clinical performance was examined in a traumatic brain injury (TBI) cohort. ResultsTwenty repeated measurements of three plasma samples gave intra- and inter-plate CVs [&le;]7.24%. A median drift of 8.00% (decrease) was observed from the start to the end of a full plate run. Analytically, BD-tau concentrations decreased linearly up to 16-fold dilution, spike recovery was 86-96%, and signals were highly specific to the CNS-abundant tau441 but not the peripherally-enriched "big-tau" isoform. Moreover, signals were stable for up to four freeze/thaw cycles. Furthermore, significant correlations were observed in the plasma/serum (r=0.8392; p<0.0001) and plasma/CSF (r=0.6150; p=0.0039) pairs. Finally, plasma BD-tau was elevated in severe-acute TBI vs. chronic-mixed TBI and unaffected controls (p<0.0001; AUC=0.9986, and p<0.0001; AUC=1.000, respectively). In severe-acute TBI patients, plasma BD-tau was correlated with plasma p-tau217 (r=0.5761, p=0.0005), NfL (r=0.8910, p=0.0001), and GFAP (r=0.5424, p=0.0011). CSF BD-tau and CSF p-tau217 were strongly correlated (r=0.9667, p=0.0002). ConclusionBD-tau Advantage PLUS produces robust brain-derived tau-specific readings that demonstrate utility in detecting severe-acute TBI.