A 5‐Year Longitudinal Clinical and Magnetic Resonance Imaging Study in Spinocerebellar Ataxia Type 3

Abstract

Background The natural history of neurodegeneration in spinocerebellar ataxia type 3/Machado Joseph disease is still unclear. Here, we built a long‐term longitudinal clinical and neuroimaging study to address this point. Methods Twenty‐three patients with spinocerebellar ataxia type 3/Machado Joseph disease and 22 healthy controls underwent 3T MRI twice 5.0 years apart. T1 and diffusion tensor imaging sequences were obtained. We used T1 multiatlas, diffusion tensor imaging multiatlas, SpineSeg, and CERES‐SUIT for cerebral gray and white matter, spinal cord and cerebellar analyses, respectively. Clinical severity was assessed with scale for assessment and rating of ataxia. Analysis of covariance evaluated longitudinal between‐group changes. Effect sizes were calculated for each significant result. Results Progressive volumetric abnormalities were most evident in the cerebellum (Lobule X and Crus II; effect size, 2.0), followed by the basal ganglia (effect size, 0.7). The cerebellar peduncles had the largest white‐matter diffusivity changes (effect size, 1.29). Scale for assessment and rating of ataxia–related effect size was 0.82. We failed to identify progressive spinal cord abnormalities. Conclusions Longitudinal changes in spinocerebellar ataxia type 3/Machado Joseph disease are more evident in the cerebellum and connections, followed by the basal ganglia. © 2020 International Parkinson and Movement Disorder Society

Regional Brain and Spinal Cord Volume Loss in Spinocerebellar Ataxia Type 3

“…The effect size of all other metrics was smaller than that of SARA, although those of cervical spinal cord segment C2 and C3, pons, midbrain, and pallidum were of the same magnitude as that of SARA. The current values are not comparable to effect sizes calculated on the basis of longitudinal data 14,16,36 …”

“…Previous studies in patients with SCA3 showed a pattern of regional brain tissue loss that faithfully reflected the distribution of neurodegenerative changes described in autopsy studies 9‐13 and revealed that regional volume loss already starts in the preataxia stage 9 . Three longitudinal volumetric studies in small numbers of patients with SCA3 suggested that MRI volume is more sensitive to change than clinical scales, which makes MRI volumes promising candidates for biomarkers in clinical trials 14‐16 . This applies in particular to preventive trials in preataxic mutation carriers, as clinical measures lack sensitivity before ataxia onset.…”

“…The current values are not comparable to effect sizes calculated on the basis of longitudinal data. 14,16,36 We suggest that extracerebellar regions represent the core sites of the disease process in SCA3. This suggestion is based on the observed time course of volume changes and the close relation of the metrics of extracerebellar regions with clinical disease severity and CAG repeat length.…”

“…9 Three longitudinal volumetric studies in small numbers of patients with SCA3 suggested that MRI volume is more sensitive to change than clinical scales, which makes MRI volumes promising candidates for biomarkers in clinical trials. [14][15][16] This applies in particular to preventive trials in preataxic mutation carriers, as clinical measures lack sensitivity before ataxia onset. However, further steps toward the validation of MRI regional volumes as biomarkers for SCA3 are hampered by the small numbers of studied MRIs and the time-consuming procedures for segmentation and volumetry.…”

Network Reconfiguration Among Cerebellar Visual, and Motor Regions Affects Movement Function in Spinocerebellar Ataxia Type 3

“…Patients with SCA3 exhibit characteristic ataxia and nystagmus, mild cognitive ( Schöls et al, 2004 ; Braga-Neto et al, 2012 ) and psychiatric symptoms ( Silva et al, 2015 ; Yuan et al, 2019 ). Previous studies in SCA3 mainly focused on the changes in brain structure, such as gray matter atrophy and micro-structural white matter abnormalities ( Meles et al, 2018 ; Guo et al, 2020 ; Piccinin et al, 2020 ). However, an increasing number of studies suggest that, in neural degeneration diseases, there is an alteration in the large-scale brain network rather than only localized dysfunction in a single brain area ( Hillary and Grafman, 2017 ).…”