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Scientific News

FARA funds research progress

In this section, you will find the most recent FA research publications, many of which are funded by FARA, as well as information on upcoming conferences and symposiums. You can search for articles by date using the archive box in the right hand column. To locate FARA Funded or Supported Research, click the hyperlink in the right hand column. You may also search for specific content using key words or phrases in the search button at the top right of your screen. Please be sure to visit other key research sections of our website for information on FARA’s Grant Program and the Treatment Pipeline.



Plasma Markers of Neurodegeneration Are Raised in Friedreich's Ataxia

Friedreich's ataxia (FRDA) is the most common autosomal recessive ataxia. Disease-modifying treatments are not available yet; however, several compounds are currently under investigation. As a result, there is a growing need for the identification of robust and easily accessible biomarkers for the monitoring of disease activity and therapeutic efficacy. The simultaneous measurement of multiple brain-derived proteins could represent a time- and cost-efficient approach for biomarker investigation in pathologically complex neurodegenerative diseases like FRDA. This paper looked at the role of plasma neurofilament-light chain (NfL), glial fibrillary acidic protein (GFAP), total tau (t-tau) and ubiquitin C-terminal hydrolase L1(UCHL1) as biomarkers in FRDA. In this study, an ultrasensitive Single molecule array (Simoa) 4-plex assay was used for the measurement of plasma NfL, GFAP, t-tau, and UCHL1 in 33 FRDA patients and 13 age-matched controls. Differences in biomarker concentrations between these groups were computed and associations with genetic and disease related parameters investigated. Additionally, the agreement between NfL measurements derived from the 4-Plex and an established Simoa NfL singleplex assay was assessed. Mean plasma NfL, GFAP and UCHL1 levels were significantly higher in FRDA patients than in controls, but there was no significant difference in concentrations of t-tau in the patient and control group. None of the proteins correlated with the GAA repeat length or the employed measures of disease severity. This is the first study demonstrating that NfL, GFAP, and UCHL1 levels are raised in FRDA, potentially reflecting ongoing neuronal degeneration and glial activation. Further studies are required to determine their role as marker for disease activity and progression. Furthermore, the novel 4-plex assay appears to be a valid tool to simultaneously measure brain-derived proteins at extremely low concentrations in the peripheral circulation.

Read the entire article HERE

Intraepidermal Nerve Fiber Density in Friedreich's Ataxia

FRDA affects primarily the peripheral nervous system (PNS) with cumulative evidence suggesting that there may be a developmental component of its pathology. In this study, the authors aimed at gaining further insight in the PNS involvement in FRDA by investigating small nerve fibers in patients. They evaluated the intraepidermal nerve fiber (IENF) density in skin-biopsies of the lower leg, and applied clinical assessments of small fiber function in 17 FRDA patients. Mean IENF density was significantly lower in FRDAs compared to controls. Clinically, cold detection threshold was decreased in FRDAs while other measures of small fiber function such as warm and pain sensation thresholds did not differ from controls. Five patients had sensory complaints, but none was diagnosed with neuropathic pain. The degree of small fiber loss was markedly variable in this cohort and showed an inverse correlation with the GAA repeat length. These findings support a genetically determined small fiber loss in FRDA

Read the entire article HERE

Calcium Deregulation: Novel Insights to Understand Friedreich's Ataxia Pathophysiology

Friedreich's Ataxia (FRDA) is a neurodegenerative disorder, characterized by degeneration of dorsal root ganglia, cerebellum and cardiomyopathy. This study investigates Ca2+ homeostasis in cerebellar granule neurons (CGNs) and in cardiomyocytes to understand the pathogenesis of degeneration. Ca2+ homeostasis in neurons and cardiomyocytes is not only crucial for cell health, but is also importantly involved in the ability of both neurons and cardiomyocytes to function. By challenging Ca2+ homeostasis in CGNs, and in adult and neonatal cardiomyocytes of FRDA models, we have assessed the impact of frataxin decrease on both neuronal and cardiac physiopathology. Interestingly, we have found that Ca2+ homeostasis is altered both cell types. CGNs showed a Ca2+ mishandling under depolarizing conditions and this was also reflected in the endoplasmic reticulum (ER) content. In cardiomyocytes we found that the sarcoplasmic reticulum (SR) Ca2+ content was pathologically reduced, and that mitochondrial Ca2+ uptake was impaired. Our findings demonstrate that in both neurons and cardiomyocytes the decreased Ca2+ level within the stores has a comparable detrimental impact in their physiology. In cardiomyocytes, we found that ryanodine receptors (RyRs) may be leaking and expel more Ca2+ out from the SR. At the same time mitochondrial uptake was altered and we found that Vitamin E can restore this defect. Moreover, Vitamin E protects from cell death induced by hypoxia-reperfusion injury, revealing novel properties of Vitamin E as potential therapeutic tool for FRDA cardiomyopathy.

Read the entire article HERE

Developmental and Neurodegenerative Damage in Friedreich Ataxia

Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide; it is characterized by early onset, sensory abnormalities and slowly progressive ataxia. This group designed a cross sectional multimodal MRI-based study to investigate the anatomical substrates involved in the early stages of FRDA. They enrolled 37 patients (12 children) and 38 controls. All subjects underwent magnetic resonance imaging in a 3T device to assess gray and white matter. They used a variety of techniques to look at the cerebral and cerebellar cortices, deep grey matter, microstructural abnormalities in brain white matter, and in the cervical spinal cord. Comparison with age-matched controls showed that pediatric patients have spinal cord, inferior cerebellar peduncle and red nucleus damage. In contrast, the adult patients showed more widespread white matter damage than pediatric patients. Regarding grey matter, they found cortical thinning at the left central sulcus and volumetric reduction in the thalami and hippocampi only in adult patients. Finally, values of FA in adult patients and RD in pediatric patients from inferior cerebellar peduncle correlated with disease duration and ataxia severity, respectively.

The authors conclude that structural damage in FRDA begins in spinal cord, inferior cerebellar peduncle as well as red nucleus, and progresses to cerebral areas in adulthood. These results shed some light in the early FRDA stages and highlight potential neuroimaging markers for therapeutic trials.

Read the entire article HERE

Corneal Confocal Microscopy: Neurologic Disease Biomarker in Friedreich's Ataxia

This group evaluated corneal confocal microscopy (CCM) quantification of corneal nerve morphology as a novel, non‐invasive, in vivo quantitative imaging biomarker for the severity of neurological manifestations in FRDA. Corneal nerve fiber density, branch density and fiber length were quantified in individuals with FRDA (n=23) and healthy age‐matched controls (n=14). All individuals underwent genetic testing and a detailed neurological assessment with the SARA and FARS scales. A subset of individuals with FRDA who were ambulatory underwent quantitative gait assessment.

CCM demonstrated a significant reduction in nerve fiber density and length in FRDA compared to healthy controls. Importantly, CCM parameters correlated with genotype, SARA and FARS neurological scales, and linear regression modeling of CCM nerve parameters generated equations that predict the neurologic severity of FRDA. Together, the data suggests that CCM quantification of corneal nerve morphology is a rapid, sensitive imaging biomarker for quantifying the severity of neurologic disease in individuals with FRDA.

Read the entire article HERE

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