Cerebral compensation during motor function in Friedreich ataxia: The IMAGE‐FRDA study

Harding, Ian H.; Corben, Louise A.; Delatycki, Martin B.; Stagnitti, Monique R.; Storey, Elsdon; Egan, Gary F.; Georgiou‐Karistianis, Nellie

doi:10.1002/mds.27023

Cited by 22 publications

(27 citation statements)

References 42 publications

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“…From the L-hand motor task, we observed significant activations of the R M1, R insula, and L superior cerebellar hemisphere (lobules V, VII, VIII). The areas activated in the cerebellum with R and L hand during the motor task were comparable to the areas found in other studies ( 20 – 23 ) (Table S4 ). Our intergroup analysis showed no significant differences during the dominant-hand task, differently from other studies that have reported either reduction of activation in M1, thalamus, DN, and lobule V ( 21 , 22 ) or increase of activation in parietal cortex, striatum, supplementary motor area, and lobule VII ( 20 – 22 ) Interestingly, we found a significant difference during the non-dominant hand motor task with a stronger activation in the L superior cerebellar hemisphere in HCs when compared to FRDA.…”

Section: Discussionsupporting

confidence: 87%

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Functional and Structural Brain Damage in Friedreich's Ataxia

et al. 2018

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Friedreich's ataxia (FRDA) is a rare hereditary neurodegenerative disorder caused by a GAA repeat expansion in the FXN gene. There is still no cure or quantitative biomarkers reliaby correlating with the progression rate and disease severity. Investigation of functional and structural alterations characterizing white (WM) and gray matter (GM) in FRDA are needed prerequisite to monitor progression and response to treatment. Here we report the results of a multimodal cross-sectional MRI study of FRDA including Voxel-Based Morphometry (VBM), diffusion-tensor imaging (DTI), functional MRI (fMRI), and a correlation analysis with clinical severity scores. Twenty-one early-onset FRDA patients and 18 age-matched healthy controls (HCs) were imaged at 3T. All patients underwent a complete cognitive and clinical assessment with ataxia scales. VBM analysis showed GM volume reduction in FRDA compared to HCs bilaterally in lobules V, VI, VIII (L>R), as well as in the crus of cerebellum, posterior lobe of the vermis, in the flocculi and in the left tonsil. Voxel-wise DTI analysis showed a diffuse fractional anisotropy reduction and mean, radial, axial (AD) diffusivity increase in both infratentorial and supratentorial WM. ROI-based analysis confirmed the results showing differences of the same DTI metrics in cortico-spinal-tracts, forceps major, corpus callosum, posterior thalamic radiations, cerebellar penduncles. Additionally, we observed increased AD in superior (SCP) and middle cerebellar peduncles. The WM findings correlated with age at onset (AAO), short-allelle GAA, and disease severity. The intragroup analysis of fMRI data from right-handed 14 FRDA and 15 HCs showed similar findings in both groups, including activation in M1, insula and superior cerebellar hemisphere (lobules V–VIII). Significant differences emerged only during the non-dominant hand movement, with HCs showing a stronger activation in the left superior cerebellar hemisphere compared to FRDA. Significant correlations were found between AAO and the fMRI activation in cerebellar anterior and posterior lobes, insula and temporal lobe. Our multimodal neuroimaging protocol suggests that MRI is a useful tool to document the extension of the neurological impairment in FRDA.

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Section: Discussionsupporting

confidence: 87%

“…Few functional MRI (fMRI) studies have been performed in FRDA, including either motor ( 19 – 23 ) or non-motor tasks ( 15 , 24 , 25 ). These studies reported overall significant differences of activation in the posterior cerebellar lobules ( 20 , 22 ) and in the cortical motor and sensory areas ( 19 – 22 ).…”

Section: Introductionmentioning

confidence: 99%

Functional and Structural Brain Damage in Friedreich's Ataxia

et al. 2018

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“…Data was collected as part of IMAGE‐FRDA, a single‐site longitudinal multi‐modal neuroimaging study (Monash University, Melbourne, data collection 2013–2016) (Harding et al, ; Harding et al, ; Selvadurai et al, ). Data from 36 individuals with FRDA and 37 age‐ and gender‐matched control participants were acquired for analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Within the central nervous system, the most prominent pathology includes atrophy of the dorsal spinal tracts and cerebellar dentate nuclei (Pandolfo, ). Neuroimaging studies of cerebral gray and white matter demonstrate compelling evidence of abnormalities in cerebral structure (Della Nave, Ginestroni, Giannelli, et al, ; Rezende et al, ; Selvadurai et al, ), function (Dogan et al, ; Georgiou‐Karistianis et al, ; Harding et al, ; Harding et al, ), and both intra‐cerebral and cerebello‐cerebral connectivity (Akhlaghi et al, ; Akhlaghi et al, ; Cocozza et al, ; Dogan et al, ; Harding et al, ; Rizzo et al, ; Zalesky et al, ). This body of evidence represents significant advances in the characterization of brain changes in individuals with FRDA.…”

Section: Introductionmentioning

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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“…In the central nervous system, pathology preferentially targets the dentate nuclei of the cerebellum, as well as the dorsal root ganglia and dorsal tracts of the spinal cord. Functional and structural changes are also evident in the cerebellar cortex, cerebellocerebral white‐matter pathways, and subcortical gray matter and selectively in the cerebrum …”

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confidence: 99%

Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in friedreich ataxia

Ward

Harding

et al. 2019

Movement Disorders

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A BS TRACT: Background: Friedreich ataxia is a recessively inherited, progressive neurological disease characterized by impaired mitochondrial iron metabolism. The dentate nuclei of the cerebellum are characteristic sites of neurodegeneration in the disease, but little is known of the longitudinal progression of abnormalities in these structures. Methods: Using in vivo magnetic resonance imaging, including quantitative susceptibility mapping, we investigated changes in iron concentration and volume in the dentate nuclei in individuals with Friedreich ataxia (n = 20) and healthy controls (n = 18) over a 2-year period. Results: The longitudinal rate of iron concentration was significantly elevated bilaterally in participants with Friedreich ataxia relative to healthy controls. Atrophy rates did not differ significantly between groups. Change in iron concentration and atrophy both correlated with baseline disease severity or duration, indicating sensitivity of these measures to disease stage. Specifically, atrophy was maximal in individuals early in the disease course, whereas the rate of iron concentration increased with disease progression. Conclusions: Progressive dentate nucleus abnormalities are evident in vivo in Friedreich ataxia, and the rates of change of iron concentration and atrophy in these structures are sensitive to the disease stage. The findings are consistent with an increased rate of iron concentration and atrophy early in the disease, followed by iron accumulation and stable volume in later stages. This pattern suggests that iron dysregulation persists after loss of the vulnerable neurons in the dentate. The significant changes observed over a 2-year period highlight the utility of quantitative susceptibility mapping as a longitudinal biomarker and staging tool.

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Cerebral compensation during motor function in Friedreich ataxia: The IMAGE‐FRDA study

Cited by 22 publications

References 42 publications

Functional and Structural Brain Damage in Friedreich's Ataxia

Functional and Structural Brain Damage in Friedreich's Ataxia

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

Longitudinal evaluation of iron concentration and atrophy in the dentate nuclei in friedreich ataxia

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