Impact of Limb Phenotype on Tongue Denervation Atrophy, Dysphagia Penetrance, and Survival Time in a Mouse Model of ALS.

Current treatments for dysphagia in ALS do not target the underlying tongue weakness and denervation atrophy that is prevalent in spinal and bulbar ALS cases. To address this clinical gap, we studied the low copy number SOD1-G93A (LCN-SOD1) mouse model of ALS to quantify the impact of limb phenotype on tongue denervation atrophy, dysphagia penetrance, and survival time in preparation for future treatment-based studies. Two male LCN-SOD1 breeders and 125 offspring were followed for limb phenotype inheritance, of which 52 (30 LCN-SOD1 and 22 wild-type/WT, both sexes) underwent characterization of dysphagia penetrance (via videofluoroscopic swallow study; VFSS) and survival time at disease end-stage (15-20% body weight loss). From these, 16 mice (8/genotype) underwent postmortem histological analysis of the genioglossus for evidence of denervation atrophy. Results revealed that both breeders displayed a mixed (hindlimb and forelimb) ALS phenotype and sired equal proportions of hindlimb vs. mixed phenotype offspring. Dysphagia penetrance was complete for mixed (100%) versus incomplete for hindlimb (64%) phenotype mice; yet survival times were similar. Regardless of limb phenotype, LCN-SOD1 mice had significantly smaller genioglossus myofibers and more centralized myonuclei compared to WT mice (p < 0.05). These biomarkers of denervation atrophy were significantly correlated with VFSS metrics (lick and swallow rates, p < 0.05) but not survival time. In conclusion, both LCN-SOD1 phenotypes had significant tongue denervation atrophy, even hindlimb phenotype mice without dysphagia. This finding recapitulates human ALS, providing robust rationale for using this preclinical model to explore targeted treatments for tongue denervation atrophy and ensuing dysphagia.

Accelerometry analysis options produce large differences in lifestyle physical activity measurement.

Objective measurement of physical activity (PA) using accelerometers has become increasingly popular across recreational and clinical applications. However, the effects of multiple processing algorithms, filters, and corrections on PA measurement variability may be underappreciated. OBJECTIVE: To examine how lifestyle PA estimates are impacted by multiple available scoring methods. APPROACH: Wrist-worn accelerometers (ActiGraph GT3X+) were worn by 132 adults (87 F) having various activity levels for one week. Lifestyle PA was assessed across four PA domains: daily energy expenditure (EE); active EE; moderate-to-vigorous PA (MVPA); and steps using 1-5 algorithms per domain, with/without wrist correction and low-frequency-extension (LFE). Estimates were compared to self-report (International Physical Activity Questionnaire). MAIN RESULTS: PA estimates differed between algorithms with variable but frequently large effect sizes (d = 0.08-1.88). The wrist correction reduced PA estimates across all domains (p < 0.05, d = 0.26-3.04) except step counts and one daily EE algorithm (d = 0.0). Conversely, the LFE increased step counts (d = 1.44, p < 0.05) but minimally affected all other outcomes (d = 0.08-0.20, p < 0.05). Correlations between objective and self-reported PA were small to moderate (ρ = 0.22-0.45) and decreased with the wrist correction. SIGNIFICANCE: Measurement of PA using accelerometry is highly dependent on algorithm and filter selection; previously validated methods are therefore not interchangeable. Users should take caution when interpreting absolute PA estimates, and reporting standards should require detailed methodology disclosure to optimize comparisons across studies.