NESSCA Validation and Responsiveness of Several Rating Scales in Spinocerebellar Ataxia Type 2.

Spinocerebellar ataxia type 2 (SCA2), caused by a CAG expansion (CAGexp) at ATXN2, has a complex clinical picture. While validated ataxia scales are available, comprehensive instruments to measure all SCA2 neurological manifestations are required. This study aims to validate the Neurological Examination Score for the assessment of Spinocerebellar Ataxias (NESSCA) to be used in SCA2 and to compare its responsiveness to those obtained with other instruments. NESSCA, SARA, SCAFI, and CCFS scales were applied in symptomatic SCA2 patients. Correlations were done with age at onset, disease duration, CAGexp, and between scales. Responsiveness was estimated by comparing deltas of stable to worse patients after 12 months, according to Patient Global Impression of change, and the area under the curve (AUC) of the Receiver Operating Characteristics curve of scores range. Eighty-eight evaluations (49 patients) were obtained. NESSCA had an even distribution and correlated with disease duration (r = 0.55), SARA (r = 0.63), and CAGexp (rho = 0.32): both explained 44% of NESSCA variance. Deltas (95% CI) after 1 year in stable and worse patients were only significantly different for SARA. NESSCA, SARA, SCAFI, and CCFS AUC were 0.63, 0.81, 0.49, and 0.48, respectively. NESSCA is valid to be used in SCA2. However, the only instrument that presented good responsiveness to change in 1 year was SARA. We suggest that NESSCA can be used as a secondary outcome in future trials in SCA2 due to the burden of neurological disabilities related to disease progression.

Corrigendum: Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype.

[This corrects the article on p. 219 in vol. 9, PMID: 26089779.].

Long-term NMDAR antagonism correlates reduced astrocytic glutamate uptake with anxiety-like phenotype.

The role of glutamate N-methyl-D-aspartate receptor (NMDAR) hypofunction has been extensively studied in schizophrenia; however, less is known about its role in anxiety disorders. Recently, it was demonstrated that astrocytic GLT-1 blockade leads to an anxiety-like phenotype. Although astrocytes are capable of modulating NMDAR activity through glutamate uptake transporters, the relationship between astrocytic glutamate uptake and the development of an anxiety phenotype remains poorly explored. Here, we aimed to investigative whether long-term antagonism of NMDAR impacts anxiety-related behaviors and astrocytic glutamate uptake. Memantine, an NMDAR antagonist, was administered daily for 24 days to healthy adult CF-1 mice by oral gavage at doses of 5, 10, or 20 mg/kg. The mice were submitted to a sequential battery of behavioral tests (open field, light-dark box and elevated plus-maze tests). We then evaluated glutamate uptake activity and the immunocontents of glutamate transporters in the frontoparietal cortex and hippocampus. Our results demonstrated that long-term administration of memantine induces anxiety-like behavior in mice in the light-dark box and elevated plus-maze paradigms. Additionally, the administration of memantine decreased glutamate uptake activity in both the frontoparietal cortex and hippocampus without altering the immunocontent of either GLT-1 or GLAST. Remarkably, the memantine-induced reduction in glutamate uptake was correlated with enhancement of an anxiety-like phenotype. In conclusion, long-term NMDAR antagonism with memantine induces anxiety-like behavior that is associated with reduced glutamate uptake activity but that is not dependent on GLT-1 or GLAST protein expression. Our study suggests that NMDAR and glutamate uptake hypofunction may contribute to the development of conditions that fall within the category of anxiety disorders.