Structural Alterations of Upper Cervical Spinal Cord in Ataxic and Non-ataxic Mutation Carriers of Spinocerebellar Ataxia Type 3 (SCA3)

Abstract

<strong>Objective: </strong> Spinocerebellar ataxia Type 3/Machado-Joseph disease (SCA3/MJD) is worldwide the most frequent autosomal dominantly inherited ataxia. Although the gene mutation causing SCA3 is known, there is up to now no treatment available. However, new therapeutic approaches including gene modifying drugs are on the horizon. Therefore, there is an urgent need to identify and validate sensitive biological markers that reflect the individual disease profile. Of particular interest are markers that are already sensitive in the pre-ataxia stage. As SCA3 is associated with widespread cerebellar, cerebral and spinal cord structural alterations, MRI-based spinal cord morphometric measures are promising candidates for such markers. Our aim was to investigate the morphometry of the upper cervical spinal cord in a large cross-sectional cohort of non-ataxic and ataxic SCA3 mutation carriers. <br /> <strong>Methods: </strong> We used T1 weighted MRI scans of 33 non-ataxic and 120 ataxic SCA3 mutation carriers and 32 healthy controls to assess the cross sectional area(CSA), anteroposterior(AP) and left-right(LR) diameter of the upper cervical spinal cord at the intervertebral level C2/C3. We applied manual delineation and a semi-automated approach. <br /> <strong>Results: </strong> CSA, AP and LR of the cervical spinal cord at the intervertebral level C2/C3 were significantly reduced already in non-ataxic SCA3 mutation carriers in comparison to healthy controls. Atrophy was highest in symptomatic mutation carriers and correlated with disease severity, assessed by SARA, and partially with disease duration and CAG repeat length of the longer allele. <br /> <strong>Conclusion: </strong> Our results show that atrophy of the upper cervical spinal cord starts already in the pre-ataxic disease stage, is progressive throughout the whole course of the disease and correlates to disease severity. Therefore, morphometry of the upper cervical spinal cord is a promising MRI biomarker candidate for future interventional trials in SCA3.