Body Mass Index Decline Is Related to Spinocerebellar Ataxia Disease Progression

Abstract

Background Spinocerebellar ataxias (SCAs) are dominantly inherited, progressive ataxia disorders. Disease progression could be preceded by weight loss. Objectives We aimed to study the course of weight loss in patients who had the most common SCAs (SCA1, SCA2 SCA3, and SCA6). Additional objectives were to identify subgroups of weight evolution, to determine the factors influencing these evolutions, and to assess the impact of these evolutions on disease progression. Methods In total, 384 patients from the EUROSCA prospective cohort study were analyzed who had SCA1, SCA2, SCA3, or SCA6 and at least 3 measurements of weight. Age was used as a time scale. Clinical outcomes were body mass index (BMI) and the Scale for the Assessment and Rating Ataxia (SARA), with scores ranging from 0 to 40. We used a linear mixed model to analyze the course of BMI and a latent class mixed model to identify subgroup BMI evolution. Results Overall, BMI declined over time (−0.11 ± 0.03 kg/m2 per decade; P = 0.0009). Three subgroups of BMI evolution were identified: “decreasing BMI” (n = 88; 23%), “increasing BMI” (n = 70; 18%) and “stable BMI” (n = 226; 59%). Patients in the decreasing BMI group were more severely affected at baseline with higher SARA scores and a higher frequency of non‐ataxia signs (especially motor symptoms) compared with those in the other groups. Weight loss was associated with faster disease progression (5.7 ± 0.7 SARA points per decade; P = 0.036). Conclusions The current data have substantial implications for the design of future interventional studies in SCA, as they provide a basis for patient stratification and emphasize the usefulness of BMI as a biomarker for monitoring disease progression.

Altered Levels of Proteins and Phosphoproteins, in the Absence of Early Causative Transcriptional Changes, Shape the Molecular Pathogenesis in the Brain of Young Presymptomatic Ki91 SCA3/MJD Mouse

“…1). Decreased body weight observed in Ki91 animals is one of the hallmarks of SCA3 phenotype in patients [17–20]. Based on preliminary pilot proteomic experiments in old Ki91 mice, we have selected 16 most promising dysregulated protein hits ( Atp2b1 , Psat1 , Ppp2r1a , Idh1 , Akr1b1 , Srsf2 , Plp1 , Glul , Ca2 , Ndufa9 , Pea15a , Tuba1a , Psmd4 , Omg , Cox7a2 , and Qdpr ) to examine potential transcriptional events in old Ki91 animals at 10 and 14 months old.…”

Prediction of Survival With Long‐Term Disease Progression in Most Common Spinocerebellar Ataxia

“…These patients also had a lower body weight at baseline than the other groups, in accord with the recent reported data on weight loss in relation to disease progression. Investigators showed that patients who lose weight exhibit faster disease progression …”

“…Investigators showed that patients who lose weight exhibit faster disease progression. 18 Furthermore, we derived a subject-specific dynamic prediction of survival from the JLC models (one-and theeclass) and showed that the three-class JLC model provides a more precise estimate and better predictive accuracy than the one-class JLC model, which assumes that the SARA score evolution is independent of risk of death conditionally to the latent classes. These findings highlight the importance of subgroup analysis that departs from the hypothesis of homogeneity of the population assumed by the one-class JLC model and confirms the presence of clinical heterogeneity and distinct ataxia progression profiles within the same genotype.…”

Adult onset pan-neuronal human tau tubulin kinase 1 expression causes severe cerebellar neurodegeneration in mice

“…The phenotypes of iTTBK1 mice, which include progressive weight loss, impaired movement and cognition, and cerebellar neurodegeneration, are reminiscent of human spinocerebellar ataxias. These disorders are likewise characterized by significant decline in body weight, impaired balance and coordination, damage to cerebellar Purkinje neurons, and cerebellar atrophy [ 5 , 11 ]. In addition to providing a system to study the neuronal functions of TTBK1, iTTBK1 mice may represent a new model for spinocerebellar ataxia or other disorders characterized by cerebellar dysfunction and degeneration.…”