Early Cerebellar Network Shifting in Spinocerebellar Ataxia Type 6

Falcon, Maria Inez; Gómez, Christopher M.; Chen, E.E.; Shereen, A. Duke; Solodkin, Ana

doi:10.1093/cercor/bhv154

Cited by 34 publications

(32 citation statements)

References 101 publications

(121 reference statements)

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“…The alteration of the brain network is found to be associated with disease severity and disease duration in SCA1 (Solodkin et al, 2011), cognitive and motor performance (Hernandez-Castillo et al, 2015) and onset of parkinsonism in SCA2 (Wu et al, 2013), visual task performance in SCA6 (Falcon et al, 2015) and CAG repeat length in SCA7 (Hernandez-Castillo et al, 2013). These studies, although mostly based on fMRI, suggest that brain network alteration is associated with clinical variables such as the CAG repeat length, disease severity, disease duration, and task performance in SCAs.…”

Section: Discussionmentioning

confidence: 99%

CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

Huang¹,

Wu²,

Jao³

et al. 2017

NeuroImage: Clinical

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This cross-sectional study investigated the correlation between the CAG repeat length and the degeneration of cerebellum in spinocerebellar ataxia type 3 (SCA3) patients based on neuroimaging approaches. Forty SCA3 patients were recruited and classified into two subgroups according to their CAG repeat lengths (≥ 74 and < 74). We measured each patient's Scale for the Assessment and Rating of Ataxia (SARA) score, N-acetylaspartate (NAA)/creatine (Cr) ratios based on magnetic resonance spectroscopy (MRS), and 3-dimensional fractal dimension (3D-FD) values derived from magnetic resonance imaging (MRI) results. Furthermore, the 3D-FD values were used to construct structural covariance networks based on graph theoretical analysis. The results revealed that SCA3 patients with a longer CAG repeat length demonstrated earlier disease onset. However, the CAG repeat length did not significantly correlate with their SARA scores, cerebellar NAA/Cr ratios or cerebellar 3D-FD values. Network dissociation between cerebellar regions and parietal-occipital regions was found in SCA3 patients with CAG ≥ 74, but not in those with CAG < 74. In conclusion, the CAG repeat length is uncorrelated with the change of SARA score, cerebellar function and cerebellar structure in SCA3. Nevertheless, a longer CAG repeat length may indicate early structural covariance network dissociation.

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Section: Discussionmentioning

confidence: 99%

CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

Huang¹,

Wu²,

Jao³

et al. 2017

NeuroImage: Clinical

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“…The significant activation of these regions beyond cerebellar activation in SCA3 patients might also represent a mechanism of compensation. This whole‐brain mechanism is reminiscent of the early intracerebellar network shifting that is observed in spinocerebellar ataxia type 6 [Falcon et al, ].…”

Section: Discussionmentioning

confidence: 99%

Parametric fMRI of paced motor responses uncovers novel whole‐brain imaging biomarkers in spinocerebellar ataxia type 3

Duarte

Faustino

Lobo

et al. 2016

Human Brain Mapping

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Machado-Joseph Disease, inherited type 3 spinocerebellar ataxia (SCA3), is the most common form worldwide. Neuroimaging and neuropathology have consistently demonstrated cerebellar alterations. Here we aimed to discover whole-brain functional biomarkers, based on parametric performance-level-dependent signals. We assessed 13 patients with early SCA3 and 14 healthy participants. We used a combined parametric behavioral/functional neuroimaging design to investigate disease fingerprints, as a function of performance levels, coupled with structural MRI and voxel-based morphometry. Functional magnetic resonance imaging (fMRI) was designed to parametrically analyze behavior and neural responses to audio-paced bilateral thumb movements at temporal frequencies of 1, 3, and 5 Hz. Our performance-level-based design probing neuronal correlates of motor coordination enabled the discovery that neural activation and behavior show critical loss of parametric modulation specifically in SCA3, associated with frequency-dependent cortico/subcortical activation/deactivation patterns. Cerebellar/cortical rate-dependent dissociation patterns could clearly differentiate between groups irrespective of grey matter loss. Our findings suggest functional reorganization of the motor network and indicate a possible role of fMRI as a tool to monitor disease progression in SCA3. Accordingly, fMRI patterns proved to be potential biomarkers in early SCA3, as tested by receiver operating characteristic analysis of both behavior and neural activation at different frequencies. Discrimination analysis based on BOLD signal in response to the applied parametric finger-tapping task significantly often reached >80% sensitivity and specificity in single regions-of-interest.Functional fingerprints based on cerebellar and cortical BOLD performance dependent signal modulation can thus be combined as diagnostic and/or therapeutic targets in hereditary ataxia. Hum Brain Mapp 37:3656-3668, 2016. © 2016 Wiley Periodicals, Inc.

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“…This approach has been validated as reliable in prior work (Planetta et al 2015b; Prodoehl et al 2013). Based on previous findings (Falcon et al 2015; Vaillancourt et al 2006), we selected seven ROIs important for visually-guided motor control and the size for each ROI was determined to cover the anatomy for all participants: (a) dentate nucleus (bilateral; 20 voxels), (b) superior cerebellar peduncle (bilateral; 14 voxels), (c) middle cerebellar peduncle (bilateral; 16 voxels), (d) inferior cerebellar peduncle (bilateral; 10 voxels), (e) lobule V (bilateral; 68 voxels), (f) lobule VI (bilateral; 125 voxels), and (g) vermis (42 voxels). Using the ROIs, we extracted the FA T and free-water values.…”

Section: Methodsmentioning

confidence: 94%

“…Across seed placed in bilateral M1, SMA, and contralateral S1, SCA6 patients showed decreased task-based functional connectivity between cortico-cortical regions (M1 vs. SMA) and cortical-cerebellar regions (M1 vs. Vermis VI and SMA vs. lobule V–VI). Falcon and colleagues reported that effective connectivity between visual-related cortex and intermediate and lateral cerebellum was reduced in individuals with more severe ataxic symptoms compared with healthy controls, presymptomatic, and mild SCA6 patients (Falcon et al 2015). Our current findings provide new evidence that functional connectivity is also impaired in SCA6 in motor-related regions of the cortex and cerebellum.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that SCA6 patients with mild and severe symptoms exhibit greater activity in the lateral cerebellum, whereas presymptomatic patients exhibit greater activity in the vermis (Falcon et al 2015). A single tensor diffusion analysis model revealed reduced fractional anisotropy (FA) values in the cerebral peduncle and middle cerebellar peduncle, and only the decreased FA in the middle cerebellar peduncle was correlated with more severe disease symptoms.…”

Section: Introductionmentioning

confidence: 99%

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Sensory and motor cortex function contributes to symptom severity in spinocerebellar ataxia type 6

et al. 2016

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Spinocerebellar ataxia type 6 (SCA6) is a genetic disease that causes degeneration of Purkinje cells, and recent evidence points to degeneration of Betz cells in the motor cortex. The relation between functional activity of motor cortex and symptom severity during a hand-grip motor control in vivo has not yet been investigated. This study explored both functional changes in the sensorimotor cortex and cerebellar regions and structural alterations in the cerebellum for SCA6 patients as compared to age-matched healthy controls using a multimodal imaging approach (task-based fMRI, task-based functional connectivity, and free-water diffusion MRI). Further, we tested their relation with the severity of ataxia symptoms. SCA6 patients had reduced functional activity in the sensorimotor cortex, supplementary motor area (SMA), cerebellar vermis, and cerebellar lobules I-VI (corrected P < 0.05). Reduced task-based functional connectivity between cortical motor regions (i.e., primary motor cortex and SMA) and cerebellar regions (i.e., vermis and lobules I–VI) was found in SCA6 (corrected P < 0.05). SCA6 had elevated free-water values throughout the cerebellum as compared with controls (corrected P < 0.05). Importantly, reduced functional activity in the sensorimotor cortex and SMA and increased free-water in the superior cerebellar peduncle and cerebellar lobule V were related to more severe symptoms in SCA6 (all pairs: R2 ≥ 0.4 and corrected P < 0.05). Current results demonstrate that impaired functional activity in sensorimotor cortex and SMA and elevated free-water of lobule V and superior cerebellar peduncle are both related to symptom severity, and may provide candidate biomarkers for SCA6.

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Early Cerebellar Network Shifting in Spinocerebellar Ataxia Type 6

Cited by 34 publications

References 101 publications

CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

CAG repeat length does not associate with the rate of cerebellar degeneration in spinocerebellar ataxia type 3

Parametric fMRI of paced motor responses uncovers novel whole‐brain imaging biomarkers in spinocerebellar ataxia type 3

Sensory and motor cortex function contributes to symptom severity in spinocerebellar ataxia type 6

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