Diffusion Tensor Imaging in Sporadic and Familial ( D 90 A SOD 1 ) Forms of Amyotrophic Lateral Sclerosis

T HERE IS CONSIDERABLE variation in the clinical presentation and rate of progression of amyotrophic lateral sclerosis (ALS), but the basis of this heterogeneity is poorly understood. About 10% of ALS cases are inherited in a mendelian fashion, with mutations in the superoxide dismutase 1 (SOD1) gene (GenBank AY450286) being responsible for 20% of these. The D90A SOD1 mutation is commonly inherited as a recessive trait with high penetrance in homozygotes. Homozygous D90A SOD1 cases are genetically homogeneous, sharing a common founder about 60 generations ago. The resulting clinical phenotype is stereotyped as a spastic paraparesis progressing to upper limb and bulbar involvement. The disease is slowly progressive, with a much longer survival than with sporadic ALS (mean, 14 vs 3 years, respectively). Groups of patients with genetic forms of ALS that are clinically homogeneousprovideauniqueopportunity tostudy the pathologic basis of the relationship between genotype and phenotype in ALS. Neuroimaging techniques have been used in ALS in an attempt to improve diagnosis and to measure disease progression, as well as to provide a quantitative method of studying the pathophysiologic function of the disease in vivo. Diffusion tensor imaging (DTI) is a magnetic resonance (MR) imaging technique in which the signal is sensitized to the diffusion of water within brain tissue (which is restricted by barriers such as cell membranes and occurs preferentially along the direction of white matter tracts). Fractional anisotropy (FA) is a measure of the directionality of diffusion in a voxel (from 0 [complete lack of directionality of diffusion] to 1 [complete anisotropy]) and is reduced when white matter tracts are disrupted. Previous studies using region-ofinterest approaches to analyze DTI data in ALS have shown reduced FA in the corticospinal tract, consistent with the known pathologic features of the disease. Voxelbased approaches to analysis have demonstrated evidence of white matter damage in extramotor pathways. Some correlations between clinical measures and Author Affiliations: Medical Research Council Centre for Neurodegeneration Research and Department of Clinical Neuroscience (Drs Stanton, Turner, V. C. Williams, S. C. R. Williams, Blain, Leigh, and Simmons), Centre for Neuroimaging Sciences (Ms Shinhmar and Drs S. C. R. Williams and Simmons), National Institute for Health Research Biomedical Research Centre for Mental Health (Drs S. C. R. Williams and Simmons), Brain Image Analysis Unit, Department of Biostatistics and Computing (Dr Giampietro), and Division of Psychological Medicine and Psychiatry (Dr Catani), Institute of Psychiatry, King’s College London, London, and Department of Neurology, John Radcliffe Hospital, Oxford (Dr Turner), England; and Department of Neurology, Umeå University Hospital, Umeå, Sweden (Dr Andersen).