Structural signature of SCA3: From presymptomatic to late disease stages

Rezende, Thiago Junqueira Ribeiro de; Paiva, Jean Levi Ribeiro de; Martinez, Alberto Rolim Muro; Lopes‐Cendes, Íscia; Pedroso, José Luiz; Barsottini, Orlando Graziani Póvoas; Cendes, Fernando; França, Marcondes C.

doi:10.1002/ana.25297

Cited by 97 publications

(133 citation statements)

References 38 publications

Supporting

Mentioning

101

Contrasting

Order By: Relevance

“…Previously, cross-sectional studies found abnormal fractional anisotropy (FA), axial diffusivity, and mainly radial diffusivity (RD) compared with controls. 3,12 Similarly, RD that reflects demyelination processes or axonal injury itself brought out most alterations and the largest ES in our analyses. In the study that divided groups of patients according to disease duration, authors were able to delineate a caudalrostral pattern of progression, and, in parallel, our study found changes only in infratentorial WM structures, corroborating for a "still in process" progress of CST damage.…”

Section: Discussionmentioning

confidence: 61%

“…SC changes indeed take place early in the disease course. 3 In our cohort with mean disease duration of 9.1 years at baseline, it is probable that maximal SC atrophy would have occurred previously, and further additional changes would be difficult to identify.…”

Section: Discussionmentioning

confidence: 88%

“…In the study that divided groups of patients according to disease duration, authors were able to delineate a caudalrostral pattern of progression, and, in parallel, our study found changes only in infratentorial WM structures, corroborating for a "still in process" progress of CST damage. 3 That the peduncles were asymmetrically altered may reflect their insidious and nonconstant rate of progression. Moreover, the wide range of disease durations in our cohort may have contributed to finding inferior and contralateral superior peduncle changes instead of more homogenous changes.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A 5‐Year Longitudinal Clinical and Magnetic Resonance Imaging Study in Spinocerebellar Ataxia Type 3

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background The natural history of neurodegeneration in spinocerebellar ataxia type 3/Machado Joseph disease is still unclear. Here, we built a long‐term longitudinal clinical and neuroimaging study to address this point. Methods Twenty‐three patients with spinocerebellar ataxia type 3/Machado Joseph disease and 22 healthy controls underwent 3T MRI twice 5.0 years apart. T1 and diffusion tensor imaging sequences were obtained. We used T1 multiatlas, diffusion tensor imaging multiatlas, SpineSeg, and CERES‐SUIT for cerebral gray and white matter, spinal cord and cerebellar analyses, respectively. Clinical severity was assessed with scale for assessment and rating of ataxia. Analysis of covariance evaluated longitudinal between‐group changes. Effect sizes were calculated for each significant result. Results Progressive volumetric abnormalities were most evident in the cerebellum (Lobule X and Crus II; effect size, 2.0), followed by the basal ganglia (effect size, 0.7). The cerebellar peduncles had the largest white‐matter diffusivity changes (effect size, 1.29). Scale for assessment and rating of ataxia–related effect size was 0.82. We failed to identify progressive spinal cord abnormalities. Conclusions Longitudinal changes in spinocerebellar ataxia type 3/Machado Joseph disease are more evident in the cerebellum and connections, followed by the basal ganglia. © 2020 International Parkinson and Movement Disorder Society

show abstract

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 88%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A 5‐Year Longitudinal Clinical and Magnetic Resonance Imaging Study in Spinocerebellar Ataxia Type 3

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…All animal procedures were approved by the University of Michigan Committee on the Use and Care of Animals (Protocol PRO00003836) and by the University of Minnesota Institutional Animal Care and Use Committee (Protocol # 1207A17510). Groups of Q84/Q84 (N=14 (7 females, 7 males), [9][10][11][12][13][14][15][16][17] month-old) and their littermate non-transgenic (wt) mice (N=11 (7 females, 4 males), 11-18 month-old), and Q135 (N= 9 (3 females, 6 males), 8-16 month-old) and their wt littermates (N=8 (5 females, 3 males), 10-16 month-old) in the C57Bl6/J background (Supplementary Table 1) were scanned. Mice were housed in cages with corncob bedding with a maximum number of five animals (range 3-5) and maintained in a standard 12-hours light/dark cycle with food and water ad libitum.…”

Section: Experimental Designmentioning

confidence: 99%

“…Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a polyQ disease caused by an expanded CAG repeat in the ATXN3 gene 12 that leads to selective dysfunction and loss of neurons of specific nuclei in the cerebellum, brain stem, midbrain, spinal cord, and peripheral nerves [9][10][11][13][14][15][16][17][18][19][20][21] . This central and peripheral nervous system pathology manifests in patients with SCA3 as ataxia and a variable degree of other symptoms, such as extrapyramidal signs, neuropathy, ophthalmoplegia, visual impairment and muscle atrophy [22][23][24][25][26] .…”

Section: Introductionmentioning

confidence: 99%

In vivomolecular signatures of cerebellar pathology in spinocerebellar ataxia type 3

Costa

Radzwion

McLoughlin

et al. 2020

Preprint

View full text Add to dashboard Cite

Background:No treatment exists for the most common dominantly inherited ataxia Machado-Joseph disease, or spinocerebellar ataxia type 3 (SCA3). Successful evaluation of candidate therapeutics will be facilitated by validated noninvasive biomarkers of aspects of disease pathology recapitulated by animal models.Objective: We sought to identify shared neurochemical signatures in two mouse models of SCA3 that reflect aspects of the human disease pathology.Methods: Cerebellar neurochemical concentrations in homozygous YACMJD84.2 (Q84/Q84) and hemizygous CMVMJD135 (Q135) mice were measured by magnetic resonance spectroscopy at 9.4 tesla. Motivated by the shared neurochemical abnormalities in the two models, we determined the levels of neurofilament medium (NFL, indicator of neuroaxonal integrity) and myelin basic protein (MBP, indicator of myelination) in cerebellar lysates from a subset of mice and from patients with SCA3. Finally, NFL and MBP levels were measured in cerebellar extracts of Q84/Q84 mice upon sustained silencing of the mutant ATXN3 gene from 6-8 weeks-of-age until death.Results: Both Q84/Q84 and Q135 mice displayed lower N-acetylaspartate than wild-type littermates, indicating neuroaxonal loss/dysfunction, and lower myo-inositol and total choline, indicating disturbances in phospholipid membrane metabolism and demyelination. Cerebellar NFL and MBP levels were accordingly lower in both models as well as in the cerebellar cortex of patients with SCA3 than controls. Furthermore, long-term sustained RNAi-mediated reduction of ATXN3 levels increased NFL and MBP in Q84/Q84 cerebella.Conclusions: N-acetylaspartate, myo-inositol and total choline levels in the cerebellum are candidate biomarkers of neuroaxonal and oligodendrocyte pathology in SCA3, which are reversible by reduction of mutant ATXN3 levels.

show abstract

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

Chen

Huang

Lin

et al. 2022

Ann Clin Transl Neurol

View full text Add to dashboard Cite

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.

show abstract

Structural signature of SCA3: From presymptomatic to late disease stages

Cited by 97 publications

References 38 publications

A 5‐Year Longitudinal Clinical and Magnetic Resonance Imaging Study in Spinocerebellar Ataxia Type 3

A 5‐Year Longitudinal Clinical and Magnetic Resonance Imaging Study in Spinocerebellar Ataxia Type 3

In vivomolecular signatures of cerebellar pathology in spinocerebellar ataxia type 3

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

Contact Info

Product

Resources

About