title: A comparison of three electrophysiological methods for the assessment of disease status in a mild spinal muscular atrophy mouse model.
abstract: OBJECTIVE
  There is a need for better, noninvasive quantitative biomarkers for assessing the rate of progression and possible response to therapy in spinal muscular atrophy (SMA). In this study, we compared three electrophysiological measures: compound muscle action potential (CMAP) amplitude, motor unit number estimate (MUNE), and electrical impedance myography (EIM) 50 kHz phase values in a mild mouse model of spinal muscular atrophy, the Smn1c/c mouse.
  
  
  METHODS
  Smn1c/c mice (N = 11) and wild type (WT) animals (-/-, N = 13) were measured on average triweekly until approximately 1 year of age. Measurements included CMAP, EIM, and MUNE of the gastrocnemius muscle as well as weight and front paw grip strength. At the time of sacrifice at one year, additional analyses were performed on the animals including serum survival motor neuron (SMN) protein levels and muscle fiber size.
  
  
  RESULTS
  Both EIM 50 kHz phase and CMAP showed strong differences between WT and SMA animals (repeated measures 2-way ANOVA, P<0.0001 for both) whereas MUNE did not. Both body weight and EIM showed differences in the trajectory over time (p<0.001 and p = 0.005, respectively). At the time of sacrifice at one year, EIM values correlated to motor neuron counts in the spinal cord and SMN levels across both groups of animals (r = 0.41, p = 0.047 and r = 0.57, p  = 0.003, respectively), while CMAP did not. Motor neuron number in Smn1c/c mice was not significantly reduced compared to WT animals.
  
  
  CONCLUSIONS
  EIM appears sensitive to muscle status in this mild animal model of SMA. The lack of a reduction in MUNE or motor neuron number but reduced EIM and CMAP values support that much of the pathology in these animals is distal to the cell body, likely at the neuromuscular junction or the muscle itself.
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Tom R
authors.initials: TR
authors.lastname: Geisbush
authors.affiliation: Department of Neurology, Ohio State University, Columbus, Ohio, United States of America.
authors.forename: William D
authors.initials: WD
authors.lastname: Arnold
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Glenn D
authors.initials: GD
authors.lastname: Rosen
authors.affiliation: PharmOptima, LLC, Portage, Michigan, United States of America.
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Zaworski
authors.affiliation: Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Seward B
authors.initials: SB
authors.lastname: Rutkove
mesh_terms: D000200:Action Potentials; D000818:Animals; D004576:Electromyography / Q000379:methods*; D051379:Mice; D018482:Muscle, Skeletal / Q000294:innervation / Q000503:physiopathology; D009134:Muscular Atrophy, Spinal / Q000175:diagnosis / Q000503:physiopathology*