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?

Dietary Vitamin D3 Supplementation at 10× the Adequate Intake Improves Functional Capacity in the G93A Transgenic Mouse Model of ALS, a Pilot Study

“…This suggests that the PaGE test is a more sensitive indicator of disease severity versus MP, and could be used as a predictor or indicator of disease onset and/or severity. This is in accordance with Weydt et al who concluded that the PaGE test is more diagnostically accurate at detecting early signs of ALS versus MP in the G93A mouse model [21].…”

Selective mitochondrial Ca2+ uptake deficit in disease endstage vulnerable motoneurons of the SOD1G93A mouse model of amyotrophic lateral sclerosis

“…SOD1 G93A mice aged postnatal day P70 ± 5 (referred to as P70) were classified as late presymptomatic according to tongue movement ability (Fuchs et al 2010). For endstage analyses, SOD1 G93A mice between P115 and P140 (referred to as P120 or endstage) were used after they were no longer able to pass a paw grip endurance test (clinical score 4; Solomon et al 2011) and results were compared to age‐matched WT littermates.…”

Vitamin D3 at 50x AI Attenuates the Decline in Paw Grip Endurance, but Not Disease Outcomes, in the G93A Mouse Model of ALS, and Is Toxic in Females

“…Beginning at age 60 d, CS was recorded daily until endpoint and followed an 8-point scale based on signs of weakness exhibited by the mice in order to establish disease severity: 0 =  no evidence of disease, 1 =  shaking or splaying of the hindlimbs when suspended by the tail (an indication of weakness in the hindlimbs), 1.5 =  weakness in one hindlimb (compensation for footdrop), 2 =  weakness in both hindlimbs (change in gait; used as disease onset when attained on two consecutive days), 2.5 =  extreme weakness in one hindlimb (inability to dorsiflex), 3 =  extreme weakness in both hindlimbs, 3.5 =  functional paralysis in one hindlimb, 4 =  functional paralysis in both hindlimbs, and 5 =  mouse cannot right itself within 20 s after being placed on its side (considered as endpoint [31]). For all mice, CS was recorded prior to all other functional measurements.…”