Exploring functional and structural connectivity disruptions in spinocerebellar ataxia type 3: Insights from gradient analysis.

AIMS: Spinocerebellar Ataxia Type 3 (SCA3) is a rare genetic ataxia that impacts the entire brain and is characterized as a neurodegenerative disorder affecting the neural network. This study explores how alterations in the functional hierarchy, connectivity, and structural changes within specific brain regions significantly contribute to the heterogeneity of symptom manifestations in patients with SCA3. METHODS: We prospectively recruited 51 patients with SCA3 and 59 age-and sex-matched healthy controls. All participants underwent comprehensive multimodal neuroimaging and clinical assessments. In SCA3 patients, an innovative approach utilizing gradients in resting-state functional connectivity (FC) was employed to examine atypical patterns of hierarchical processing topology from sensorimotor to supramodal regions in the cerebellum and cerebrum. Coupling analyses of abnormal FC and structural connectivity among regions of interest (ROIs) in the brain were also performed to characterize connectivity alterations. Additionally, relationships between quantitative ROI values and clinical variables were explored. RESULTS: Patients with SCA3 exhibited either compression or expansion within the primary sensorimotor-to-supramodal gradient through four distinct calculation methods, along with disruptions in FC and structural connectivity coupling. A comprehensive correlation was identified between the altered gradients and the clinical manifestations observed in patients. Notably, altered fractional anisotropy values were not significantly correlated with clinical variables. CONCLUSION: Abnormal gradients and connectivity in the cerebellar and cerebral cortices in SCA3 patients may contribute to disrupted motor-to-supramodal functions. Moreover, these findings support the potential utility of FCG analysis as a biomarker for diagnosing SCA3 and assessing treatment efficacy.

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

Spinocerebellar ataxia type 3 (SCA3) is primarily characterized by progressive cerebellar degeneration, including gray matter atrophy and disrupted anatomical and functional connectivity. The alterations 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 MRI 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, SCA3 patients exhibited reduced global and nodal efficiency, along with a widespread decrease in edge strength, particularly affecting edges connected to hub regions. The strength of inter-module connections was lower in SCA3 group and negatively correlated with the Scale for the Assessment and Rating of Ataxia score, International Cooperative Ataxia Rating Scale score, and cytosine-adenine-guanine repeat number. Moreover, the transcriptome-connectome association study identified the expression of genes involved in synapse-related and metabolic biological processes. 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.

Molecular Imaging in CANVAS: A Contribution for Differential Diagnosis?

BACKGROUND: Phenotypes of CANVAS are increasingly diversified, including bradykinesia and dysautonomia, so that its primary differential diagnoses are multiple system atrophy-cerebellar type (MSA-c), and spinocerebellar ataxia type 3 (SCA3). This case series aims to highlight key molecular imaging findings in CANVAS. CASES: We report a case series of six patients with CANVAS who underwent nuclear medicine examinations in our center and 13 patients from the literature. These include 18F-FDG brain positron emission tomography (PET), single photon emission computed tomography (SPECT) of dopamine transporter (DaT) activity, and 123I-MIBG cardiac scintigraphy of noradrenergic transmission. CONCLUSIONS: In CANVAS, 18F-FDG brain PET mainly shows cerebellar hypometabolism, with preserved brainstem and striatum metabolism, contrasting with SCA3 and MSA-c. Dopaminergic denervation on scintigraphy seems to be associated with clinical parkinsonism, ranging from normal to severely impaired DaT SPECT. Additionally, 123I-MIBG cardiac scintigraphy might show denervation in CANVAS, similar to SCA3, but not in most MSA-c patients.

Compressed cerebellar functional connectome hierarchy in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is an inherited movement disorder characterized by a progressive decline in motor coordination. Despite the extensive functional connectivity (FC) alterations reported in previous SCA3 studies in the cerebellum and cerebellar-cerebral pathways, the influence of these FC disturbances on the hierarchical organization of cerebellar functional regions remains unclear. Here, we compared 35 SCA3 patients with 48 age- and sex-matched healthy controls using a combination of voxel-based morphometry and resting-state functional magnetic resonance imaging to investigate whether cerebellar hierarchical organization is altered in SCA3. Utilizing connectome gradients, we identified the gradient axis of cerebellar hierarchical organization, spanning sensorimotor to transmodal (task-unfocused) regions. Compared to healthy controls, SCA3 patients showed a compressed hierarchical organization in the cerebellum at both voxel-level (p < .05, TFCE corrected) and network-level (p < .05, FDR corrected). This pattern was observed in both intra-cerebellar and cerebellar-cerebral gradients. We observed that decreased intra-cerebellar gradient scores in bilateral Crus I/II both negatively correlated with SARA scores (left/right Crus I/II: r = -.48/-.50, p = .04/.04, FDR corrected), while increased cerebellar-cerebral gradients scores in the vermis showed a positive correlation with disease duration (r = .48, p = .04, FDR corrected). Control analyses of cerebellar gray matter atrophy revealed that gradient alterations were associated with cerebellar volume loss. Further FC analysis showed increased functional connectivity in both unimodal and transmodal areas, potentially supporting the disrupted cerebellar functional hierarchy uncovered by the gradients. Our findings provide novel evidence regarding alterations in the cerebellar functional hierarchy in SCA3.

Cognitive impairment associated with cerebellar volume loss in spinocerebellar ataxia type 3.

BACKGROUND: Many neuroscience and neurology studies have forced a reconsideration of the traditional motor-related scope of cerebellar function, which has now expanded to include various cognitive functions. Spinocerebellar ataxia type 3 (SCA3; the most common hereditary ataxia) is neuropathologically characterized by cerebellar atrophy and frequently presents with cognitive impairment. OBJECTIVE: To characterize cognitive impairment in SCA3 and investigate the cerebellum-cognition associations. METHODS: This prospective, cross-sectional cohort study recruited 126 SCA3 patients and 41 healthy control individuals (HCs). Participants underwent a brain 3D T1-weighted images as well as neuropsychological tests. Voxel-based morphometry (VBM) and region of interest (ROI) approaches were performed on the 3D T1-weighted images. CERES was used to automatically segment cerebellums. Patients were grouped into cognitively impaired (CI) and cognitively preserved (CP), and clinical and MRI parameters were compared. Multivariable regression models were fitted to examine associations between cerebellar microstructural alterations and cognitive domain impairments. RESULTS: Compared to HCs, SCA3 patients showed cognitive domain impairments in information processing speed, verbal memory, executive function, and visuospatial perception. Between CI and CP subgroups, the CI subgroup was older and had lower education, as well as higher severity scores. VBM and ROI analyses revealed volume loss in cerebellar bilateral lobule VI, right lobule Crus I, and right lobule IV of the CI subgroup, and all these cerebellar lobules were associated with the above cognitive domain impairments. CONCLUSIONS: Our findings demonstrate the multiple cognitive domain impairments in SCA3 patients and indicate the responsible cerebellar lobules for the impaired cognitive domain(s).

Altered large-scale individual-based morphological brain network in spinocerebellar ataxia type 3.

BACKGROUND: Accumulating evidences indicate regional gray matter (GM) morphology atrophy in spinocerebellar ataxia type 3 (SCA3); however, whether large-scale morphological brain networks (MBNs) undergo widespread reorganization in these patients remains unclear. OBJECTIVE: To investigate the topological organization of large-scale individual-based MBNs in SCA3 patients. METHODS: The individual-based MBNs were constructed based on the inter-regional morphological similarity of GM regions. Graph theoretical analysis was taken to assess GM structural connectivity in 76 symptomatic SCA3, 24 pre-symptomatic SCA3, and 54 healthy normal controls (NCs). Topological parameters of the resulting graphs and network-based statistics analysis were compared among symptomatic SCA3, pre-symptomatic SCA3, and NCs groups. The inner association between network properties and clinical variables was further analyzed. RESULTS: Compared to NCs and pre-symptomatic SCA3 patients, symptomatic SCA3 indicated significantly decreased integration and segregation, a shift to "weaker small-worldness", characterized by decreased Cp , lower Eloc, and Eglob (all p < 0.005). Regarding nodal properties, symptomatic SCA3 exhibited significantly decreased nodal profiles in the central executive network (CEN)-related left inferior frontal gyrus, limbic regions involving the bilateral amygdala, left hippocampus, and bilateral pallidum, thalamus; and increased nodal degree, efficiency in bilateral caudate (all pFDR <0.05). Meanwhile, clinical variables were correlated with altered nodal profiles (pFDR ≤0.029). SCA3-related subnetwork was closely interrelated with dorsolateral cortico-striatal circuitry extending to orbitofrontal-striatal circuits and dorsal visual systems (lingual gyrus-striatal). CONCLUSION: Symptomatic SCA3 patients undergo an extensive and significant reorganization in large-scale individual-based MBNs, probably due to disrupted prefrontal cortico-striato-thalamo-cortical loops, limbic-striatum circuitry, and enhanced connectivity in the neostriatum. This study highlights the crucial role of abnormal morphological connectivity alterations beyond the pattern of brain atrophy, which might pave the way for therapeutic development in the future.

The longitudinal progression of MRI changes in pre-ataxic carriers of SCA3/MJD.

BACKGROUND: The natural history of magnetic resonance imaging (MRI) in pre-ataxic stages of spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is not well known. We report cross-sectional and longitudinal data obtained at this stage. METHODS: Baseline (follow-up) observations included 32 (17) pre-ataxic carriers (SARA < 3) and 20 (12) related controls. The mutation length was used to estimate the time to onset (TimeTo) of gait ataxia. Clinical scales and MRIs were performed at baseline and after a median (IQR) of 30 (7) months. Cerebellar volumetries (ACAPULCO), deep gray-matter (T1-Multiatlas), cortical thickness (FreeSurfer), cervical spinal cord area (SCT) and white matter (DTI-Multiatlas) were assessed. Baseline differences between groups were described; variables that presented a p < 0.1 after Bonferroni correction were assessed longitudinally, using TimeTo and study time. For TimeTo strategy, corrections for age, sex and intracranial volume were done with Z-score progression. A significance level of 5% was adopted. RESULTS: SCT at C1 level distinguished pre-ataxic carriers from controls. DTI measures of the right inferior cerebellar peduncle (ICP), bilateral middle cerebellar peduncles (MCP) and bilateral medial lemniscus (ML), also distinguished pre-ataxic carriers from controls, and progressed over TimeTo, with effect sizes varying from 0.11 to 0.20, larger than those of the clinical scales. No MRI variable showed progression over study time. DISCUSSION: DTI parameters of the right ICP, left MCP and right ML were the best biomarkers for the pre-ataxic stage of SCA3/MJD. TimeTo is an interesting timescale, since it captured the longitudinal worsening of these structures.

Synaptic Loss in Spinocerebellar Ataxia Type 3 Revealed by SV2A Positron Emission Tomography.

BACKGROUND: Severe reduced synaptic density was observed in spinocerebellar ataxia (SCA) in postmortem neuropathology, but in vivo assessment of synaptic loss remains challenging. OBJECTIVE SPINOCEREBELLAR ATAXIA TYPE 3: The objective of this study was to assess in vivo synaptic loss and its clinical correlates in spinocerebellar ataxia type 3 (SCA3) patients by synaptic vesicle glycoprotein 2A (SV2A)-positron emission tomography (PET) imaging. METHODS: We recruited 74 SCA3 individuals including preataxic and ataxic stages and divided into two cohorts. All participants received SV2A-PET imaging using 18 F-SynVesT-1 for synaptic density assessment. Specifically, cohort 1 received standard PET procedure and quantified neurofilament light chain (NfL), and cohort 2 received simplified PET procedure for exploratory purpose. Bivariate correlation was performed between synaptic loss and clinical as well as genetic assessments. RESULTS: In cohort 1, significant reductions of synaptic density were observed in cerebellum and brainstem in SCA3 ataxia stage compared to preataxic stage and controls. Vermis was found significantly involved in preataxic stage compared to controls. Receiver operating characteristic (ROC) curves highlighted SV2A of vermis, pons, and medulla differentiating preataxic stage from ataxic stage, and SV2A combined with NfL improved the performance. Synaptic density was significantly negatively correlated with disease severity in cerebellum and brainstem (International Co-operative Ataxia Rating Scale: ρ ranging from -0.467 to -0.667, P ≤ 0.002; Scale of Assessment and Rating of Ataxia: ρ ranging from -0.465 to -0.586, P ≤ 0.002). SV2A reduction tendency of cerebellum and brainstem identified in cohort 1 was observed in cohort 2 with simplified PET procedure. CONCLUSIONS: We first identified in vivo synaptic loss was related to disease severity of SCA3, suggesting SV2A PET could be a promising clinical biomarker for disease progression of SCA3. © 2023 International Parkinson and Movement Disorder Society.

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

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.

Cerebello-cerebral resting-state functional connectivity in spinocerebellar ataxia type 3.

Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder characterized by progressive motor and nonmotor deficits concomitant with degenerative pathophysiological changes within the cerebellum. The cerebellum is topographically organized into cerebello-cerebral circuits that create distinct functional networks regulating movement, cognition, and affect. SCA3-associated motor and nonmotor symptoms are possibly related not only to intracerebellar changes but also to disruption of the connectivity within these cerebello-cerebral circuits. However, to date, no comprehensive investigation of cerebello-cerebral connectivity in SCA3 has been conducted. The present study aimed to identify cerebello-cerebral functional connectivity alterations and associations with downstream clinical phenotypes and upstream topographic markers of cerebellar neurodegeneration in patients with SCA3. This study included 45 patients with SCA3 and 49 healthy controls. Voxel-based morphometry and resting-state functional magnetic resonance imaging (MRI) were performed to characterize the cerebellar atrophy and to examine the cerebello-cerebral functional connectivity patterns. Structural MRI confirmed widespread gray matter atrophy in the motor and cognitive cerebellum of patients with SCA3. We found reduced functional connectivity between the cerebellum and the cerebral cortical networks, including the somatomotor, frontoparietal, and default networks; however, increased connectivity was observed between the cerebellum and the dorsal attention network. These abnormal patterns correlated with the CAG repeat expansion and deficits in global cognition. Our results indicate the contribution of cerebello-cerebral networks to the motor and cognitive impairments in patients with SCA3 and reveal that such alterations occur in association with cerebellar atrophy. These findings add important insights into our understanding of the role of the cerebellum in SCA3.

Structural alterations of spinocerebellar ataxias type 3: from pre-symptomatic to symptomatic stage.

OBJECTIVES: To investigate and characterize the structural alterations of the brain in SCA3, and their correlations with the scale for the assessment and rating of ataxia (SARA) and normal brain ATXN3 expression. METHODS: We performed multimodal analyses in 52 SCA3 (15 pre-symptomatic) and healthy controls (HCs) (n = 35) to assess the abnormalities of gray and white matter (WM) of the cerebrum, brainstem, and cerebellum via FreeSurfer, SUIT, and TBSS, and their associations with disease severity. Twenty SCA3 patients (5 pre- and 15 symptomatic) were followed for at least a year. Besides, we uncovered the normal pattern of brain ATXN3 spatial distribution. RESULTS: Pre-symptomatic patients showed only WM damage, mainly in the cerebellar peduncles, compared to HCs. In the advanced stage, the WM damage followed a caudal-rostral pattern. Meanwhile, continuous nonlinear structure damage was characterized by brainstem volumetric reduction and relatively symmetric cerebellar and basal ganglia atrophy but spared the cerebral cortex, partially explained by the ATXN3 overexpression. The bilateral pallidum, brainstem, and cerebellar peduncles demonstrated a very large effect size. Besides, all these alterations were significantly correlated with SARA; the pons (r = -0.65) and superior cerebellar peduncle (r = -0.68) volume demonstrated a higher correlation than the cerebellum with SARA. The longitudinal study further uncovered progressive atrophy of pons in symptomatic SCA3. CONCLUSIONS: Significant WM damage starts before the ataxia onset. The bilateral pallidum, brainstem, and cerebellar peduncles are the most vulnerable targets. The volume of pons appears to be the most promising imaging biomarker for a longitudinal study. TRIAL REGISTRATION: ClinicalTrial ID: ChiCTR2100045857 ( http://www.chictr.org.cn/edit.aspx?pid=55652&htm=4 ) KEY POINTS: • Pre- SCA3 showed WM damage mainly in cerebellar peduncles. Continuous brain damage was characterized by brainstem, widespread, and relatively symmetric cerebellar and basal ganglia atrophy. • Volumetric abnormalities were most evident in the bilateral pallidum, brainstem, and cerebellar peduncles in SCA3. • The volume of pons might identify the disease progression longitudinally.

A resting-state fMRI pattern of spinocerebellar ataxia type 3 and comparison with 18F-FDG PET.

Spinocerebellar ataxia type 3 (SCA3) is a rare genetic neurodegenerative disease. The neurobiological basis of SCA3 is still poorly understood, and up until now resting-state fMRI (rs-fMRI) has not been used to study this disease. In the current study we investigated (multi-echo) rs-fMRI data from patients with genetically confirmed SCA3 (n = 17) and matched healthy subjects (n = 16). Using independent component analysis (ICA) and subsequent regression with bootstrap resampling, we identified a pattern of differences between patients and healthy subjects, which we coined the fMRI SCA3 related pattern (fSCA3-RP) comprising cerebellum, anterior striatum and various cortical regions. Individual fSCA3-RP scores were highly correlated with a previously published 18F-FDG PET pattern found in the same sample (rho = 0.78, P = 0.0003). Also, a high correlation was found with the Scale for Assessment and Rating of Ataxia scores (r = 0.63, P = 0.007). No correlations were found with neuropsychological test scores, nor with levels of grey matter atrophy. Compared with the 18F-FDG PET pattern, the fSCA3-RP included a more extensive contribution of the mediofrontal cortex, putatively representing changes in default network activity. This rs-fMRI identification of additional regions is proposed to reflect a consequence of the nature of the BOLD technique, enabling measurement of dynamic network activity, compared to the more static 18F-FDG PET methodology. Altogether, our findings shed new light on the neural substrate of SCA3, and encourage further validation of the fSCA3-RP to assess its potential contribution as imaging biomarker for future research and clinical use.

Hypothalamic Atrophy, Expanded CAG Repeat, and Low Body Mass Index in Spinocerebellar Ataxia Type 3.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is an inherited motor disorder that is characterized by low body mass index (BMI). Considering the role of the hypothalamus in regulating appetitive behaviors and metabolism, low BMI may result from hypothalamic degeneration. OBJECTIVES: To examine hypothalamic volume changes in SCA3 by comparing patients and matched healthy controls and to identify potential mediating effects of hypothalamic pathology on CAG repeats for BMI. METHODS: Magnetic resonance imaging datasets of hypothalamic volumes from 41 SCA3 patients and 49 matched controls were analyzed. Relationships among CAG repeat number, hypothalamic volumes, and BMI were assessed using correlation and mediation analyses. RESULTS: SCA3 patients exhibited significant hypothalamic atrophy. Tubular hypothalamic volume was significantly associated with BMI. Mediation analysis revealed an indirect effect of CAG repeat number on BMI via tubular hypothalamic atrophy. CONCLUSIONS: Low BMI in SCA3 is related to neurodegeneration within the tubular hypothalamus, providing a potential target for energy-based treatment. © 2022 International Parkinson and Movement Disorder Society.

Quantitative magnetic resonance neurographic characterization of peripheral nerve involvement in manifest and pre-ataxic spinocerebellar ataxia type 3.

BACKGROUND AND PURPOSE: Knowledge about the exact underlying pathophysiological changes involved in the genesis and progression of spinocerebellar ataxia type 3 (SCA3) is limited. Lower extremity peripheral nerve lesions in clinically, genetically and electrophysiologically classified ataxic and pre-ataxic SCA3 mutation carriers were characterized and quantified by magnetic resonance neurography (MRN). METHODS: Eighteen SCA3 mutation carriers and 20 age-/sex-matched healthy controls were prospectively enrolled. All SCA3 mutation carriers underwent detailed neurological and electrophysiological examinations. 3 T MRN covered the lumbosacral plexus and proximal thigh to the tibiotalar joint by using T2-weighted inversion recovery sequences, dual-echo relaxometry sequences with spectral fat saturation, and two gradient-echo sequences with and without an off-resonance saturation rapid frequency pulse. Detailed quantification of nerve lesions by morphometric and microstructural MRN markers, including T2 relaxometry and magnetization transfer contrast imaging, was conducted in all study participants. RESULTS: MRN detected peripheral nerve damage in ataxic and pre-ataxic SCA3. The quantitative markers proton spin density (ρ), T2 relaxation time, magnetization transfer ratio and cross-sectional area were decreased in SCA3, indicating chronic axonopathy. MTR and ρ identified early, subclinical nerve damage in pre-ataxic SCA3 and in SCA3 mutation carriers without polyneuropathy and were superior in differentiating between all subgroups. Additionally, microstructural markers correlated well with clinical symptom scores and electrophysiological results. CONCLUSIONS: Our data provide a comprehensive characterization of peripheral nerve damage in SCA3 and assist in understanding the mechanisms of the multisystemic disease evolution. Evidence of peripheral nerve involvement prior to the onset of clinically overt ataxia might have important implications for designing early intervention studies.

Pattern of cerebellar grey matter loss associated with ataxia severity in spinocerebellar ataxias type 3: a multi-voxel pattern analysis.

Spinocerebellar ataxias type 3 (SCA3) patients are clinically characterized by progressive cerebellar ataxia combined with degeneration of the cerebellum. Previous neuroimaging studies have indicated ataxia severity associated with cerebellar atrophy using univariate methods. However, whether cerebellar atrophy patterns can be used to quantitatively predict ataxia severity in SCA3 patients at the individual level remains largely unexplored. In this study, a group of 66 SCA3 patients and 58 healthy controls were included. Disease duration and ataxia assessment, including the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS), were collected for SCA3 patients. The high-resolution T1-weighted MRI was obtained, and cerebellar grey matter (GM) was extracted using a spatially unbiased infratentorial template toolbox for all participants. We investigated the association between the pattern of cerebellar grey matter (GM) loss and ataxia assessment in SCA3 by using a multivariate machine learning technique. We found that the application of RVR allowed quantitative prediction of both SARA scores (leave-one-subject-out cross-validation: correlation = 0.56, p-value = 0.001; mean squared error (MSE) = 20.51, p-value = 0.001; ten-fold cross-validation: correlation = 0.52, p-value = 0.001; MSE = 21.00, p-value = 0.001) and ICARS score (leave-one-subject-out cross-validation: correlation = 0.59, p-value = 0.001; MSE = 139.69, p-value = 0.001; ten-fold cross-validation: correlation = 0.57, p-value = 0.001; MSE = 145.371, p-value = 0.001) with statistically significant accuracy. These results provide proof-of-concept that ataxia severity in SCA3 patients can be predicted by the alteration pattern of cerebellar GM using multi-voxel pattern analysis.

A Young Japanese Patient with Spinocerebellar Ataxia Type 3 Presenting Depressive State with Cenesthopathy and Delusion: a Case Report.

Depressive state is a common complication of spinocerebellar ataxia type 3 (SCA3). To the best of our knowledge, cases of SCA3 presenting with cenesthopathy have not been described. Here, we present a case of a severe depressive state with cenesthopathy and delusion in a young Japanese man with SCA3. A 43-year-old Japanese man with SCA3 developed a severe depressive state with associated cenesthopathy and delusion. He was treated with escitalopram (10 mg/day) and olanzapine (2.5 mg/day). Computed tomography showed atrophy of the cerebellum, bilateral superior cerebellar peduncle, and tegmentum of the pons. Single-photon emission computed tomography demonstrated reduced blood flow in the cerebellum, vermis, and brainstem. After 8 weeks, his depressive state and delusion improved; however, his cenesthopathy persisted. We encountered a case of a severe depressive state with cenesthopathy and delusion in a young Japanese man with SCA3. This case supports previous studies that the cerebellum could have a role beyond motor functions.

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.

OBJECTIVE: To investigate whether neurite orientation dispersion and density imaging (NODDI) could provide the added value for detecting brain microstructural alterations in the preclinical stage of Machado-Joseph disease/spinocerebellar ataxia type 3 (MJD/SCA3) compared with MRI morphometry and diffusion tensor imaging (DTI). METHODS: Twenty preclinical MJD/SCA3 patients and 21 healthy controls were enrolled. Three b values DWI and 3D T1-weighted images were acquired at 3.0 T. Tract-based spatial statistics (TBSS) approach was used to investigate the white matter (WM) alterations in the DTI metrics and NODDI metrics. Gray matter-based spatial statistics (GBSS) approach was used to investigate the grey matter (GM) alterations in the NODDI metrics. Voxel-based morphometry (VBM) approach was performed on the 3D T1-weighted images. The relationship between the cytosine-adenine-guanine (CAG) repeat length and brain microstructural alterations of preclinical MJD/SCA3 was identified. RESULTS: Compared with healthy controls, the preclinical MJD/SCA3 patients showed decreased FA and NDI as well as increased MD, AD, and RD in the WM of cerebellum and brainstem (corrected P < 0.05), and decreased NDI in the GM of cerebellar vermis (corrected P < 0.05). The CAG repeat length in preclinical MJD/SCA3 patients was negatively correlated with the reduced FA and NDI of the infratentorial WM and the reduced NDI of the cerebellum, and positively with the increased MD and RD of the infratentorial WM. CONCLUSIONS: NOODI can provide novel quantitative microstructural changes in MJD/SCA3 carriers, expanding our understanding of the gray and white matter (axons and dendrites) degeneration in this frequent ataxia syndrome.

Characterization of Retinal Architecture in Spinocerebellar Ataxia Type 3 and Correlation with Disease Severity.

BACKGROUND: Neurodegeneration affects the brain and peripheral nervous system in spinocerebellar ataxia type 3 (SCA3). As the retina is also involved, studying the retinal architecture in a cohort of patients could reveal clinically relevant biomarkers. OBJECTIVE: The aim is to investigate retinal architecture in SCA3 to identify potential biomarkers. METHODS: We evaluated 38 patients with SCA3 and 25 healthy age-matched controls, who underwent visual acuity assessment, intraocular pressure measurement, and fundoscopy and macular and peripapillary spectral domain optical coherence tomography (SD-OCT). We measured the peripapillary retinal nerve fiber layer (pRNFL) thickness in each quadrant of the temporal-superior-nasal-inferior-temporal chart and the macular layer thicknesses in each sector of the inner circle of the Early Treatment Diabetic Retinopathy Study (IC-ETDRS) grid. Linear regression analysis was employed to test the associations between retinal parameters and age, disease duration, CAG repeats, and SARA (Scale of the Assessment and Rating of Ataxia) and ICARS (International Cooperative Ataxia Rating Scale) scores in SCA3. RESULTS: In all sectors, except for the temporal quadrant, pRNFL was significantly thinner in SCA3 patients than in controls. Average total macular, ganglion cell layer (GCL), and inner plexiform layer (IPL) thicknesses were significantly decreased in SCA3 patients in comparison to controls. The average total macular thickness and the average thicknesses of RNFL, GCL, and IPL negatively correlated with ICARS scores, whereas average GCL and IPL thicknesses negatively correlated with SARA scores. CONCLUSIONS: The retinal ganglion cells, their dendrites, and axons are selectively affected in SCA3 patients. The RNFL, GCL, and IPL thicknesses in SD-OCT correlate with the clinical phenotype and represent potential biomarkers for future clinical trials and natural history studies. © 2021 International Parkinson and Movement Disorder Society.

Plasma neurofilament light chain predicts cerebellar atrophy and clinical progression in spinocerebellar ataxia.

Neurofilament light chain (NfL) is a marker of brain atrophy and predictor of disease progression in rare diseases such as Huntington Disease, but also in more common neurological disorders such as Alzheimer's disease. The aim of this study was to measure NfL longitudinally in autosomal dominant spinocerebellar ataxias (SCAs) and establish correlation with clinical and imaging parameters. We enrolled 62 pathological expansions carriers (17 SCA1, 13 SCA2, 19 SCA3, and 13 SCA7) and 19 age-matched controls in a prospective biomarker study between 2011 and 2015 and followed for 24 months at the Paris Brain Institute. We performed neurological examination, brain 3 T MRI and plasma NfL measurements using an ultrasensitive single-molecule array at baseline and at the two-year follow-up visit. We evaluated NfL correlations with ages, CAG repeat sizes, clinical scores and volumetric brain MRIs. NfL levels were significantly higher in SCAs than controls at both time points (p < 0.001). Age-adjusted NfL levels were significantly correlated at baseline with clinical scores (p < 0.01). We identified optimal NfL cut-off concentrations to differentiate controls from carriers for each genotype (SCA1 16.87 pg/mL, SCA2, 19.1 pg/mL, SCA3 16.04 pg/mL, SCA7 16.67 pg/mL). For all SCAs, NfL concentration was stable over two years (p = 0.95) despite a clinical progression (p < 0.0001). Clinical progression between baseline and follow-up was associated with higher NfL concentrations at baseline (p = 0.04). Of note, all premanifest carriers with NfL levels close to cut off concentrations had signs of the disease at follow-up. For all SCAs, the higher the observed NfL, the lower the pons volume at baseline (p < 0.01) and follow-up (p = 0.02). Higher NfL levels at baseline in all SCAs predicted a decrease in cerebellar volume (p = 0.03). This result remained significant for SCA2 only among all genotypes (p = 0.02). Overall, plasma NfL levels at baseline in SCA expansion carriers predict cerebellar volume change and clinical score progression. NfL levels might help refine inclusion criteria for clinical trials in carriers with very subtle signs.

Corticospinal tract involvement in spinocerebellar ataxia type 3: a diffusion tensor imaging study.

PURPOSE: The aim of this study was to evaluate the integrity of the corticospinal tracts (CST) in patients with SCA3 and age- and gender-matched healthy control subjects using diffusion tensor imaging (DTI). We also looked at the clinical correlates of such diffusivity abnormalities. METHODS: We assessed 2 cohorts from different Brazilian centers: cohort 1 (n = 29) scanned in a 1.5 T magnet and cohort 2 (n = 91) scanned in a 3.0 T magnet. We used Pearson's coefficients to assess the correlation of CST DTI parameters and ataxia severity (expressed by SARA scores). RESULTS: Two different results were obtained. Cohort 1 showed no significant between-group differences in DTI parameters. Cohort 2 showed significant between-group differences in the FA values in the bilateral precentral gyri (p < 0.001), bilateral superior corona radiata (p < 0.001), bilateral posterior limb of the internal capsule (p < 0.001), bilateral cerebral peduncle (p < 0.001), and bilateral basis pontis (p < 0.001). There was moderate correlation between CST diffusivity parameters and SARA scores in cohort 2 (Pearson correlation coefficient: 0.40-0.59). CONCLUSION: DTI particularly at 3 T is able to uncover and quantify CST damage in SCA3. Moreover, CST microstructural damage may contribute with ataxia severity in the disease.