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FARAFARA Cure FA

 

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.

 


 

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

Phenothiazine antioxidants increase mitochondrial biogenesis and frataxin levels in Friedreich's ataxia cells

Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease that is linked to transcriptional repression of the nuclear FXN gene encoding the essential mitochondrial protein frataxin (FXN). Compounds that increase frataxin levels may enable effective therapeutic intervention for blunting disease progression. Recently, we showed that lipophilic methylene violet (MV) and methylene blue (MB) analogues both conferred benefit to cultured FRDA cells in several regards, including ROS suppression, maintenance of mitochondrial membrane potential and increased ATP production. Some of the MB analogues were also shown to promote increased frataxin levels and mitochondrial biogenesis. Presently, we report that two of the MV analogues studied previously (1 and 2) also increased frataxin levels and mitochondrial biogenesis significantly. Because the substitution pattern in the two series of compounds was not the same, we also prepared new MV derivatives having the same substitution pattern as the original MB derivatives studied to enable a more direct comparison. Two of the new MV compounds, 4b and 6b, exhibited enhanced antioxidant capability, increased frataxin levels and mitochondrial biogenesis, and improved aconitase activity. These encouraging findings demonstrated that the MV analogues had better overall activity with less cytotoxicity.

Read the entire article HERE

Automated functional upper limb evaluation of patients with Friedreich ataxia using serious games rehabilitation exercises

Friedreich ataxia (FRDA) is a disease with neurological and systemic involvement. Clinical assessment tools commonly used for FRDA become less effective in evaluating decay in patients with advanced FRDA, particularly when they are in a wheelchair. Further motor worsening mainly impairs upper limb function. In this study, we tested if serious games (SG) developed for rehabilitation can be used as an assessment tool for upper limb function even in patients with advanced FRDA.

A specific SG has been developed for physical rehabilitation of patients suffering from neurologic diseases. The use of this SG, coupled with Kinect sensor, has been validated to perform functional evaluation of the upper limbs with healthy subjects across lifespan. Twenty-seven FRDA patients were included in the study. Patients were invited to perform upper limb rehabilitation exercises embedded in SG. Motions were recorded by the Kinect and clinically relevant parameters were extracted from the collected motions. We tested if the existence of correlations between the scores from the serious games and the severity of the disease using clinical assessment tools commonly used for FRDA. Results of patients were compared with a group a healthy subjects of similar age.

Very highly significant differences were found for time required to perform the exercise (increase of 76%, t(68) = 7.22, P < 0.001) and for accuracy (decrease of 6%, t(68) = - 3.69, P < 0.001) between patients and healthy subjects. Concerning the patients significant correlations were found between age and time (R = 0.65, p = 0.015), accuracy (R = - 0.75, p = 0.004) and the total displacement of upper limbs. (R = 0.55, p = 0.031). Statistically significant correlations were found between the age of diagnosis and speed related parameters.

The results of this study indicate that SG reliably captures motor impairment of FRDA patients due to cerebellar and pyramidal involvement. Results also show that functional evaluation of FRDA patients can be performed during rehabilitation therapy embedded in games with the patient seated in a wheelchair.

The study was approved as a component of the EFACTS study ( Clinicaltrials.gov identifier NCT02069509 , registered May 2010) by the local institutional Ethics Committee (ref. P2010/132).

Read the entire article HERE

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