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Quantitative objective markers for upper and lower motor neuron dysfunction in ALS

H. Mitsumoto, MD, DSc, A. M. Ulu, PhD, S. L. Pullman, MD, FRCPC, C. L. Gooch, MD, S. Chan, MD, MPH, MBA, M. -X. Tang, PhD, X. Mao, MS, A. P. Hays, MD, A. G. Floyd, BA, V. Battista, BA, J. Montes, RPT, MA, S. Hayes, RPT, MA, S. Dashnaw, P. Kaufmann, MD, MSc, P. H. Gordon, MD, J. Hirsch, PhD, B. Levin, PhD, L. P. Rowland, MD and D. C. Shungu, PhD

From the Eleanor and Lou Gehrig MDA/ALS Research Center (H.M., V.B., J.M., P.K., P.H.G., L.P.P.) and Department of Neurology (H.M., S.L.P., C.L.G., A.G.F., V.B., J.M., S.H., P.K., P.H.G., L.P.R.), Columbia University, and Department of Radiology (S.C.), Sergievsky Center (M.-X.T.), Department of Pathology (Neuropathology) (A.P.H.), Functional MRI Center (J.H., S.D.), Department of Radiology, and Department of Biostatistics (M.-X.T., B.L.), Mailman School of Public Health, Columbia University, and Department of Radiology (A.M.U., X.M., D.C.S.), Weill Medical College of Cornell University, New York, NY.

Address correspondence and reprint requests to Dr. H. Mitsumoto, Eleanor and Lou Gehrig MDA/ALS Research Center, Neurological Institute, Columbia University, 710 W. 168 St., New York, NY 10032 hm246{at}columbia.edu

Objective: To investigate the value of objective biomarkers for upper (UMN) and lower (LMN) motor neuron involvement in ALS.

Methods: We prospectively studied 64 patients with ALS and its subsets using clinical measures, proton MR spectroscopic imaging (¹H MRSI), diffusion tensor imaging, transcranial magnetic stimulation, and the motor unit number estimation (MUNE) at baseline and every 3 months for 15 months and compared them with control subjects.

Results: ¹H MRSI measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration were markedly reduced in ALS (p = 0.009) and all UMN syndromes combined (ALS, familial ALS [fALS], and primary lateral sclerosis; p = 0.03) vs control values. Central motor conduction time to the tibialis anterior was prolonged in ALS (p < 0.0005) and combined UMN syndromes (p = 0.001). MUNE was lower in ALS (p < 0.0005) and all LMN syndromes combined (ALS, fALS, and progressive muscular atrophy; p = 0.001) vs controls. All objective markers correlated well with the ALS Functional Rating Scale–Revised, finger and foot tapping, and strength testing, suggesting these markers related to disease activity. Regarding changes over time, MUNE changed rapidly, whereas neuroimaging markers changed more slowly and did not significantly differ from baseline.

Conclusions: ¹H MR spectroscopic imaging measures of the primary motor cortex N-acetyl-aspartate (NAA) concentration and ratio of NAA to creatine, central motor conduction time to the tibialis anterior, and motor unit number estimation significantly differed between ALS, its subsets, and control subjects, suggesting they have potential to provide insight into the pathobiology of these disorders.

Supplemental data at www.neurology.org

Received June 29, 2006. Accepted in final form December 20, 2006.

Disclosure: The authors report no conflicts of interest.

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