MR Imaging in Spinocerebellar Ataxias: A Systematic Review

Klaes, Amália Izaura Nair de Medeiros; Reckziegel, Estela R.; Franca, MC; Rezende, Thiago Junqueira Ribeiro de; Vedolin, Leonardo; Jardim, Laura Bannach; Saute, Jonas Alex Morales

doi:10.3174/ajnr.a4760

Cited by 44 publications

(39 citation statements)

References 41 publications

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“…Recent improvements in neuroimaging techniques have made it possible to map the degenerative processes in vivo. Different methods, including volumetry and voxel-based morphometry (VBM), have been used to study the patterns of brain tissue atrophy in several SCA subtypes ( Pulst et al, 1996 ; Schulz et al, 2010 ; Goel et al, 2011 ; D'Abreu et al, 2012 ; Hernandez-Castillo et al, 2013 , Hernandez-Castillo et al, 2015 , Hernandez-Castillo et al, 2017 ; Jacobi et al, 2013 ; Reetz et al, 2013 ; Fahl et al, 2015 ; de Rezende et al, 2015 ; for a recent review see Klaes et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

“…Previous studies have been limited by two factors. First, most of these studies have used manual segmentation to calculate the total volume of pre-defined regions-of-interest (ROIs) ( Klaes et al, 2016 ). The specific ROI's (cerebellar lobules, hemisphere, vermis, etc) differ between those studies, making it difficult to compare and integrate the results across them.…”

Section: Introductionmentioning

confidence: 99%

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Unique degeneration signatures in the cerebellar cortex for spinocerebellar ataxias 2, 3, and 7

Hernandez‐Castillo

King

Diedrichsen

et al. 2018

NeuroImage: Clinical

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Spinocerebellar ataxias (SCAs) are a heterogeneous group of neurodegenerative diseases that selectively affect vulnerable neuronal populations in the cerebellum and other subcortical regions. While previous studies have reported subtype differences in the absolute amount of degeneration in specific regions of interest, they failed to account for two important factors. First, they did not control for overall differences in the severity of the degeneration pattern, and second, they did not fully characterize the spatial pattern of degeneration for each SCA subtype. Here, we provide a systematic characterization of the spatial degeneration patterns for three polyQ SCAs (55 patients, either SCA2, SCA3, or SCA7) while controlling for the severity of the degeneration pattern. After this correction, the cerebellar degeneration pattern can successfully classify between the three different SCA subtypes with high cross-validated accuracy. Specifically, degeneration in SCA3 disproportionally affects motor regions of the cerebellar cortex, which explains the relatively severe motor symptoms observed in this subtype. Our results demonstrate that each of the three studied SCA subtypes has a unique cerebellar degeneration signature, hinting at differences in the disease process. Clinically, these differentiable patterns of cerebellar degeneration can be used to reliably discern subtypes, even at relatively early stages of the disease.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Unique degeneration signatures in the cerebellar cortex for spinocerebellar ataxias 2, 3, and 7

Hernandez‐Castillo

King

Diedrichsen

et al. 2018

NeuroImage: Clinical

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“…Previous magnetic resonance imaging (MRI) studies of SCA2 have disclosed significant atrophies of the pons, mesencephalon, middle cerebellar peduncles, and cerebellum [ 5 , 6 ], which are consistent with typical changes of severe olivopontocerebellar atrophy [ 5 ]. However, these morphological changes often overlap with those in other autosomal dominant spinocerebellar ataxias, such as SCA1, SCA3, or SCA6.…”

Section: Introductionmentioning

confidence: 82%

MRI Signal Abnormalities of the Inferior Olivary Nuclei in Spinocerebellar Ataxia Type 2

et al. 2017

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Spinocerebellar ataxia type 2 (SCA2) is an autosomal dominant spinocerebellar degeneration, associated with extended repeats of the trinucleotide CAG in the ATXN2 gene on the long arm of chromosome 12. Magnetic resonance imaging (MRI) of SCA2 showed significant atrophies of the brainstem, middle cerebellar peduncles, and cerebellum. We report two genetically proven SCA2 patients who showed hypertrophy of the inferior olivary nuclei on proton density- and T2-weighted MRI. This pattern has never been reported in patients with SCA1, SCA3, or SCA6, and may make it possible to differentiate SCA2 from other hereditary spinocerebellar ataxias.

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“…Further, this gene has been shown to be robustly upregulated in several transcriptomic studies on HD (Becanovic et al 2010, Giles et al 2012, Langfelder et al 2016. The most interesting aspect about Acy3 as biomarker lies in the fact that this enzyme breaks down N-acetyl aspartate (NAA) a commonly used marker in magnetic resonance imaging, which is decreased not only in HD but also several SCAs (Sanchez-Pernaute et al 1999, Lopes et al 2013, Klaes et al 2016. Therefore, also NAA is worthy to be investigated as a useful imaging biomarker for SCA3.…”

Section: Discussionmentioning

confidence: 99%

A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities

Haas

Incebacak

Hentrich

et al. 2020

Preprint

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Background: Spinocerebellar ataxia type 3 is the most common autosomal dominant inherited ataxia worldwide and is caused by a CAG repeat expansion in the Ataxin-3 gene resulting in a polyQ expansion in the corresponding protein. The disease is characterized by neuropathological (aggregate formation, cell loss), phenotypical (gait instability, body weight reduction), and specific transcriptional changes in affected brain regions. So far, there is no mouse model available representing all the different aspects of the disease, yet highly needed to gain a better understanding of the disease pathomechanism.Methods: Here, we characterized a novel Ataxin-3 knock-in mouse model, expressing either a heterozygous or homozygous expansion of 304 CAG/CAAs in the murine Ataxin-3 locus using biochemical, behavioral, and transcriptomic approaches. Further, we compared the transcriptional changes of the knock-in mice to those found in human SCA3 patients, to evaluate the comparability of our model. Results:The novel Ataxin-3 knock-in mouse is characterized by the expression of a polyQ-expansion in the murine Ataxin-3 protein, leading to massive aggregate formation, especially in brain regions known to be vulnerable in SCA3 patients, and impairment of Purkinje cells. Along these neuropathological changes, mice showed a reduction in body weight accompanied by gait and balance instability. Transcriptomic analysis of cerebellar tissue revealed age-dependent differential expression, enriched for genes attributed to myelinating oligodendrocytes. Comparing these transcriptional changes with those found in cerebellar tissue of SCA3 patients, we discovered an overlap of differentially expressed genes pointing towards similar gene expression perturbances in several genes linked to myelin sheaths and myelinating oligodendrocytes. Conclusion:The novel Ataxin-3 knock-in model shares neuropathological, behavioral, and transcriptomic features with human SCA3 patients and, therefore, represents an ideal model to investigate early-onset developments, therapy studies, or longitudinal biomarker alterations.

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MR Imaging in Spinocerebellar Ataxias: A Systematic Review

Cited by 44 publications

References 41 publications

Unique degeneration signatures in the cerebellar cortex for spinocerebellar ataxias 2, 3, and 7

Unique degeneration signatures in the cerebellar cortex for spinocerebellar ataxias 2, 3, and 7

MRI Signal Abnormalities of the Inferior Olivary Nuclei in Spinocerebellar Ataxia Type 2

A novel Ataxin-3 knock-in mouse model mimics the human SCA3 disease phenotype including neuropathological, behavioral, and transcriptional abnormalities

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