Sensitivity of Neuroimaging Indicators in Monitoring the Effects of Interferon Gamma Treatment in Friedreich’s Ataxia

Abstract

The identification of efficient markers of disease progression and response to possibly effective treatments is a key priority for slowly progressive, rare and neurodegenerative diseases, such as Friedreich’s ataxia. Various imaging modalities have documented specific abnormalities in Friedreich’s ataxia that could be tracked to provide useful indicators of efficacy in clinical trials. Advanced MRI imaging (diffusion tensor imaging, DTI; functional MRI, fMRI; and resting-state fMRI, rs-fMRI) and retinal imaging (optical coherence tomography, OCT) were tested longitudinally in a small group of Friedreich’s ataxia patients participating in an open-label clinical trial testing the safety and the efficacy of 6-month treatment with interferon gamma. While the DTI indices documented the slow progression of fractional anisotropy loss, fMRI and rs-fMRI were significantly modified during and after treatment. The fMRI changes significantly correlated with the Scale for the Assessment and Rating of Ataxia, which is used to monitor clinical response. OCT documented the known thickness reduction of the retinal nerve fiber layer thickness, but there was no change over time. This pilot study provides indications for the potential utility of fMRI and rs-fMRI as ancillary measures in clinical trials for Friedreich’s ataxia.

Functional MRI Studies in Friedreich's Ataxia: A Systematic Review

“…Treatment of the FRDA group was reported only in two studies, mentioned as chronic treatment ( 13 , 30 ) or an ongoing open-label phase II study ( 34 , 35 ).…”

“…One study performed imaging in different types of patients with ataxia, including FRDA, SCA3, and SCA6, analyzing the groups separately and comparing with HC groups (12). (13,30) or an ongoing open-label phase II study (34,35).…”

“…Screen projections were used by most studies to present inscanner instructions to the participants for the cognitive and motor tasks (12,13,20,(29)(30)(31)34).…”

“…Alternatively, one study performed only a qualitative evaluation of the group differences by a visual inspection (26), while the two task fMRI studies exploited a two-stage Bayesian method (37) to perform intragroup and intergroup analyses (28,29). Activation map analyses were generally performed at a voxel level across the whole brain (at least for exploratory purposes) (27)(28)(29)31), restricted to some ROIs that were identified either a priori (12,30), data-driven (13,20,34), or a with a mixed approach (33). The ROI-based approach was usually exploited for detailed post-hoc analyses, where the activation values measured in the significant clusters/ROIs, the average time series, or the ROI-based connectivity measures were further investigated.…”

Drug Repositioning in Friedreich Ataxia

“…However, the 12 months open-label extension of the same study showed a potential benefit toward expected disease progression in treated patients ( Lynch et al, 2019 ). More recently, an open-label phase II trial measuring the SARA score and using instrumental evaluations including electro/echocardiography ( Vavla et al, 2020b ) and Diffusion Tensor Magnetic Resonance Imaging of the brain ( Vavla et al, 2020a ), was completed over an observation time of 18 months. The progression of SARA was completely halted during IFN-γ treatment and slightly resumed after termination of the treatment.…”