Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias

Abstract

The cerebellar nuclei are a brain region with high iron content. Surprisingly little is known about iron content in the cerebellar nuclei and its possible contribution to pathology in cerebellar ataxias, with the only exception of Friedreich’s ataxia. In the present exploratory cross-sectional study, quantitative susceptibility mapping was used to investigate volume, iron concentration and total iron content of the dentate nuclei in common types of hereditary and non-hereditary degenerative ataxias. Seventy-nine patients with spinocerebellar ataxias of type 1 (SCA1), 2 (SCA2), 3 (SCA3) and 6 (SCA6), fifteen patients with Friedreich’s ataxia, eighteen patients with multiple system atrophy, cerebellar type (MSA-C), and one hundred eleven healthy controls were included. All underwent 3T-MRI and clinical assessments. For each specific ataxia subtype, voxel-based and volumes-of-interest-based group analyses were performed in comparison to a corresponding age- and sex-matched control group, both for volume, magnetic susceptiblity (indicating iron concentration) and susceptibility mass (indicating total iron content) of the dentate nuclei. SCA1 and MSA-C patients showed higher susceptibilities in large parts of the dentate nucleus but unaltered susceptibility masses compared to controls. Friedreich’s ataxia patients and, only on a trend level, SCA2 patients showed higher susceptibilities in more circumscribed parts of the dentate. In contrast, SCA6 patients revealed lower susceptibilities and susceptibility masses compared to controls throughout the dentate nucleus. SCA3 patients showed no significant changes in susceptibility and susceptibility mass. Lower volume of the dentate nuclei was found to varying degrees in all ataxia types. It was most pronounced in SCA6 patients and least prominent in SCA3 patients. The findings show that alterations in susceptibility revealed by quantitative susceptibiltiy mapping are common in the dentate nuclei in different types of cerebellar ataxias. The most striking changes in susceptibility were found in SCA1, MSA-C, and SCA6. Because iron content is known to be high in glial cells but not in neurons of the cerebellar nuclei, the higher susceptibility in SCA1 and MSA-C may be explained by a reduction of neurons (increase in iron concentration) and/or an increase in iron-rich glial cells, e.g. microgliosis. Hypomyelination also leads to higher susceptibility and could also contribute. The lower susceptibility in SCA6 suggests a loss of iron-rich glial cells. Quantitative susceptibility maps warrant future studies of iron content and iron-rich cells in ataxias to gain a more comprehensive understanding of the pathogenesis of these diseases.

Quantitative susceptibility mapping of basal ganglia iron is associated with cognitive and motor functions that distinguish spinocerebellar ataxia type 6 and type 3

“…First, dentate susceptibility mass in SCA6 was markedly reduced relative to those found in the SCA3 and control groups. This finding replicates those from a previous study ( Deistung et al, 2022 ), with significant iron loss in the dentate observed in SCA6, but not in SCA3. Second, susceptibility mass levels in BG regions did not differ across groups, but associations with supplemental measures did.…”

“…Structural volume measures in this study also revealed group differences. The cerebellar dentate was smaller in the SCA6 group than in the SCA3 or healthy control groups, consistent with a recent study that examined the dentate specifically ( Deistung et al, 2022 ). The PT was smaller in both SCA groups relative to the healthy control group.…”

“…In a recent QSM study of SCA iron levels by Deistung et al (2022) , dentate iron content and volume declined in SCA6, without an increase in iron concentration. This suggested a net loss of iron-rich cells in the dentate.…”

“…This suggested a net loss of iron-rich cells in the dentate. Regions like the BG may have the ability to absorb additional iron that is released into the milieu, which has been considered conceptually as “iron relocation,” observed as inversely associated iron levels between two brain regions ( Koeppen et al, 2007 ; Deistung et al, 2022 ). Moreover, excess iron can lead to cell death through free radicals ( Imam et al, 2017 ).…”

“…Two years later, however, iron concentration in the dentate rose more in FA while dentate structural volume loss had similar rate in FA as compared to controls, suggesting that structural volume loss in the dentate preceded iron accumulation. More recently, Deistung et al (2022) reported QSM measure of dentate iron concentration and volume in SCA types 1, 2, 3, and 6 and healthy controls in a cross-sectional design ( Deistung et al, 2022 ). They reported higher dentate iron concentrations in SCA1 and SCA2 compared to that of controls, with no change in SCA3.…”