Brain structural abnormalities in the preclinical stage of Machado–Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3): evaluation by MRI morphometry, diffusion tensor imaging and neurite orientation dispersion and density imaging

Li, Mengcheng; Chen, Xinyuan; Xu, Hao-Ling; Huang, Ziqiang; Chen, Naping; Tu, Yuqing; Gan, Shi‐Rui; Hu, Jianping

doi:10.1007/s00415-021-10890-2

Cited by 10 publications

(6 citation statements)

References 43 publications

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“…Therefore, to assess regional mature (myelinating) oligodendrocyte impairments in SCA3 patient tissue, we assessed myelination using a Luxol Fast Blue stain in cerebellar and cortical tissue from SCA3 and control post-mortem subjects ( Figures 1A, B and Supplementary Figure 1 ). Consistent with MRI studies assessing white matter changes ( Kang et al, 2014 ; Arruda et al, 2020 ; Park et al, 2020 ; Piccinin et al, 2020 ; Li et al, 2022 ), we discovered reduced cerebellar myelin staining in SCA3 patient brains relative to controls ( Figure 1A ). In contrast, we found similar myelin staining between SCA3 patients and control subjects in the frontal cortex ( Figure 1B ).…”

Section: Resultssupporting

confidence: 88%

“…Here, we extend our foundational studies to relate SCA3 phenotypic and regional vulnerability to the onset and progression of disease-associated oligodendrocyte signatures in both Knock-In and overexpression mouse models of SCA3 ( Figure 5 ). In line with SCA3 patient imaging of white matter changes ( Kang et al, 2014 ; Li et al, 2022 ), we observed transcriptional dysregulation of oligodendrocyte maturation in SCA3 mice first in brain regions most vulnerable to SCA3, including the brainstem and spinal cord, followed by the cerebellum, with little to no changes in the forebrain. More detailed regional histological assessment revealed the SCA3 vulnerable DCN within the cerebellum is in fact similarly affected by oligodendrocyte maturation impairments as the pons.…”

Section: Discussionsupporting

confidence: 77%

“…Spinocerebellar ataxia type 3 (SCA3) research has historically focused on the dysfunction of neuronal cells in disease pathogenesis, despite patient data showing early atrophy of white matter regions ( Joers et al, 2018 ; Rezende et al, 2018 ; McLoughlin et al, 2020 ; Li et al, 2022 ). In-life assessments via MRI and DTI reveal that tissue degeneration in the spinal cord, cerebellar peduncles, and substantia nigra occurs early in disease pathogenesis, whereas the cerebral cortex is not affected until later stages of disease ( Rezende et al, 2018 ; Piccinin et al, 2020 ; Wan et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

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Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3

et al. 2023

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Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease caused by a CAG repeat expansion in the ATXN3 gene. Though the ATXN3 protein is expressed ubiquitously throughout the CNS, regional pathology in SCA3 patients is observed within select neuronal populations and more recently within oligodendrocyte-rich white matter tracts. We have previously recapitulated these white matter abnormalities in an overexpression mouse model of SCA3 and demonstrated that oligodendrocyte maturation impairments are one of the earliest and most progressive changes in SCA3 pathogenesis. Disease-associated oligodendrocyte signatures have recently emerged as significant contributors to several other neurodegenerative diseases, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease, but their role in regional vulnerability and disease progression remains unexplored. Here, we are the first to comparatively assess myelination in human tissue in a region-dependent manner. Translating these findings to SCA3 mouse models of disease, we confirmed endogenous expression of mutant Atxn3 leads to regional transcriptional dysregulation of oligodendrocyte maturation markers in Knock-In models of SCA3. We then investigated the spatiotemporal progression of mature oligodendrocyte transcriptional dysregulation in an overexpression SCA3 mouse model and how it relates to the onset of motor impairment. We further determined that regional reduction in mature oligodendrocyte cell counts in SCA3 mice over time parallels the onset and progression of brain atrophy in SCA3 patients. This work emphasizes the prospective contributions of disease-associated oligodendrocyte signatures to regional vulnerability and could inform timepoints and target regions imperative for biomarker assessment and therapeutic intervention in several neurodegenerative diseases.

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Section: Resultssupporting

confidence: 88%

Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

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Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3

et al. 2023

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“…This result reflects cerebral‐cerebellar connectivity disruption, which is also found in other types of ataxia. 24 , 48 , 49 A recent neuroimage study 12 , 50 in preclinical SCA3/MJD patients reported white matter fiber damage in the bilateral cerebellar peduncles and cerebellum. As a bridge between the cerebellum and other brain areas, the WM fiber damage in cerebellum peduncles decreases the structural connectivity between the cerebellum, thalamus, and base ganglia, which may lead to a change in the motor network of patients with preclinical SCA3/MJD.…”

Section: Discussionmentioning

confidence: 99%

Altered brain white matter structural motor network in spinocerebellar ataxia type 3

Chen

Huang

Lin

et al. 2022

Ann Clin Transl Neurol

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Objectives Spinocerebellar ataxia type 3 is a disorder within the brain network. However, the relationship between the brain network and disease severity is still unclear. This study aims to investigate changes in the white matter (WM) structural motor network, both in preclinical and ataxic stages, and its relationship with disease severity. Methods For this study, 20 ataxic, 20 preclinical SCA3 patients, and 20 healthy controls were recruited and received MRI scans. Disease severity was quantified using the SARA and ICARS scores. The WM motor structural network was created using probabilistic fiber tracking and was analyzed using graph theory and network‐based statistics at global, nodal, and edge levels. In addition, the correlations between network topological measures and disease duration or clinical scores were analyzed. Results Preclinical patients showed increasing assortativity of the motor network, altered subnetwork including 12 edges of 11 nodes, and 5 brain regions presenting reduced nodal strength. In ataxic patients assortativity of the motor network also increased, but global efficiency, global strength, and transitivity decreased. Ataxic patients showed a wider altered subnetwork and a higher number of reduced nodal strengths. A negative correlation between the transitivity of the motor network and SARA and ICARS scores was observed in ataxic patients. Interpretation Changes to the WM motor network in SCA3 start before ataxia onset, and WM motor network involvement increases with disease progression. Global network topological measures of the WM motor network appear to be a promising image biomarker for disease severity. This study provides new insights into the pathophysiology of disease in SCA3/MJD.

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“…As for the correlation between CAG repeat number and imaging parameters, previous studies had controversial findings. A study identified the relationship between the CAG repeat length and brain microstructural alterations of preclinical SCA3 58 , while several studies found no significant correlation between DTI parameters and CAG repeat number 10,11 . Our results supported that the CAG repeat number may intensify white matter damage of cerebellum in SCA3 patients.…”

Section: Discussionmentioning

confidence: 99%

Disrupted cerebellar structural connectome in spinocerebellar ataxia type 3 and its association with transcriptional profiles

Dong,

Liu,

Huang

et al. 2023

Preprint

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Spinocerebellar ataxia type 3 (SCA3) is primarily characterized by progressive cerebellar degeneration, including gray matter atrophy and disrupted anatomical and functional connectivity of the cerebellum. The alterations of topological organization of cerebellar white matter structural network in SCA3 and the underlying neurobiological mechanism remain unknown. Using a cohort of 20 patients with SCA3 and 20 healthy controls, we constructed cerebellar structural networks from diffusion magnetic resonance imaging and investigated alterations of topological organization. Then we mapped the alterations with transcriptome data from the Allen Human Brain Atlas to identify possible biological mechanisms for regional selective vulnerability to white matter damage. Compared with healthy controls, decreased global and nodal efficiency, and widely distributed decreased edge strength were observed in SCA3 patients. The regions with decreased nodal global efficiency were mainly located in cerebellar anterior lobe, and the genes express higher in these regions were significantly enriched in synapse-related biological processes. The regions with decreased nodal local efficiency were mainly located in cerebellar posterior lobe, and the higher gene expression in these regions were significantly enriched in metabolic biological processes. Similar hub distributions were found in two groups of subjects, whereas the strengths of rich-club and feeder connections were lower in SCA3 patients. Moreover, strength of the inter-module connections was lower in SCA3 group and negatively correlated with SARA score, ICARS score, and CAG repeat number. These findings suggest a mechanism of white matter vulnerability and a potential image biomarker for the disease severity, providing insights into neurodegeneration and pathogenesis in this disease.

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Brain structural abnormalities in the preclinical stage of Machado–Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3): evaluation by MRI morphometry, diffusion tensor imaging and neurite orientation dispersion and density imaging

Cited by 10 publications

References 43 publications

Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3

Disease-associated oligodendrocyte signatures are spatiotemporally dysregulated in spinocerebellar ataxia type 3

Altered brain white matter structural motor network in spinocerebellar ataxia type 3

Disrupted cerebellar structural connectome in spinocerebellar ataxia type 3 and its association with transcriptional profiles

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