FARA Funded Research

Using a multimodal neuroimaging protocol, combined with advanced analysis methods, the authors sought to identify macrostructural and microstructural alterations in the brain of patients with early-stage Friedreich ataxia to better understand its distribution patterns and progression. 28 patients with Friedreich ataxia and 20 age- and gender-matched controls were enrolled. Longitudinal clinical and imaging data were collected in the patients at baseline, 12, 24 and 36 months. Macrostructural differences were observed in patients with Friedreich ataxia, compared to controls, including lower volume of the cerebellar white matter (but not cerebellar grey matter), superior cerebellar peduncle, thalamus and brainstem structures, and higher volume of the fourth ventricle. Diffusion tensor imaging and fixel-based analysis metrics also showed microstructural differences in several brain regions, especially in the cerebellum and corticospinal tract. Over time, many of these macrostructural and microstructural alterations progressed, especially cerebellar grey and white matter volumes, and microstructure of the superior cerebellar peduncle, posterior limb of the internal capsule and superior corona radiata. In addition, linear regressions showed significant associations between many of those imaging metrics and clinical scales. This study provides evidence of early-stage macrostructural and microstructural alterations and of progression over time in the brain in Friedreich ataxia. Moreover, it allows to non-invasively map such brain alterations over a longer period (3 years) than any previous study, and identifies several brain regions with significant involvement in the disease progression besides the cerebellum. The authors show that fixel-based analysis of diffusion MRI data is particularly sensitive to longitudinal change in the cerebellar peduncles, as well as motor and sensory white matter tracts. In combination with other morphometric measures, they may therefore provide sensitive imaging biomarkers of disease progression for clinical trials.

Read More Here
 
 

Transforming growth factor beta (TGFβ) is named for the function it was originally discovered to perform-transformation of normal cells into aggressively growing malignant cells. It became apparent after more than 30 years of research, however, that TGFβ is a multifaceted molecule with a myriad of different activities. TGFβs are widely expressed with almost every cell in the human body producing one or another TGFβ family member and expressing its receptors. Importantly, specific effects of this growth factor family differ in different cell types and under different physiologic and pathologic conditions. One of the more important and critical TGFβ activities is the regulation of cell fate, especially in the vasculature, that will be the focus of this review.

Read More Here
 
 

In this study, the authors characterize features of vision loss in a large cohort of adults and children with FRDA. Using optical coherence tomography (OCT), we measured peripapillary retinal nerve fiber layer (RNFL) thickness in 198 people with FRDA, and 77 controls. Sloan letter charts were used to determine visual acuity. RNFL thickness and visual acuity were compared to measures of disease severity obtained from the Friedreich Ataxia Clinical Outcomes Measures Study (FACOMS). The majority of patients, including children, had pathologically thin RNFLs (mean = 73 ± 13 μm in FRDA; 98 ± 9 μm in controls) and low-contrast vision deficits early in the disease course. Variability in RNFL thickness in FRDA (range: 36 to 107 μm) was best predicted by disease burden (GAA-triplet repeat length X disease duration). Significant deficits in high-contrast visual acuity were apparent in patients with an RNFL thickness of ≤68 μm. RNFL thickness decreased at a rate of -1.2 ± 1.4 μm/year and reached 68 μm at a disease burden of approximately 12,000 GAA years, equivalent to disease duration of 17 years for participants with 700 GAAs. These data suggest that both hypoplasia and subsequent degeneration of the RNFL may be responsible for the optic nerve dysfunction in FRDA and support the development of a vision-directed treatment for selected patients early in the disease to prevent RNFL loss from reaching the critical threshold.

Read More Here
 
 

The aim of this work was to investigate whether anodal cerebellar transcranial direct current stimulation (ctDCS) reduces ataxic and cognitive symptoms in individuals with Friedreich's ataxia (FRDA) and to assess the effects of ctDCS on the activity of the secondary somatosensory (SII) cortex. The authors performed a single-blind, randomized, sham-controlled, crossover trial with anodal ctDCS (5 days/week for 1 week, 20 min/day, density current: 0.057 mA/cm2 ) in 24 patients with FRDA. Each patient underwent a clinical evaluation (Scale for the Assessment and Rating of Ataxia, composite cerebellar functional severity score, cerebellar cognitive affective syndrome scale) before and after anodal and sham ctDCS. Activity of the SII cortex contralateral to a tactile oddball stimulation of the right index finger was evaluated with brain functional magnetic resonance imaging at baseline and after anodal/sham ctDCS. Anodal ctDCS led to a significant improvement in the Scale for the Assessment and Rating of Ataxia (-6.5%) and in the cerebellar cognitive affective syndrome scale (+11%) compared with sham ctDCS. It also led to a significant reduction in functional magnetic resonance imaging signal at the SII cortex contralateral to tactile stimulation (-26%) compared with sham ctDCS. One week of treatment with anodal ctDCS reduces motor and cognitive symptoms in individuals with FRDA, likely by restoring the neocortical inhibition normally exerted by cerebellar structures. This study provides class I evidence that ctDCS stimulation is effective and safe in FRDA.

Read More Here