Cerebral abnormalities in Friedreich ataxia: A review

Selvadurai, Louisa P.; Harding, Ian H.; Corben, Louise A.; Georgiou‐Karistianis, Nellie

doi:10.1016/j.neubiorev.2017.08.006

Cited by 48 publications

(36 citation statements)

References 114 publications

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“…Additionally, the three pairs of cerebellar peduncles are of particular interest in FRDA as a cerebellar disorder, and there is previous MRI evidence of disruption to these pathways, most consistently in the superior cerebellar peduncle (Selvadurai et al, 2018). Furthermore, the corticospinal tracts are implicated in FRDA given the pyramidal weakness and extensor plantar reflexes forming part of the clinical picture, previous evidence of disruption across multiple diffusion metrics, and evidence of loss of Betz cells at the cortical termination of the tract (Koeppen & Makurkiewicz, 2013; Parkinson et al, ; Selvadurai et al, ). The superior longitudinal fasciculus was selected as a representative association tract due to consistent evidence of between‐group differences across the metrics in the current analysis (differences were found in FA, MD, AD, and RD).…”

Section: Methodsmentioning

confidence: 99%

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE‐FRDA study

Selvadurai

Corben

Delatycki

et al. 2020

Human Brain Mapping

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Friedreich ataxia is a progressive neurodegenerative disorder with reported abnormalities in cerebellar, brainstem, and cerebral white matter. White matter structure can be measured using in vivo neuroimaging indices sensitive to different white matter features. For the first time, we examined the relative sensitivity and relationship between multiple white matter indices in Friedreich ataxia to more richly characterize disease expression and infer possible mechanisms underlying the observed white matter abnormalities. Diffusion‐tensor, magnetization transfer, and T1‐weighted structural images were acquired from 31 individuals with Friedreich ataxia and 36 controls. Six white matter indices were extracted: fractional anisotropy, diffusivity (mean, axial, radial), magnetization transfer ratio (microstructure), and volume (macrostructure). For each index, whole‐brain voxel‐wise between‐group comparisons and correlations with disease severity, onset age, and gene triplet‐repeat length were undertaken. Correlations between pairs of indices were assessed in the Friedreich ataxia cohort. Spatial similarities in the voxel‐level pattern of between‐group differences across the indices were also assessed. Microstructural abnormalities were maximal in cerebellar and brainstem regions, but evident throughout the brain, while macroscopic abnormalities were restricted to the brainstem. Poorer microstructure and reduced macrostructural volume correlated with greater disease severity and earlier onset, particularly in peri‐dentate nuclei and brainstem regions. Microstructural and macrostructural abnormalities were largely independent. Reduced fractional anisotropy was most strongly associated with axial diffusivity in cerebral tracts, and magnetization transfer in cerebellar tracts. Multiple mechanisms likely underpin white matter abnormalities in Friedreich ataxia, with differential impacts in cerebellar and cerebral pathways.

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Section: Methodsmentioning

confidence: 99%

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE‐FRDA study

Selvadurai

Corben

Delatycki

et al. 2020

Human Brain Mapping

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“…Iron dysregulation has been observed consistently in different organs in Friedreich ataxia (FA) [ 148 ]. 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 [ 149 ]. FA is caused by a defective frataxin, which main functions include involvement in iron-sulfur cluster formation and in iron delivery to ferrochelatase [ 148 ].…”

Section: Hepcidin In Brain Diseasesmentioning

confidence: 99%

Hepcidin, an emerging and important player in brain iron homeostasis

Vela

2018

J Transl Med

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Hepcidin is emerging as a new important factor in brain iron homeostasis. Studies suggest that there are two sources of hepcidin in the brain; one is local and the other comes from the circulation. Little is known about the molecular mediators of local hepcidin expression, but inflammation and iron-load have been shown to induce hepcidin expression in the brain. The most important source of hepcidin in the brain are glial cells. Role of hepcidin in brain functions has been observed during neuronal iron-load and brain hemorrhage, where secretion of abundant hepcidin is related with the severity of brain damage. This damage can be reversed by blocking systemic and local hepcidin secretion. Studies have yet to unveil its role in other brain conditions, but the rationale exists, since these conditions are characterized by overexpression of the factors that stimulate brain hepcidin expression, such as inflammation, hypoxia and iron-overload.

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“…Indeed, FA has been typically considered as a neurodegenerative disorder [ 3 , 11 , 12 , 22 ], depending upon an imbalance of the oxidative metabolism [ 22 , 63 ], whose consequences at the tissue level were found to primarily concern the spinal cord in either the posterior funiculus or the spinothalamic and spinocerebellar pathways [ 2 , 7 , 8 , 11 , 12 , 28 , 34 , 64 ], which bear a relevant significance in modulating afferent information as well as motor function. This resulted in a complex deficit of sensory functions and of deep reflexes, in turn leading to the observed ataxic phenotype, typical of the disorder [ 9 , 16 , 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

“…The neural and the cardiovascular phenotypes share a common pathogenic mechanism, based on the evidence that FA is a mitochondrial disorder, affecting at the same time the nervous and the hearth tissue [ 6 , 12 , 20 , 21 , 22 , 23 ] as a consequence of the mutation of the gene encoding the mitochondrial protein Frataxin [ 24 ]. This protein plays a relevant role in modulating oxidative phosphorylation, consistent with the contribution of the mutation of the underlying gene to the disorder pathogenesis, in turn implying mitochondrial iron and sulfur accumulation within the nervous and the cardiac tissues, which results in their degeneration [ 7 , 12 , 23 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 96%

Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration

et al. 2020

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In this study, the neural phenotype is explored in rodent models of the spinocerebellar disorder known as the Friedreich Ataxia (FA), which results from mutations within the gene encoding the Frataxin mitochondrial protein. For this, the M12 line, bearing a targeted mutation, which disrupts the Frataxin gene exon 4 was used, together with the M02 line, which, in addition, is hemizygous for the human Frataxin gene mutation (Pook transgene), implying the occurrence of 82–190 GAA repeats within its first intron. The mutant mice phenotype was compared to the one of wild type littermates in regions undergoing differential profiles of neurogenesis, including the cerebellar cortex and the spinal cord by using neuronal (β-tubulin) and glial (Glial Fibrillary Acidic Protein) markers as well as the Contactin 1 axonal glycoprotein, involved in neurite growth control. Morphological/morphometric analyses revealed that while in Frataxin mutant mice the neuronal phenotype was significantly counteracted, a glial upregulation occurred at the same time. Furthermore, Contactin 1 downregulation suggested that changes in the underlying gene contributed to the disorder pathogenesis. Therefore, the FA phenotype implies an alteration of the developmental profile of neuronal and glial precursors. Finally, epigallocatechin gallate polyphenol administration counteracted the disorder, indicating protective effects of antioxidant administration.

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Cerebral abnormalities in Friedreich ataxia: A review

Cited by 48 publications

References 114 publications

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE‐FRDA study

Multiple mechanisms underpin cerebral and cerebellar white matter deficits in Friedreich ataxia: The IMAGE‐FRDA study

Hepcidin, an emerging and important player in brain iron homeostasis

Molecular and Cellular Substrates for the Friedreich Ataxia. Significance of Contactin Expression and of Antioxidant Administration

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