Adriano Chiò1, Andrea Calvo2, Giacomo Bovio3, Antonio Canosa4, Davide Bertuzzo4, Francesco Galmozzi4, Paolo Cugnasco4, Marinella Clerico5, Stefania De Mercanti5, Enrica Bersano6, Stefania Cammarosano4, Antonio Ilardi4, Umberto Manera4, Cristina Moglia4, Riccardo Sideri7, Kalliopi Marinou7, Edo Bottacchi8, Fabrizio Pisano9, Roberto Cantello10, Letizia Mazzini6, Gabriele Mora7. 1. Amyotrophic Lateral Sclerosis Center, Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy2Città della Salute e della Scienza, Azienda Ospedaliero Universitaria, Turin, Italy3Neuroscience Institute of Torino, Turin, Italy. 2. Amyotrophic Lateral Sclerosis Center, Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy2Città della Salute e della Scienza, Azienda Ospedaliero Universitaria, Turin, Italy. 3. Salvatore Maugeri Foundation, Istituto Di Ricovero e Cura a Carattere Scientifico, Scientific Institute of Pavia, Pavia, Italy. 4. Amyotrophic Lateral Sclerosis Center, Rita Levi Montalcini Department of Neuroscience, University of Turin, Turin, Italy. 5. Department of Biological and Clinical Science, Azienda Ospedaliero Universitaria San Luigi Gonzaga, University of Turin, Orbassano, Italy. 6. Amyotrophic Lateral Sclerosis Center, Department of Neurology, Azienda Ospedaliero Universitaria Maggiore di Novara, Novara, Italy. 7. Salvatore Maugeri Foundation, Istituto Di Ricovero e Cura a Carattere Scientifico, Scientific Institute of Milano, Milano, Italy. 8. Department of Neurology, Azienda Ospedaliera Regionale di Aosta, Azienda Unità Sanitaria Locale Valle d'Aosta, Aosta, Italy. 9. Salvatore Maugeri Foundation, Istituto Di Ricovero e Cura a Carattere Scientifico, Scientific Institute of Veruno, Pavia, Italy. 10. Eastern Piedmont University, Department of Neurology, Novara, Italy.
Abstract
IMPORTANCE: There is an urgent need to identify reliable biomarkers of amyotrophic lateral sclerosis (ALS) progression for clinical practice and pharmacological trials. OBJECTIVES: To correlate several hematological markers evaluated at diagnosis with ALS outcome in a population-based series of patients (discovery cohort) and replicate the findings in an independent validation cohort from an ALS tertiary center. DESIGN, SETTING, AND PARTICIPANTS: The discovery cohort included 712 patients with ALS from the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis from January 1, 2007, to December 31, 2011. The validation cohort comprised 122 patients with ALS at different stages of disease consecutively seen at an ALS tertiary center between January 1, 2007, and January 1, 2009. MAIN OUTCOMES AND MEASURES: The following hematological factors were investigated and correlated with survival: total leukocytes, neutrophils, lymphocytes, monocytes, glucose, creatinine, uric acid, albumin, bilirubin, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, creatine kinase, thyroid-stimulating hormones, and erythrocyte sedimentation rate; all analyses were performed separately by sex. The patient of the validation cohort also underwent bioelectrical impedance analysis for the calculation of fat-free mass. RESULT: Of the 712 patients in the examined period in Piemonte and Valle d'Aosta, 638 (89.6%) were included in the study. Only serum albumin (men: ≤ 4.3 vs >4.3 mg/dL, P < .001; women: ≤ 4.3 vs >4.3 mg/dL, P < .001) and creatinine levels (men: ≤ 0.82 vs >0.82 mg/dL, P = .004; women: ≤ 0.65 vs >0.05 mg/dL, P = .004) and lymphocyte count (men: ≤ 1700 vs >1700/μL, P = .04; women: ≤ 1700 vs >1700/μL, P = .02) were significantly associated with ALS outcome in both sexes with a dose-response effect (better survival with increasing levels). These findings were confirmed in the validation cohort. Multivariable analysis showed that serum albumin (men: hazard ratio [HR], 1.39; 95% CI, 1.05-1.90; P = .02; women: HR, 1.73; 95 % CI, 1.35-2.39; P = .001) and creatinine (men: HR, 1.47; 95% CI, 1.11-1.95; P = .007; women: HR, 1.49; 95% CI, 1.07-2.05; P = .02) were independent predictors of survival in both sexes; no other hematological factor was retained in the model. In patients with ALS, serum albumin was correlated with markers of inflammatory state while serum creatinine was correlated with fat-free mass, which is a marker of muscle mass. CONCLUSIONS AND RELEVANCE: In ALS, serum albumin and creatinine are independent markers of outcome in both sexes. Creatinine reflects the muscle waste whereas albumin is connected with inflammatory state. Both creatinine and albumin are reliable markers of the severity of clinical status in patients with ALS and can be used in defining prognosis at the time of diagnosis.
IMPORTANCE: There is an urgent need to identify reliable biomarkers of amyotrophic lateral sclerosis (ALS) progression for clinical practice and pharmacological trials. OBJECTIVES: To correlate several hematological markers evaluated at diagnosis with ALS outcome in a population-based series of patients (discovery cohort) and replicate the findings in an independent validation cohort from an ALS tertiary center. DESIGN, SETTING, AND PARTICIPANTS: The discovery cohort included 712 patients with ALS from the Piemonte and Valle d'Aosta Register for Amyotrophic Lateral Sclerosis from January 1, 2007, to December 31, 2011. The validation cohort comprised 122 patients with ALS at different stages of disease consecutively seen at an ALS tertiary center between January 1, 2007, and January 1, 2009. MAIN OUTCOMES AND MEASURES: The following hematological factors were investigated and correlated with survival: total leukocytes, neutrophils, lymphocytes, monocytes, glucose, creatinine, uric acid, albumin, bilirubin, total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, creatine kinase, thyroid-stimulating hormones, and erythrocyte sedimentation rate; all analyses were performed separately by sex. The patient of the validation cohort also underwent bioelectrical impedance analysis for the calculation of fat-free mass. RESULT: Of the 712 patients in the examined period in Piemonte and Valle d'Aosta, 638 (89.6%) were included in the study. Only serum albumin (men: ≤ 4.3 vs >4.3 mg/dL, P < .001; women: ≤ 4.3 vs >4.3 mg/dL, P < .001) and creatinine levels (men: ≤ 0.82 vs >0.82 mg/dL, P = .004; women: ≤ 0.65 vs >0.05 mg/dL, P = .004) and lymphocyte count (men: ≤ 1700 vs >1700/μL, P = .04; women: ≤ 1700 vs >1700/μL, P = .02) were significantly associated with ALS outcome in both sexes with a dose-response effect (better survival with increasing levels). These findings were confirmed in the validation cohort. Multivariable analysis showed that serum albumin (men: hazard ratio [HR], 1.39; 95% CI, 1.05-1.90; P = .02; women: HR, 1.73; 95 % CI, 1.35-2.39; P = .001) and creatinine (men: HR, 1.47; 95% CI, 1.11-1.95; P = .007; women: HR, 1.49; 95% CI, 1.07-2.05; P = .02) were independent predictors of survival in both sexes; no other hematological factor was retained in the model. In patients with ALS, serum albumin was correlated with markers of inflammatory state while serum creatinine was correlated with fat-free mass, which is a marker of muscle mass. CONCLUSIONS AND RELEVANCE: In ALS, serum albumin and creatinine are independent markers of outcome in both sexes. Creatinine reflects the muscle waste whereas albumin is connected with inflammatory state. Both creatinine and albumin are reliable markers of the severity of clinical status in patients with ALS and can be used in defining prognosis at the time of diagnosis.
Authors: Hiroshi Mitsumoto; Diana C Garofalo; Regina M Santella; Eric J Sorenson; Björn Oskarsson; J Americo M Fernandes; Howard Andrews; Jonathan Hupf; Madison Gilmore; Daragh Heitzman; Richard S Bedlack; Jonathan S Katz; Richard J Barohn; Edward J Kasarskis; Catherine Lomen-Hoerth; Tahseen Mozaffar; Sharon P Nations; Andrea J Swenson; Pam Factor-Litvak Journal: Amyotroph Lateral Scler Frontotemporal Degener Date: 2020-04-10 Impact factor: 4.092
Authors: Catherine Jutzeler; John L K Kramer; Anh K Vo; Fred Geisler; Lukas Grassner; Jan Schwab; Gale Whiteneck Journal: Spinal Cord Date: 2020-08-24 Impact factor: 2.772
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