JNNP236018 843..849

Background The homogeneous genotype and stereotyped phenotype of a unique familial form of amyotrophic lateral sclerosis (ALS) (patients homozygous for aspartate-to-alanine mutations in codon 90 (homD90A) superoxide dismutase 1) provides an ideal model for studying genotype/phenotype interactions and pathological features compared with heterogeneous apparently sporadic ALS. The authors aimed to use diffusion tensor tractography to quantify and compare changes in the intracerebral corticospinal tracts of patients with both forms of ALS, building on previous work using whole-brain voxelwise group analysis. Method 21 sporadic ALS patients, seven homD90A patients and 20 healthy controls underwent 1.5 T diffusion tensor MRI. Patients were assessed using ‘upper motor neuron burden,’ El Escorial and ALSFR-R scales. The intracranial corticospinal tract was assessed using diffusion tensor tractography measures of fractional anisotropy (FA), mean diffusivity, and radial and axial diffusivity obtained from its entire length. Results Corticospinal tract FA was reduced in sporadic ALS patients compared with both homD90A ALS patients and controls. The diffusion measures in sporadic ALS patients were consistent with anterograde (Wallerian) degeneration of the corticospinal tracts. In sporadic ALS, corticospinal tract FA was related to clinical measures. Despite a similar degree of clinical upper motor neuron dysfunction and disability in homD90A ALS patients compared with sporadic ALS, there were no abnormalities in corticospinal tract diffusion measures compared with controls. Conclusions Diffusion tensor tractography has shown axonal degeneration within the intracerebral portion of the corticospinal tract in sporadic ALS patients, but not those with a homogeneous form of familial ALS. This suggests significant genotypic influences on the phenotype of ALS and may provide clues to slower progression of disease in homD90A patients. INTRODUCTION Amyotrophic lateral sclerosis (ALS) is a complex progressive neurodegenerative disease affecting upper (UMN) and lower (LMN) motor neurons of the motor cortex, brainstem and spinal cord. An estimated 90% of ALS cases are apparently sporadic. Clinical manifestations include muscle weakness, wasting and spasticity, resulting in death 2e5 years after onset. The remaining 10% of ALS cases are understood to be familial, with 20% of these being closely associated with over 100 predominantly missense genetic mutations in a gene that codes for cytosolic Cu/Zn binding superoxide dismutase (SOD-1) on chromosome 21. SOD-1 mutations are typically inherited in a dominant fashion, but recessive patterns of inheritance have been shown in patients homozygous for aspartate-to-alanine mutations in codon 90 (homD90A), representing the most common SOD-1 mutation. Although homD90A patients have a disease phenotype similar to sporadic ALS (see Weber et al for a review), they have a longer mean survival (mean 12.6 years vs 4 years), the reason for which is unknown. Imaging techniques such as diffusion tensor MRI (DTI) have been used to quantify corticospinal tract degeneration in vivo in sporadic ALS patients. DTI can be used to estimate organisational properties of tissue microstructure and orientation of white-matter fibre tracts based on the principles of water displacement. Diffusion of water molecules is higher parallel to fibre bundles than perpendicular to them, creating a directional bias, which can be detected using DTI. Four principal outcome measures can be computed: fractional anisotropy (FA), a measure of directionality of diffusion, mean diffusivity (MD), a measure of overall diffusion of water in a voxel, axial diffusivity, which reflects diffusion along fibre bundles, and radial diffusivity, which reflects diffusion perpendicular to fibre bundles. By determining the relationship of diffusion information between adjacent voxels, detailed 3-D images of fibre tracts can be constructed (tractography) for quantitative analysis. The corticospinal tracts (CSTs) contain the major efferent UMN fibre projection connecting the motor cortex with the brainstem and spinal cord. Projections from UMN, originating in the motor cortex, converge in the corona radiata, descend through the posterior limb of the internal capsule and continue into the cerebral peduncles and pons before entering the spinal cord. By placing regions of interest (ROI) at several of these known anatomical locations, it is possible to delineate the CSTs and quantify UMN degeneration throughout their entire intracerebral length as reflected by abnormal diffusion values. Previously, we have demonstrated differences between sALS, homD90A and controls using whole-brain voxelwise group analysis of FA. The current study used a different and newer analysis technique, diffusion tensor tractography to examine diffusion characteristics along the < See Editorial commentary, p 827 Department of Clinical Neuroscience, King’s College London, Institute of Psychiatry, London, UK MRC Centre for Neurodegeneration Research, King’s College London, Institute of Psychiatry, London, UK Department of Neuroimaging, King’s College London, Institute of Psychiatry, London, UK NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry, King’s College London, London, UK Image Sciences Institute, University Medical Center Utrecht, Heidelberglaan, Utrecht, The Netherlands Department of Clinical Neurology, John Radcliffe Hospital, Oxford University, Oxford, UK Department of Neurology, Umeå University Hospital, Umeå, Sweden CUBRIC Centre, Cardiff University, Cardiff, UK