Effectiveness of Levodopa/Carbidopa in Slowing the Progression of MJD/SCA3

Background and ObjectivesIn Machado-Joseph disease or spinocerebellar ataxia type 3 (MJD/SCA3), ataxin-3 accumulates as neuronal nuclear inclusions in specific regions of the brain. 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 exposure to LA/CA is associated with a decreased progression of MJD/SCA3. MethodsWe assessed the natural history of individuals with MJD/SCA3 enrolled by the Clinical Research Consortium for Spinocerebellar Ataxias (CRC-SCA). Our analysis focused on individuals with genetic and age data available whose ataxia progression was assessed by the Scale for the Assessment and Rating of Ataxia (SARA) between 2010 and 2023. A linear mixed model was used to determine the effects of LA/CA and other antiparkinsonian drugs on MJD/SCA3 progression. To assess the adverse effects associated with long-term levodopa, we conducted a supplementary nonparametric analysis including all SCA types available in the CRC-SCA dataset. ResultsA multivariate analysis of 146 MJD/SCA3 individuals, including 24 LA/CA cases (mean age 50.2 ± 14.1 years, 63% female) and 122 controls (mean age 51.6 ± 12.4 years, 50% female), showed statistically significant effects in favor of LA/CA exposure: 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). The diminished effect at 13 years compared with 6 years is consistent with a potential ∼6-year threshold observed in the larger CRC-SCA group (716 individuals with various SCA types), beyond which LA/CA-exposed individuals showed a major disease decline. DiscussionThe use of LA/CA to treat noncerebellar 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 patients with MJD/SCA3 might slow down disease progression. Our findings warrant further investigation on whether individuals with MJD/SCA3 should also be treated with LA/CA and at what doses.