Urinary p75ECD A prognostic, disease progression, and pharmacodynamic biomarker in ALS

ABSTRACT

Objective: To evaluate urinary neurotrophin receptor p75 extracellular domain (p75^ECD) levels as disease progression and prognostic biomarkers in amyotrophic lateral sclerosis (ALS).

Methods: The population in this study comprised 45 healthy controls and 54 people with ALS, 31 of whom were sampled longitudinally. Urinary p75^ECD was measured using an enzyme-linked immunoassay and validation included intra-assay and inter-assay coefficients of variation, effect of circadian rhythm, and stability over time at room temperature, 4°C, and repeated freeze-thaw cycles. Longitudinal changes in urinary p75^ECD were examined by mixed model analysis, and the prognostic value of baseline p75^ECD was explored by survival analysis.

Results: Confirming our previous findings, p75^ECD was higher in patients with ALS (5.6 ± 2.2 ng/mg creatinine) compared to controls (3.6 ± 1.4 ng/mg creatinine, p < 0.0001). Assay reproducibility was high, with p75^ECD showing stability across repeated freeze-thaw cycles, at room temperature and 4°C for 2 days, and no diurnal variation. Urinary p75^ECD correlated with the revised ALS Functional Rating Scale at first evaluation (r = −0.44, p = 0.008) and across all study visits (r = −0.36, p < 0.0001). p75^ECD also increased as disease progressed at an average rate of 0.19 ng/mg creatinine per month (p < 0.0001). In multivariate prognostic analysis, bulbar onset (hazard ratio [HR] 3.0, p = 0.0035), rate of disease progression from onset to baseline (HR 4.4, p < 0.0001), and baseline p75^ECD (HR 1.3, p= 0.0004) were predictors of survival.

Conclusions: The assay for urinary p75^ECD is analytically robust and shows promise as an ALS biomarker with prognostic, disease progression, and potential pharmacodynamic application. Baseline urinary p75^ECD provides prognostic information and is currently the only biological fluid–based biomarker of disease progression.

Neurology 2017