Hiroshi Mitsumoto1, Diana C Garofalo2, Regina M Santella3, Eric J Sorenson4, Björn Oskarsson5, J Americo M Fernandes6, Howard Andrews7, Jonathan Hupf1, Madison Gilmore1, Daragh Heitzman8, Richard S Bedlack9, Jonathan S Katz10, Richard J Barohn11, Edward J Kasarskis12, Catherine Lomen-Hoerth13, Tahseen Mozaffar14, Sharon P Nations15, Andrea J Swenson16, Pam Factor-Litvak2. 1. Department of Neurology, Eleanor and Lou Gehrig ALS Center, Columbia University Irving Medical Center, New York, NY, USA. 2. Department of Epidemiology, Mailman School of Public Health, Columbia University Irving Medical Center, New York, NY, USA. 3. Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University Medical Center, New York, NY, USA. 4. Department of Neurology, Mayo Clinic, Rochester, MN, USA. 5. Department of Neurology, Mayo Clinic, Jacksonville, FL, USA. 6. Department of Neurological Sciences, University of Nebraska Medical Center, Omaha, NE, USA. 7. Data Coordinating Center (DCC), Mailman School of Public Health Biostatistics Department, Columbia University Irving Medical Center, New York State Psychiatric Institute & Department of Psychiatry, Columbia University. 8. Texas Neurology, PA, Dallas, TX, USA. 9. Department of Neurology, Duke University, Durham, NC, USA. 10. Forbes Norris ALS Center, California Pacific Medical Center, San Francisco, CA, USA. 11. Department of Neurology, University of Kansas, San Francisco, CA, USA. 12. Department of Neurology, University of Kentucky, San Francisco, CA, USA. 13. Department of Neurology, University of California, San Francisco, CA, USA. 14. Department of Neurology, University of California, Irvine, CA, USA. 15. Department of Neurology and Neurotherapeutics, University of Texas Southwestern, Dallas, TX, USA, and. 16. Department of Neurology, University of Iowa, Iowa City, IA, USA.
Abstract
Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355). Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival. Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = -0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time.Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.
Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355). Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival. Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = -0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time.Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.
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