title: Urinary p75ECD: A prognostic, disease progression, and pharmacodynamic biomarker in ALS.
abstract: OBJECTIVE
  To evaluate urinary neurotrophin receptor p75 extracellular domain (p75ECD) 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 p75ECDwas 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 p75ECDwere examined by mixed model analysis, and the prognostic value of baseline p75ECDwas explored by survival analysis.
  
  
  RESULTS
  Confirming our previous findings, p75ECDwas 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 p75ECDshowing stability across repeated freeze-thaw cycles, at room temperature and 4°C for 2 days, and no diurnal variation. Urinary p75ECDcorrelated 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). p75ECDalso 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 p75ECD(HR 1.3,p= 0.0004) were predictors of survival.
  
  
  CONCLUSIONS
  The assay for urinary p75ECDis analytically robust and shows promise as an ALS biomarker with prognostic, disease progression, and potential pharmacodynamic application. Baseline urinary p75ECDprovides prognostic information and is currently the only biological fluid-based biomarker of disease progression.
authors.affiliation: From the Department of Human Physiology & Centre for Neuroscience (S.R.S., L.W., T.C., M.-L.R.), Department of Gastroenterology and Surgery, Flinders Medical Centre (P.G.D.), and Department of Human Physiology, Centre for Neuroscience (P.G.D.), Flinders University, Adelaide, South Australia; Department of Neurology (J.W., M.B.), Miller School of Medicine, University of Miami, FL; and Neurology Department and MND Clinic (D.S.), Flinders Medical Centre, Bedford Park, South Australia.
authors.forename: Stephanie R
authors.initials: SR
authors.lastname: Shepheard
authors.affiliation: From the Department of Human Physiology & Centre for Neuroscience (S.R.S., L.W., T.C., M.-L.R.), Department of Gastroenterology and Surgery, Flinders Medical Centre (P.G.D.), and Department of Human Physiology, Centre for Neuroscience (P.G.D.), Flinders University, Adelaide, South Australia; Department of Neurology (J.W., M.B.), Miller School of Medicine, University of Miami, FL; and Neurology Department and MND Clinic (D.S.), Flinders Medical Centre, Bedford Park, South Australia.
authors.forename: Joanne
authors.initials: J
authors.lastname: Wuu
authors.affiliation: From the Department of Human Physiology & Centre for Neuroscience (S.R.S., L.W., T.C., M.-L.R.), Department of Gastroenterology and Surgery, Flinders Medical Centre (P.G.D.), and Department of Human Physiology, Centre for Neuroscience (P.G.D.), Flinders University, Adelaide, South Australia; Department of Neurology (J.W., M.B.), Miller School of Medicine, University of Miami, FL; and Neurology Department and MND Clinic (D.S.), Flinders Medical Centre, Bedford Park, South Australia.
authors.forename: Michell
authors.initials: M
authors.lastname: Cardoso
authors.affiliation: From the Department of Human Physiology & Centre for Neuroscience (S.R.S., L.W., T.C., M.-L.R.), Department of Gastroenterology and Surgery, Flinders Medical Centre (P.G.D.), and Department of Human Physiology, Centre for Neuroscience (P.G.D.), Flinders University, Adelaide, South Australia; Department of Neurology (J.W., M.B.), Miller School of Medicine, University of Miami, FL; and Neurology Department and MND Clinic (D.S.), Flinders Medical Centre, Bedford Park, South Australia.
authors.forename: Luke
authors.initials: L
authors.lastname: Wiklendt
authors.affiliation: From the Department of Human Physiology & Centre for Neuroscience (S.R.S., L.W., T.C., M.-L.R.), Department of Gastroenterology and Surgery, Flinders Medical Centre (P.G.D.), and Department of Human Physiology, Centre for Neuroscience (P.G.D.), Flinders University, Adelaide, South Australia; Department of Neurology (J.W., M.B.), Miller School of Medicine, University of Miami, FL; and Neurology Department and MND Clinic (D.S.), Flinders Medical Centre, Bedford Park, South Australia.
authors.forename: Phil G
authors.initials: PG
authors.lastname: Dinning
authors.affiliation: From the Department of Human Physiology & Centre for Neuroscience (S.R.S., L.W., T.C., M.-L.R.), Department of Gastroenterology and Surgery, Flinders Medical Centre (P.G.D.), and Department of Human Physiology, Centre for Neuroscience (P.G.D.), Flinders University, Adelaide, South Australia; Department of Neurology (J.W., M.B.), Miller School of Medicine, University of Miami, FL; and Neurology Department and MND Clinic (D.S.), Flinders Medical Centre, Bedford Park, South Australia.
authors.forename: Tim
authors.initials: T
authors.lastname: Chataway
authors.affiliation: From the Department of Human Physiology & Centre for Neuroscience (S.R.S., L.W., T.C., M.-L.R.), Department of Gastroenterology and Surgery, Flinders Medical Centre (P.G.D.), and Department of Human Physiology, Centre for Neuroscience (P.G.D.), Flinders University, Adelaide, South Australia; Department of Neurology (J.W., M.B.), Miller School of Medicine, University of Miami, FL; and Neurology Department and MND Clinic (D.S.), Flinders Medical Centre, Bedford Park, South Australia.
authors.forename: David
authors.initials: D
authors.lastname: Schultz
authors.affiliation: From the Department of Human Physiology & Centre for Neuroscience (S.R.S., L.W., T.C., M.-L.R.), Department of Gastroenterology and Surgery, Flinders Medical Centre (P.G.D.), and Department of Human Physiology, Centre for Neuroscience (P.G.D.), Flinders University, Adelaide, South Australia; Department of Neurology (J.W., M.B.), Miller School of Medicine, University of Miami, FL; and Neurology Department and MND Clinic (D.S.), Flinders Medical Centre, Bedford Park, South Australia. Mary-louise.rogers@flinders.edu.au mbenatar@miami.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Benatar
authors.affiliation: From the Department of Human Physiology & Centre for Neuroscience (S.R.S., L.W., T.C., M.-L.R.), Department of Gastroenterology and Surgery, Flinders Medical Centre (P.G.D.), and Department of Human Physiology, Centre for Neuroscience (P.G.D.), Flinders University, Adelaide, South Australia; Department of Neurology (J.W., M.B.), Miller School of Medicine, University of Miami, FL; and Neurology Department and MND Clinic (D.S.), Flinders Medical Centre, Bedford Park, South Australia. Mary-louise.rogers@flinders.edu.au mbenatar@miami.edu.
authors.forename: Mary-Louise
authors.initials: ML
authors.lastname: Rogers
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000175:diagnosis / Q000503:physiopathology / Q000652:urine; D015415:Biomarkers / Q000652:urine*; D015331:Cohort Studies; D003404:Creatinine / Q000378:metabolism; D018450:Disease Progression; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000652:urine*; D016016:Proportional Hazards Models; D017475:Receptors, Nerve Growth Factor; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers; C484065:NGFR protein, human; D009419:Nerve Tissue Proteins; D017475:Receptors, Nerve Growth Factor; D003404:Creatinine