Quantitative studies of lower motor neuron degeneration in amyotrophic lateral sclerosis: Evidence for exponential decay of motor unit numbers and greatest rate of loss at the site of onset

OBJECTIVE To use our Bayesian method of motor unit number estimation (MUNE) to evaluate lower motor neuron degeneration in ALS. METHODS In subjects with ALS we performed serial MUNE studies. We examined the repeatability of the test and then determined whether the loss of MUs was fitted by an exponential or Weibull distribution. RESULTS The decline in motor unit (MU) numbers was well-fitted by an exponential decay curve. We calculated the half life of MUs in the abductor digiti minimi (ADM), abductor pollicis brevis (APB) and/or extensor digitorum brevis (EDB) muscles. The mean half life of the MUs of ADM muscle was greater than those of the APB or EDB muscles. The half-life of MUs was less in the ADM muscle of subjects with upper limb than in those with lower limb onset. CONCLUSIONS The rate of loss of lower motor neurons in ALS is exponential, the motor units of the APB decay more quickly than those of the ADM muscle and the rate of loss of motor units is greater at the site of onset of disease. SIGNIFICANCE This shows that the Bayesian MUNE method is useful in following the course and exploring the clinical features of ALS.

[1]  J. Shefner,et al.  Mice lacking cytosolic copper/zinc superoxide dismutase display a distinctive motor axonopathy , 1999, Neurology.

[2]  J. Daube,et al.  Decrement in surface-recorded motor unit potentials in amyotrophic lateral sclerosis , 2004, Neurology.

[3]  L. H. van den Berg,et al.  A long-term prospective study of the natural course of sporadic adult-onset lower motor neuron syndromes. , 2009, Archives of neurology.

[4]  A. Beckett,et al.  AKUFO AND IBARAPA. , 1965, Lancet.

[5]  A. Wilbourn,et al.  The “split hand syndrome” , 2000, Muscle & nerve.

[6]  S. Hesse,et al.  Amyotrophic lateral sclerosis: Macro–EMG and twitch forces of single motor units , 1990, Muscle & nerve.

[7]  D. Altman,et al.  STATISTICAL METHODS FOR ASSESSING AGREEMENT BETWEEN TWO METHODS OF CLINICAL MEASUREMENT , 1986, The Lancet.

[8]  A. Eisen,et al.  The split hand in ALS has a cortical basis , 2000, Journal of the Neurological Sciences.

[9]  D. F. Andrews,et al.  A one-hit model of cell death in inherited neuronal degenerations , 2000, Nature.

[10]  Pico Caroni,et al.  Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF , 2006, Nature Neuroscience.

[11]  Anthony N Pettitt,et al.  Bayesian statistical MUNE method , 2007, Muscle & nerve.

[12]  P. Andres,et al.  The natural history of motoneuron loss in amyotrophic lateral sclerosis , 1988, Neurology.

[13]  B. Pant,et al.  Amyotrophic lateral sclerosis (ALS): A phylogenetic disease of the corticomotoneuron? , 1992, Muscle & nerve.

[14]  Mb Alan J. McComas Dr.,et al.  The extent and time course of motoneuron involvement in amyotrophic lateral sclerosis. , 1991 .

[15]  Anthony N. Pettitt,et al.  Motor unit number estimation using reversible jump Markov chain Monte Carlo methods , 2007 .

[16]  P. G. Ridall,et al.  Biological basis for motor unit number estimation through Bayesian statistical analysis of the stimulus-response curve. , 2009, Supplements to Clinical neurophysiology.

[17]  M. Brandstater,et al.  Motor unit number estimate–based rates of progression of ALS predict patient survival , 1999, Muscle & nerve.

[18]  Peter M Andersen,et al.  Human extraocular muscles in ALS. , 2010, Investigative ophthalmology & visual science.

[19]  Yuxin Fan,et al.  Implications of ALS focality , 2007, Neurology.

[20]  Dick F Stegeman,et al.  Monitoring disease progression using high‐density motor unit number estimation in amyotrophic lateral sclerosis , 2010, Muscle & nerve.

[21]  J. Shefner,et al.  Motor unit number estimation in neurologic disease. , 2002, Advances in neurology.

[22]  Sanjeev D Nandedkar,et al.  Motor unit number index (MUNIX): principle, method, and findings in healthy subjects and in patients with motor neuron disease , 2010, Muscle & nerve.

[23]  Kyung Seok Park,et al.  Reproducibility of the motor unit number index (MUNIX) in normal controls and amyotrophic lateral sclerosis patients , 2010, Muscle & nerve.

[24]  A. Hyodo,et al.  Longitudinal study of functional spinal alpha motor neuron loss in amyotrophic lateral sclerosis , 2002, Muscle & nerve.

[25]  A. Pettitt,et al.  Biomarkers of disease in a case of familial lower motor neuron ALS , 2010, Amyotrophic Lateral Sclerosis.

[26]  Mark B Bromberg,et al.  Motor Unit Number Estimation: Con , 2002, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[27]  P. Andres,et al.  Use of composite scores (megascores) to measure deficit in amyotrophic lateral sclerosis , 1988, Neurology.

[28]  S. Kuwabara,et al.  Dissociated small hand muscle involvement in amyotrophic lateral sclerosis detected by motor unit number estimates , 1999, Muscle & nerve.

[29]  P. Caroni,et al.  Early and Selective Loss of Neuromuscular Synapse Subtypes with Low Sprouting Competence in Motoneuron Diseases , 2000, The Journal of Neuroscience.

[30]  A N Pettitt,et al.  The stimulus–response curve and motor unit variability in normal subjects and subjects with amyotrophic lateral sclerosis , 2006, Muscle & nerve.

[31]  Steven Finkbeiner,et al.  Quantitative Relationships between Huntingtin Levels, Polyglutamine Length, Inclusion Body Formation, and Neuronal Death Provide Novel Insight into Huntington's Disease Molecular Pathogenesis , 2010, The Journal of Neuroscience.

[32]  M. Swash,et al.  El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral sclerosis , 2000, Amyotrophic lateral sclerosis and other motor neuron disorders : official publication of the World Federation of Neurology, Research Group on Motor Neuron Diseases.

[33]  M. Johnson,et al.  Data on fibre size in thirty-six human muscles. An autopsy study. , 1973, Journal of the neurological sciences.

[34]  T. Gordon,et al.  Preferential motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis , 2008, The Journal of physiology.

[35]  P. G. Ridall,et al.  The relationship between Bayesian motor unit number estimation and histological measurements of motor neurons in wild-type and SOD1G93A mice , 2012, Clinical Neurophysiology.

[36]  P. Mccombe,et al.  Effects of prolonged repetitive stimulation of median, ulnar and peroneal nerves , 2010, Muscle & nerve.

[37]  D. Cox,et al.  Analysis of Survival Data. , 1985 .

[38]  D. Gutmann,et al.  Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis , 2008, Nature Neuroscience.

[39]  Joleen H Blok,et al.  The electrophysiological muscle scan , 2007, Muscle & nerve.

[40]  T. Gordon,et al.  Time course of preferential motor unit loss in the SOD1G93A mouse model of amyotrophic lateral sclerosis , 2007, Neurobiology of Disease.

[41]  E. Melamed,et al.  The “Dying-Back” Phenomenon of Motor Neurons in ALS , 2011, Journal of Molecular Neuroscience.

[42]  S. Kuwabara,et al.  Differences in excitability properties of FDI and ADM motor axons , 2009, Muscle & nerve.

[43]  M. Cudkowicz,et al.  Comparison of incremental with multipoint MUNE methods in transgenic ALS mice , 2002, Muscle & nerve.

[44]  D. Schoenfeld,et al.  The use of statistical MUNE in a multicenter clinical trial , 2004, Muscle & nerve.