Adriano Chiò1, Maura Brunetti2, Marco Barberis2, Barbara Iazzolino2, Anna Montuschi2, Antonio Ilardi2, Stefania Cammarosano2, Antonio Canosa2, Cristina Moglia2, Andrea Calvo3. 1. ALS Center, "Rita Levi Montalcini" Department of Neuroscience, University of Torino, Torino, Italy2The Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy3The Neuroscience Institute of Torino, Torino, Italy4The In. 2. ALS Center, "Rita Levi Montalcini" Department of Neuroscience, University of Torino, Torino, Italy. 3. ALS Center, "Rita Levi Montalcini" Department of Neuroscience, University of Torino, Torino, Italy2The Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Torino, Italy3The Neuroscience Institute of Torino, Torino, Italy.
Abstract
IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with a wide spectrum of involvement of cognitive functions. The mechanisms of this heterogeneity are still largely unknown, but genetic variants may account for this variability. OBJECTIVE: To assess the influence of the apolipoprotein E (APOE) and C9ORF72 genotypes on cognitive impairment in a population-based series of Italian patients with ALS. DESIGN, SETTING, AND PARTICIPANTS: All 504 patients with ALS living in Piemonte, Italy, diagnosed between January 1, 2009, and December 31, 2013, and identified through the Piemonte and Valle d'Aosta register for ALS, were eligible to participate in the study. Controls were 223 age- and sex-matched individuals identified through the patients' general practitioners. Data analysis was performed from June 1 to December 31, 2014. MAIN OUTCOMES AND MEASURES: The presence of APOE and C9ORF72 genotypes was assessed. Patients were cognitively classified as having ALS with normal cognition, ALS with frontotemporal dementia (FTD), ALS with executive or nonexecutive impairment, and ALS with behavioral impairment. RESULTS: Of the 504 patients with incident ALS, 357 (70.8%) were included in the study; 154 were women, 203 were men, they had a mean (SD) age at onset of 64.8 (10.2) years, and 37 of them carried a C9ORF72 repeat expansion. Cognitive testing revealed that 184 patients (51.5%) had ALS with normal cognition, 51 (14.3%) had ALS with FTD, 103 (28.9%) had ALS with executive or nonexecutive impairment, and 19 (5.3%) had ALS with behavioral impairment. Distribution of APOE haplotypes did not significantly differ between patients and controls or among patients with different levels of cognitive impairment. According to multivariate logistic regression, the presence of C9ORF72 repeat expansions was the strongest determinant of FTD (odds ratio, 13.08; 95% CI, 4.75-36.02; P < .001); however, the presence of an APOE ε2 allele significantly increased the risk of FTD (odds ratio, 2.61; 95% CI, 1.14-6.10; P = .03). Presence of an APOE ε4 allele was ineffectual. CONCLUSIONS AND RELEVANCE: C9ORF72 repeat expansions have a primary role in increasing the risk of cognitive impairment in patients with ALS; the APOE ε2 allele, to a lesser extent, also increases the risk of FTD. These study findings highlight the importance of considering the genetic background of patients with ALS when analyzing the putative effect of genetic modifiers.
IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with a wide spectrum of involvement of cognitive functions. The mechanisms of this heterogeneity are still largely unknown, but genetic variants may account for this variability. OBJECTIVE: To assess the influence of the apolipoprotein E (APOE) and C9ORF72 genotypes on cognitive impairment in a population-based series of Italian patients with ALS. DESIGN, SETTING, AND PARTICIPANTS: All 504 patients with ALS living in Piemonte, Italy, diagnosed between January 1, 2009, and December 31, 2013, and identified through the Piemonte and Valle d'Aosta register for ALS, were eligible to participate in the study. Controls were 223 age- and sex-matched individuals identified through the patients' general practitioners. Data analysis was performed from June 1 to December 31, 2014. MAIN OUTCOMES AND MEASURES: The presence of APOE and C9ORF72 genotypes was assessed. Patients were cognitively classified as having ALS with normal cognition, ALS with frontotemporal dementia (FTD), ALS with executive or nonexecutive impairment, and ALS with behavioral impairment. RESULTS: Of the 504 patients with incident ALS, 357 (70.8%) were included in the study; 154 were women, 203 were men, they had a mean (SD) age at onset of 64.8 (10.2) years, and 37 of them carried a C9ORF72 repeat expansion. Cognitive testing revealed that 184 patients (51.5%) had ALS with normal cognition, 51 (14.3%) had ALS with FTD, 103 (28.9%) had ALS with executive or nonexecutive impairment, and 19 (5.3%) had ALS with behavioral impairment. Distribution of APOE haplotypes did not significantly differ between patients and controls or among patients with different levels of cognitive impairment. According to multivariate logistic regression, the presence of C9ORF72 repeat expansions was the strongest determinant of FTD (odds ratio, 13.08; 95% CI, 4.75-36.02; P < .001); however, the presence of an APOE ε2 allele significantly increased the risk of FTD (odds ratio, 2.61; 95% CI, 1.14-6.10; P = .03). Presence of an APOE ε4 allele was ineffectual. CONCLUSIONS AND RELEVANCE: C9ORF72 repeat expansions have a primary role in increasing the risk of cognitive impairment in patients with ALS; the APOE ε2 allele, to a lesser extent, also increases the risk of FTD. These study findings highlight the importance of considering the genetic background of patients with ALS when analyzing the putative effect of genetic modifiers.
Authors: Michael J Strong; Sharon Abrahams; Laura H Goldstein; Susan Woolley; Paula Mclaughlin; Julie Snowden; Eneida Mioshi; Angie Roberts-South; Michael Benatar; Tibor HortobáGyi; Jeffrey Rosenfeld; Vincenzo Silani; Paul G Ince; Martin R Turner Journal: Amyotroph Lateral Scler Frontotemporal Degener Date: 2017-01-05 Impact factor: 4.092
Authors: Marco Orsini; Ana Carolina Andorinho de Freitas Ferreira; Osvaldo J M Nascimento; Jano Alves de Souza; Thaís Nascimento Magalhães; Anna Carolina Damm de Assis; Larissa Kozow Westin; Bruno Pessoa; Acary Bulle Oliveira; Rossano Fiorelli; Marcos R G de Freitas; Juliana Bittencourt; Stenio Fiorelli; Maria Fernanda Freitas Ferreira Moreira; Pedro Ribeiro Journal: Neurol Int Date: 2016-06-29
Authors: Wan Yun Ho; Jer-Cherng Chang; Kenneth Lim; Amaury Cazenave-Gassiot; Aivi T Nguyen; Juat Chin Foo; Sneha Muralidharan; Ashley Viera-Ortiz; Sarah J M Ong; Jin Hui Hor; Ira Agrawal; Shawn Hoon; Olubankole Aladesuyi Arogundade; Maria J Rodriguez; Su Min Lim; Seung Hyun Kim; John Ravits; Shi-Yan Ng; Markus R Wenk; Edward B Lee; Greg Tucker-Kellogg; Shuo-Chien Ling Journal: J Cell Biol Date: 2021-08-04 Impact factor: 10.539