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

Abstract

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.

Toward quantitative neuroimaging biomarkers for Friedreich's ataxia at 7 Tesla: Susceptibility mapping, diffusion imaging, R2 and R1 relaxometry

“…A recent study (Selvadurai et al, 2020), that used multiple diffusion imaging-based metrics as well as magnetization transfer imaging to assess microstructural and T 1 -weighted imaging to assess macrostructural white matter changes found extensive disruption of cerebello-cerebral and intracerebral white matter tracts. Quantitative methods such as quantitative susceptibility mapping (QSM; Ward et al, 2019) and T 2 mapping (da Silva et al, 2014) seemed to provide useful information on longitudinal change of disease severity that correlated with longitudinal change in DN magnetic susceptibility. Most conclusive among several studies is the relation of disease severity and degenerative changes in the superior cerebellar peduncles and in peridentate white matter as well as the DN pathology which is an established observation in FRDA.…”

Molecular Defects in Friedreich’s Ataxia: Convergence of Oxidative Stress and Cytoskeletal Abnormalities

“…MRI of patients throughout disease progression has revealed significant differences in patient CDN compared with healthy controls, including increased iron accumulation and gross tissue atrophy (Ward et al, 2019). Iron deposits are also commonly seen in the heart accompanying fibrosis and the onset of cardiomyopathy.…”

“…This compromises the function of the FXN protein as an iron chaperone, with severe metabolic consequences, as is discussed throughout this review. Other repeat expansion disorders include Huntington's disease (HD) and Fragile X syndrome (FXS), all of which are associated with forms of neurodegeneration (FRDA and HD) or mental retardation (FXS) consistent with atrophied areas of brain tissue (Brunberg et al, 2002;Kassubek et al, 2004;Ward et al, 2019). This highlights the sensitivity of the CNS to diseases with such profound protein dyshomeostasis.…”

“…This study laid the groundwork for the importance of longitudinal examination of CDN iron content in FRDA patients and its use in diagnostic criteria (Bonilha da Silva et al, 2014). Ward et al (2019) longitudinal study imaged separately CDN atrophy and iron accumulation throughout FRDA disease progression via quantitative susceptibility mapping (QSM)-MRI in a 2-year study. By separately examining the iron content and atrophy in the CDN in a temporally linear manner, different stages of disease can more easily be assessed.…”

“…QSM provides more sensitive detection of metal-rich tissues and is therefore a desirable neuroimaging technique. QSM-MRI was used to examine the following aspects sensitively and temporally through disease finding: (1) changes in iron concentration and (2) tissue volume of the CDN as a function of tissue atrophy (Ward et al, 2019). Tissue volume is essential in neuroimaging as it can influence metal detection-the same amount of iron particles in a smaller amount of tissue gives a higher reading than in a larger tissue volume.…”