Central motor conduction time as prodromal biomarker in spinocerebellar ataxia type 2

One important current focus of research in spinocerebellar ataxias (SCAs) is the characterization of the prodromal disease stage that provides novel insight into the SCAs pathogenesis, which might offer early treatment and provides prodromal biomarkers that serve as outcome measures in future interventional trials. In the case of SCA2, the existence of a large and homogeneous population of families in Cuba has allowed us to characterize the prodromal stage comprehensively. Nevertheless, evidence about corticospinal tract involvement before ataxia onset is scarce and has been demonstrated only clinically by the presence of hyperreflexia in 35% to 45% of cases. Here we performed a cross-sectional study of the corticospinal tract in 37 nonataxic SCA2 mutation carriers and their ageand sex-matched healthy controls by employing transcranial magnetic stimulation (TMS) to study corticospinal tract function to the tibialis anterior muscles. Central motor conduction time (CMCT) was determined by using the F-wave method. The study was approved by the ethics committee of the Centre for Research and Rehabilitation of Hereditary Ataxias, and all participants gave their written informed consent. Student’s t-tests revealed a significant prolongation of CMCT in nonataxic SCA2 mutation carriers (20.24 6 7.85 ms) when compared with controls (13.94 6 1.74 ms; P 5 .00001). Of 37 (59.46%) mutation carriers, 22 showed abnormal CMCTs (defined by values above the mean CMCT 1 2 standard deviations in the control group), whereas only 15 (40.54%) cases were detected with hyperreflexia by the neurological examination. Of these, 73.33% had prolonged CMCTs. Correlation analyses revealed that CMCT directly correlated to the cytosine-adenine-guanine (CAG) repeat size (Figure 1A) and inversely correlated to the predicted time to ataxia onset (Figure 1B). This study demonstrates for the first time in SCAs that CMCT measures by TMS has superior sensitivity when compared with a standard neurological examination to detect involvement of the corticospinal tract in the prodromal phase of SCA2. The prolongation of CMCT suggests demyelination or degeneration of the fastest conducting corticospinal tract fibers, a concept that is supported by neuropathological data. The direct correlation between the CMCT and the CAG repeat size suggests an important role of the CAG repeat expansion in corticospinal tract dysfunction, conferring to CMCT a particular value in the search of genetic and/or nongenetic factors modifying polyglutamine toxicity, which could impact future therapeutic approaches and provide new clues on SCA2 physiopathology. The inverse correlation between the CMCT and the predicted time to ataxia onset classifies this TMS measure as a prodromal biomarker with potential utility to track the natural SCA2 progression and its modification in clinical trials. In conclusion, our findings identify novel electrophysiological evidence for early affection of the corticospinal tract in prodromal SCA2 and provide a useful biomarker that predicts time to ataxia onset and reflects polyglutamine neurotoxicity. Longitudinal studies are warranted to further validate CMCT as progression biomarker in SCA2.