title: One universal common endpoint in mouse models of amyotrophic lateral sclerosis.
abstract: There is no consensus among research laboratories around the world on the criteria that define endpoint in studies involving rodent models of amyotrophic lateral sclerosis (ALS). Data from 4 nutrition intervention studies using 162 G93A mice, a model of ALS, were analyzed to determine if differences exist between the following endpoint criteria: CS 4 (functional paralysis of both hindlimbs), CS 4+ (CS 4 in addition to the earliest age of body weight loss, body condition deterioration or righting reflex), and CS 5 (CS 4 plus righting reflex >20 s). The age (d; mean ± SD) at which mice reached endpoint was recorded as the unit of measurement. Mice reached CS 4 at 123.9±10.3 d, CS 4+ at 126.6±9.8 d and CS 5 at 127.6±9.8 d, all significantly different from each other (P<0.001). There was a significant positive correlation between CS 4 and CS 5 (r = 0.95, P<0.001), CS 4 and CS 4+ (r = 0.96, P<0.001), and CS 4+ and CS 5 (r = 0.98, P<0.001), with the Bland-Altman plot showing an acceptable bias between all endpoints. Logrank tests showed that mice reached CS 4 24% and 34% faster than CS 4+ (P = 0.046) and CS 5 (P = 0.006), respectively. Adopting CS 4 as endpoint would spare a mouse an average of 4 days (P<0.001) from further neuromuscular disability and poor quality of life compared to CS 5. Alternatively, CS 5 provides information regarding proprioception and severe motor neuron death, both could be important parameters in establishing the efficacy of specific treatments. Converging ethics and discovery, would adopting CS 4 as endpoint compromise the acquisition of insight about the effects of interventions in animal models of ALS?
authors.affiliation: School of Kinesiology and Health Science, Faculty of Health, York University, Toronto, Ontario, Canada.
authors.forename: Jesse A
authors.initials: JA
authors.lastname: Solomon
authors.forename: Mark A
authors.initials: MA
authors.lastname: Tarnopolsky
authors.forename: Mazen J
authors.initials: MJ
authors.lastname: Hamadeh
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology*; D000818:Animals; D004195:Disease Models, Animal; D023381:Endpoint Determination / Q000379:methods*; D005260:Female; D006614:Hindlimb / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010243:Paralysis / Q000503:physiopathology; D057897:Reflex, Righting / Q000502:physiology; D015203:Reproducibility of Results; D013315:Stress, Psychological / Q000517:prevention & control; D013482:Superoxide Dismutase / Q000235:genetics; D016019:Survival Analysis
chemical_list: C109415:SOD1 G93A protein; D013482:Superoxide Dismutase