Neuroimagem na ataxia de Friedreich = novas abordagens e aplicações clínicas = Neuroimaging in Friedreich's ataxia = new approaches and clinical aplication

Rezende, Thiago Junqueira Ribeiro de; Advisor: França Junior, Marcondes Cavalcante. TESE DIGITAL (2017)(POR)

Abstract: Friedreich¿s ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide; it is characterized by early onset, sensory abnormalities and slowly progressive ataxia. Besides that, most of neuroimaging studies have been focused only in infratentorial structures of adult patients. Furthermore, studies comparing different phenotypes of disease does not exist. Therefore, the objective of this study is to assess, using multimodal magnetic (MRI) resonance imaging, patients with Friedreich ataxia to better comprehend the progression of brain damage, to identify the pattern of damage across disease phenotypes, to identify areas with abnormal iron deposits in the brain and to characterize the structures initially damaged in early disease stages. To accomplish that, we enrolled 25 adult patients with classical FRDA, 13 patients with late-onset FRDA and 12 pediatric patients. The FARS scale was employed to quantify the disease severity. To assess the structural damage in gray and white matter, we acquired T1-weighted, T2-weighted and DTI images of the brain. To evaluate these images, we used the following tools: FreeSurfer, T1 MultiAtlas, SPM, DTI MultiAtlas, SpineSeg and TBSS. After group comparisons, there was widespread microstructural damage in the cerebral white matter, including cerebellar peduncles, corpus callosum and pyramidal tracts of patients with FRDA. We also found gray matter volumetric reduction in the dentate nuclei of the cerebellum, brainstem and motor cortex. We did not find volumetric reduction over time, but there was progressive white matter microstructural damage in the corpus callosum, pyramidal tracts and superior cerebellar peduncles after 1 year of follow-up. Regarding the disease phenotypes, we found that both classical FRDA and LOFA have similar, but not identical neuroimaging signatures. Although subtle, the structural differences might help to explain the phenotypic differences seen in both conditions. The corticospinal tracts are damaged in both conditions, but more severely in the late-onset FRDA group, which may explain why pyramidal signs are more evident in the latter subgroup. We failed to identify iron deposits in brain regions other than the dentate nuclei of patients with FRDA. Finally, we found that the spinal cord and inferior cerebellar peduncles are the structures compromised in pediatric patients with FRDA.

Iron Sulfur and Molybdenum Cofactor Enzymes Regulate the Drosophila Life Cycle by Controlling Cell Metabolism

Marelja Z, Leimkühler S and Missirlis F (2018); Front. Physiol. 9:50. doi: 10.3389/fphys.2018.00050


Despite general agreement that frataxin is required for a functional nervous system, disagreement has been expressed on the cause, with different authors favoring oxidative stress (Llorens et al., 2007; Anderson et al., 2008; Kondapalli et al., 2008), iron toxicity (Soriano et al., 2013; Navarro et al., 2015), altered mitochondrial metabolism (Navarro et al., 2010; Tricoire et al., 2014; Calap-Quintana et al., 2015; Soriano et al., 2016), sphingolipid signaling (Chen et al., 2016b), and failure to maintain neuronal membrane potential (Shidara and Hollenbeck, 2010). We do not see any contradiction in the various positive claims made in the above-cited literature, whereas the negative claim that is often repeated—refuting a role for oxidative stress in explaining the phenotypes—normally arises because of failure to rescue the phenotypes with some transgenes as opposed to others.

Coenzyme Q10 Supplementation in Aging and Disease

Hernández-Camacho JD, Bernier M, López-Lluch G and Navas P. Front. Physiol. 9:44. doi: 10.3389/fphys.2018.00044

Coenzyme Q (CoQ) is an essential component of the mitochondrial electron transport chain and an antioxidant in plasma membranes and lipoproteins. It is endogenously produced in all cells by a highly regulated pathway that involves a mitochondrial multiprotein complex. Defects in either the structural and/or regulatory components of CoQ complex or in non-CoQ biosynthetic mitochondrial proteins can result in a decrease in CoQ concentration and/or an increase in oxidative stress. Besides CoQ10 deficiency syndrome and aging, there are chronic diseases in which lower levels of CoQ10 are detected in tissues and organs providing the hypothesis that CoQ10 supplementation could alleviate aging symptoms and/or retard the onset of these diseases. Here, we review the current knowledge of CoQ10 biosynthesis and primary CoQ10 deficiency syndrome, and have collected published results from clinical trials based on CoQ10 supplementation. There is evidence that supplementation positively affects mitochondrial deficiency syndrome and the symptoms of aging based mainly on improvements in bioenergetics. Cardiovascular disease and inflammation are alleviated by the antioxidant effect of CoQ10. There is a need for further studies and clinical trials involving a greater number of participants undergoing longer treatments in order to assess the benefits of CoQ10 treatment in metabolic syndrome and diabetes, neurodegenerative disorders, kidney diseases, and human fertility.

Commentary: Novelty Seeking and Reward Dependence-Related Large-Scale Brain Networks Functional Connectivity Variation During Salience Expectancy

Cristiano Crescentini. Front. Psychol. doi: 10.3389/fpsyg.2018.00242 (General Commentary ARTICLE Provisionally accepted, The full-text will be published soon)

In recent years several neuropsychological and psychiatry studies employed the psychobiological model of temperament and character to investigate the relationship between personality and neuropsychological function in patients with Parkinson’s disease, Friedreich Ataxia, attention-deficit/hyperactivity disorder, eating disorders, and antisocial behavior.
These studies indicated that alterations in personality and cognition are not independent from each other, in that poor development of specific personality traits appears to be associated with deficits in neuropsychological performance, in particular in advanced cognition such as executive functions.

GAA•TTC repeat expansion in human cells is mediated by mismatch repair complex MutLγ and depends upon the endonuclease domain in MLH3 isoform one

Anasheh Halabi Kayla T B Fuselier Ed Grabczyk. Nucleic Acids Research, gky143, doi:10.1093/nar/gky143

DNA repeat expansion underlies dozens of progressive neurodegenerative disorders. While the mechanisms driving repeat expansion are not fully understood, increasing evidence suggests a central role for DNA mismatch repair. The mismatch repair recognition complex MutSβ (MSH2-MSH3) that binds mismatched bases and/or insertion/deletion loops has previously been implicated in GAA•TTC, CAG•CTG and CGG•CCG repeat expansion, suggesting a shared mechanism. MutSβ has been studied in a number of models, but the contribution of subsequent steps mediated by the MutL endonuclease in this pathway is less clear. Here we show that MutLγ (MLH1-MLH3) is the MutL complex responsible for GAA•TTC repeat expansion. Lentiviral expression of shRNA targeting MutL nuclease components MLH1, PMS2, and MLH3 revealed that reduced expression of MLH1 or MLH3 reduced the repeat expansion rate in a human Friedreich ataxia cell model, while targeting PMS2 did not. Using splice-switching oligonucleotides we show that MLH3 isoform 1 is active in GAA•TTC repeat expansion while the nuclease-deficient MLH3 isoform 2 is not. MLH3 isoform switching slowed repeat expansion in both model cells and FRDA patient fibroblasts. Our work indicates a specific and active role for MutLγ in the expansion process and reveals plausible targets for disease-modifying therapies.

BMN 290 for Friedreich's Ataxia

News provided by BioMarin Pharmaceutical Inc.; SAN RAFAEL, Calif., Feb. 22, 2018 /PRNewswire/

In the fourth quarter of 2017, BioMarin announced that it had selected as its next drug development candidate, BMN 290, a selective chromatin modulation therapy intended for treatment of Friedreich's ataxia. Friedreich's ataxia is a rare autosomal recessive disorder that results in disabling neurologic and cardiac progressive decline. Prior to the compound being acquired by BioMarin from Repligen Corporation (Repligen), it demonstrated increases in frataxin in Friedreich's ataxia patients. In preclinical models, BMN 290 increases frataxin expression in brain tissues more than two-fold. The Company selected BMN 290 for its favorable penetration into the central nervous system and cardiac target tissues, and its preservation of the selectivity of the original Repligen compound. Currently, there are no approved disease modifying therapies for Friedreich's ataxia. The Company expects to submit the IND application for BMN 290 in the second half of 2018.

Mapping the Structural Determinants Required for AAVrh.10 Transport across the Blood-Brain Barrier

Blake H. Albright, Claire M. Storey, Giridhar Murlidharan, Ruth M. Castellanos Rivera, Garrett E. Berry, Victoria J. Madigan, Aravind Asokan; Molecular Therapy, Volume 26, Issue 2, p510–523, 7 February 2018 DOI: 10.1016/j.ymthe.2017.10.017

Effective gene delivery to the CNS by intravenously administered adeno-associated virus (AAV) vectors requires crossing the blood-brain barrier (BBB). To achieve therapeutic CNS transgene expression, high systemic vector doses are often required, which poses challenges such as scale-up costs and dose-dependent hepatotoxicity. To improve the specificity and efficiency of CNS gene transfer, a better understanding of the structural features that enable AAV transit across the BBB is needed. We generated a combinatorial domain swap library using AAV1, a serotype that does not traverse the vasculature, and AAVrh.10, which crosses the BBB in mice. We then screened individual variants by phylogenetic and structural analyses and subsequently conducted systemic characterization in mice. Using this approach, we identified key clusters of residues on the AAVrh.10 capsid that enabled transport across the brain vasculature and widespread neuronal transduction in mice. Through rational design, we mapped a minimal footprint from AAVrh.10, which, when grafted onto AAV1, confers the aforementioned CNS phenotype while diminishing vascular and hepatic transduction through an unknown mechanism. Functional mapping of this capsid surface footprint provides a roadmap for engineering synthetic AAV capsids for efficient CNS gene transfer with an improved safety profile.

Hepcidin, an emerging and important player in brain iron homeostasis

Driton Vela. Journal of Translational Medicine 201816:25 doi:10.1186/s12967-018-1399-5

Iron dysregulation has been observed consistently in different organs in Friedreich ataxia (FA). This disease affects CNS by causing neurodegenerative damages in dentate nuclei of the cerebellum, dorsal root ganglia, but also in cerebrum, thalamus and other structures. FA is caused by a defective frataxin, which main functions include involvement in iron-sulfur cluster formation and in iron delivery to ferrochelatase. Although some observations did find iron accumulation in dentate nuclei in FA patients, other studies have revealed a pattern of iron redistribution, rather than iron accumulation in FA. Studies suggest that iron dysregulation in FA is not needed for neurodegeneration to occur, while animal models reveal tissue-specific damages due to frataxin deficiency. These differences are related with levels of frataxin expression, where most of the damage is observed in tissues with higher expression of frataxin, such as the heart and dorsal root ganglia. In the heart, inflammatory infiltrate produces hepcidin and has been proposed as one of the pathogenic mechanisms of heart damage in FA. Frataxin deficiency in animal models can cause a strong inflammatory reaction in Schwann cells, which are known to enwrap neurons of dorsal root ganglia. These neurons are frequently affected in FA and are characterized with iron dysregulation and inappropriate myelination. But, hepcidin expression in these cells has not been studied in models of FA, therefore it is not known what role, if any, does hepcidin have in the pathophysiology of neurodegeneration in FA.

Perceived Fatigue and Energy are Independent Unipolar States: Supporting Evidence

Bryan D. Loy, Michelle H. Cameron, Patrick J. O'Connor, Medical Hypotheses, Available online 19 February 2018, ISSN 0306-9877, doi:10.1016/j.mehy.2018.02.014.

Persistent fatigue is a common problem (∼20-45% of U.S. population), with higher prevalence and severity in people with medical conditions such as cancer, depression, fibromyalgia, heart failure, sleep apnea and multiple sclerosis. There are few FDA-approved treatments for fatigue and great disagreement on how to measure fatigue, with over 250 instruments used in research. Many instruments define fatigue as “a lack of energy”, thus viewing energy and fatigue states as opposites on a single bipolar continuum. In this paper, we hypothesize that energy and fatigue are distinct perceptual states, should be measured using separate unipolar scales, have different mechanisms, and deficits should be treated using tailored therapies. Energy and fatigue independence has been found in both exploratory and confirmatory factor analysis studies. Experiments in various fields, including behavioral pharmacology and exercise science, often find changes in energy and not fatigue, or vice versa. If the hypothesis that energy and fatigue are independent is correct, there are likely different mechanisms that drive energy and fatigue changes. Energy could be increased by elevated dopamine and norepinephrine transmission and binding. Fatigue could be increased by elevated brain serotonin and inflammatory cytokines and reduced histamine binding. The hypothesis could be tested by an experiment that attempts to produce simultaneously high ratings of energy and fatigue (such as with two drugs using a randomized, double-blind, placebo-controlled design), which would offer strong evidence against the common viewpoint of a bipolar continuum. If the hypothesis is correct, prior literature using bipolar instruments will be limited, and research on the prevalence, mechanisms, and treatment of low energy and elevated fatigue as separate conditions will be needed. In the immediate future, measuring both energy and fatigue using unipolar measurement tools may improve our understanding of these states and improve therapeutic outcomes.
When mental and physical aspects of energy and fatigue were measured in individuals with Friedreich’s ataxia, low physical energy was found while no differences were observed for mental energy or mental or physical fatigue. This type of information appears logical and is potentially useful because Friedreich’s ataxia is a disease that targets pyramidal nerves, causing muscle incoordination and reduced physical activity that worsens over time yet largely preserves mental functioning.

Progress in the treatment of Friedreich ataxia

Geneieve Tai, Louise A. Corben, Eppie M. Yiu, Sarah C. Milne, Martin B. Delatycki, Neurologia i Neurochirurgia Polska, Available online 19 February 2018, ISSN 0028-3843, doi:10.1016/j.pjnns.2018.02.003.

Friedreich ataxia (FRDA) is a progressive neurological disorder affecting approximately 1 in 29,000 individuals of European descent. At present, there is no approved pharmacological treatment for this condition however research into treatment of FRDA has advanced considerably over the last two decades since the genetic cause was identified. Current proposed treatment strategies include decreasing oxidative stress, increasing cellular frataxin, improving mitochondrial function as well as modulating frataxin controlled metabolic pathways. Genetic and cell based therapies also hold great promise. Finally, physical therapies are being explored as a means of maximising function in those affected by FRDA.