Effect of levodopa/carbidopa on the progression of Machado-Joseph disease /spinocerebellar ataxia type 3 (MJD/SCA3)

Background and Objectives In Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3), ataxin-3 accumulates as neuronal nuclear inclusions in specific regions of the brain such as the substantia nigra and the dentate cerebellar nucleus. Ataxin-3 aggregation is strongly inhibited by dopamine, a neurotransmitter whose brain levels can be increased through the use of medication containing levodopa/carbidopa (LA/CA). Here we perform a retrospective study to determine whether exposition to LA/CA is associated with a decreased progression of MJD/SCA3. Methods We assessed the natural history of individuals with MJD/SCA3 and also SCA1, 2, 6, 7, 8, and 10 enrolled by the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA). Our initial analysis focused on individuals with all spinocerebellar ataxias (SCAs) whose ataxia progression was assessed by the Scale for the Assessment and Rating of Ataxia (SARA) between 2010 and 2023. To account for important covariates affecting the time evolution of SARA scores, our study was then limited to MJD/SCA3 cases with genetic and age information available. A linear mixed model was used to determine the effects of LA/CA and other anti-parkinsonian drugs at 6 and 13 years of MJD/SCA3 progression. Results Among the group of 716 individuals with SCAs with monitored SARA scores, 58 (8.1%) had taken LA/CA formulations, whereas 26 (3.6%) had taken other anti-parkinsonian drugs, mainly dopamine receptor agonists. A non-parametric analysis suggested a positive effect of LA/CA on the probability of major disease decline during the initial 6 years of patient monitoring. A multivariate analysis of 262 MJD/SCA3 cases (of which 30 were taken LA/CA) showed statistically significant effects in favor of LA/CA exposition: after adjusting for age and number of CAG repeats in the expanded allele, the yearly SARA response demonstrated a positive effect at 6 years (linear mixed model coefficient β = −0.651 [95% confidence interval −1.141 to −0.161 ], P = 0.009 ) and 13 years ( β = −0.274 [ −0.547 to −0.002 ], P = 0.048 ). Conclusions The use of LA/CA to treat non-cerebellar symptoms had a beneficial effect on the SARA score progression in MJD/SCA3. This observation supports the hypothesis that restoring the dopamine levels in the brains of MJD/SCA3 patients might slow down disease progression. Our findings warrant further investigation on whether individuals with MJD/SCA3, even in the absence of Parkinsonian symptoms should also be treated with LA/CA and at what doses.