Ataxia Severity Correlates with White Matter Degeneration in Spinocerebellar Ataxia Type 7

Hernandez‐Castillo, Carlos R.; Vaca‐Palomares, Israel; Barrios, Fernando A.; Martínez, Leticia; Boll, Marie‐Catherine; Fernández-Ruíz, Juan

doi:10.3174/ajnr.a4903

Cited by 11 publications

(5 citation statements)

References 32 publications

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“…Similarly, the FA differed from the pFA by also being smaller in patients in almost every voxel of the cerebellar peduncles. Other studies using DTI to study SCA7 corroborated this, finding that the MD and FA were abnormal in the same regions we found the single-compartment MD and FA to be abnormal in 13, 19 .…”

Section: Discussionsupporting

confidence: 86%

“…[13][14][15][16] . DTI, which is typically used to assess WM microstructural integrity via measures of water diffusivity 17,18 , has detected microstructural abnormalities in the cerebellar WM, cerebellar peduncles, brainstem, cerebral peduncles, and several cerebral WM tracts including the internal and external capsules, corona radiata, optical radiation, corpus callosum, and miscellaneous temporal, occipital, parietal, and frontal WM in patients 13,19 . These abnormalities were indicated by both an increased mean diffusivity (MD), a measure of the magnitude of diffusion in all directions, and decreased fractional anisotropy (FA), a measure of how preferentially water diffuses in the principal direction of diffusion as compared to the other directions 20 .…”

Section: Introductionmentioning

confidence: 99%

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In vivoassessment of neurodegeneration in Spinocerebellar Ataxia type 7

Parker

Merchant

Attaripour-Isfahani

et al. 2020

Preprint

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Spinocerebellar Ataxia type 7 (SCA7) is a neurodegenerative disease characterized by progressive cerebellar ataxia and retinal degeneration. Increasing loss of visual function complicates the use of clinical scales to track the progression of motor symptoms, hampering our ability to develop accurate biomarkers of disease progression, and thus test the efficacy of potential treatments. In this cross-sectional study, we aimed to identify imaging measures of neurodegeneration, which may more accurately reflect SCA7 severity and progression. We analyzed diffusion tensor imaging (DTI) data collected from a cohort of 13 SCA7 patients and 14 healthy volunteers using two recent methodological advances: 1) a diffusion tensor-based image registration technique, and 2) a dual-compartment DTI model to control for the potential increase in extracellular CSF-like water due to neurodegeneration. These methodologies allowed us to assess both volumetric and microstructural abnormalities in both white and gray matter brain-wide in SCA7 patients for the first time. To measure tissue volume, we performed diffusion tensor-based morphometry (DTBM) using the tensor-based registration. To assess tissue microstructure, we computed the parenchymal mean diffusivity (pMD) and parenchymal fractional anisotropy (pFA) using the dual compartment model. This model also enabled us to estimate the parenchymal volume fraction (pVF), a measure of parenchymal tissue volume within a given voxel. While DTBM and pVF revealed tissue loss primarily in the brainstem, cerebellum, thalamus, and a subset of cerebral white matter tracts in patients, pMD and pFA detected microstructural abnormalities brain-wide (p < 0.05, FWE corrected; Hedge's g > 1). This distinction was meaningful in terms of motor symptom severity, as we found that patient scores on the Scale for the Assessment and Rating of Ataxia correlated most strongly with cerebellar pVF (r = -0.66, p = 0.015) and global white matter pFA (r = -0.64, p = 0.018). Since this contrast between focal tissue loss and global microstructural abnormality has previously been described in neuropathology, we believe the approach employed here is well suited for the in-vivo assessment of neurodegeneration. Moving forward, this approach could be applied to characterize the full spatiotemporal pattern of neurodegeneration in SCA7, and potentially develop an accurate imaging biomarker of disease progression.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

In vivoassessment of neurodegeneration in Spinocerebellar Ataxia type 7

Parker

Merchant

Attaripour-Isfahani

et al. 2020

Preprint

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“…In addition, both the striatum and thalamus are part of the sensory-motor network, which was found to be altered in SCA7 patients [ 30 , 31 ], as well as in HD in correlation with the severity of motor symptoms [ 32 ]. In SCA7, correlations were found between ataxia severity score of patients and impairment of several white matter tracts, including the anterior thalamic radiation [ 33 ]. Thus, the vulnerability of thalamus and striatum may reflect ataxia severity in the SCA7 140Q/5Q model.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies showed altered functional connectivity between the cerebellum and hippocampus or parahippocampal areas of patients, which may account for specific memory dysfunctions [ 4 , 30 , 33 ]. Interestingly, hippocampal neurons show accumulation of mATXN7 and alteration of short-term synaptic plasticity in SCA7 266Q/5Q mice [ 7 ].…”

Section: Discussionmentioning

confidence: 99%

Longitudinal MRI and 1H-MRS study of SCA7 mouse forebrain reveals progressive multiregional atrophy and early brain metabolite changes indicating early neuronal and glial dysfunction

Pérot,

Niewiadomska-Cimicka,

Brouillet

et al. 2024

PLoS ONE

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SpinoCerebellar Ataxia type 7 (SCA7) is an inherited disorder caused by CAG triplet repeats encoding polyglutamine expansion in the ATXN7 protein, which is part of the transcriptional coactivator complex SAGA. The mutation primarily causes neurodegeneration in the cerebellum and retina, as well as several forebrain structures. The SCA7140Q/5Q knock-in mouse model recapitulates key disease features, including loss of vision and motor performance. To characterize the temporal progression of brain degeneration of this model, we performed a longitudinal study spanning from early to late symptomatic stages using high-resolution magnetic resonance imaging (MRI) and in vivo 1H-magnetic resonance spectroscopy (1H-MRS). Compared to wild-type mouse littermates, MRI analysis of SCA7 mice shows progressive atrophy of defined brain structures, with the striatum, thalamus and cortex being the first and most severely affected. The volume loss of these structures coincided with increased motor impairments in SCA7 mice, suggesting an alteration of the sensory-motor network, as observed in SCA7 patients. MRI also reveals atrophy of the hippocampus and anterior commissure at mid-symptomatic stage and the midbrain and brain stem at late stage. 1H-MRS of hippocampus, a brain region previously shown to be dysfunctional in patients, reveals early and progressive metabolic alterations in SCA7 mice. Interestingly, abnormal glutamine accumulation precedes the hippocampal atrophy and the reduction in myo-inositol and total N-acetyl-aspartate concentrations, two markers of glial and neuronal damage, respectively. Together, our results indicate that non-cerebellar alterations and glial and neuronal metabolic impairments may play a crucial role in the development of SCA7 mouse pathology, particularly at early stages of the disease. Degenerative features of forebrain structures in SCA7 mice correspond to current observations made in patients. Our study thus provides potential biomarkers that could be used for the evaluation of future therapeutic trials using the SCA7140Q/5Q model.

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“…Furthermore, it has also been reported that gluten sensitivity can also be manifested without enteropathy (Aziz et al, 2012 ), rendering the diagnosis of such GA patients difficult. The symptoms of GA include gait ataxia, dysarthria, upper limb/lower limb ataxia, and ocular signs (Hernandez-Castillo et al, 2016 ). However, the onset of GA is usually not apparent, but it can rapidly progress, mimicking paraneoplastic cerebellar degeneration (Zis and Hadjivassiliou, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Cerebellar Abnormalities on Proton MR Spectroscopy and Imaging in Patients With Gluten Ataxia: A Pilot Study

Rawat

Tyagi

Singh

et al. 2022

Front. Hum. Neurosci.

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Gluten ataxia is a rare immune-mediated neurological disorder caused by the ingestion of gluten. The diagnosis is not straightforward as antibodies are present in only up to 38% of patients, but often at lower titers. The symptoms of ataxia may be mild at the onset but lead to permanent damage if remain untreated. It is characterized by damage to the cerebellum however, the pathophysiology of the disease is not clearly understood. The present study investigated the neurochemical profile of vermis and right cerebellum and structural changes in various brain regions of patients with gluten ataxia (n = 6, age range 40–65 years) and compared it with healthy controls (n = 10, 40–55 years). Volumetric 3-D T1 and T1-weighted magnetic resonance imaging (MRI) in the three planes (axial, coronal, and sagittal) of the whole brain and single-voxel 1H- magnetic resonance spectroscopy (MRS) of the vermis and right cerebellum were acquired on 3 T human MR scanner. The metabolite concentrations were estimated using LC Model (6.1–4A) while brain volumes were estimated using the online tool volBrain pipeline and CERES and corrected for partial volumes. The levels of neuro-metabolites (N-acetyl aspartate + N-acetyl aspartate glutamate, glycerophosphocholine + phosphocholine, and total creatine) were found to be significantly lower in vermis, while N-acetyl aspartate + N-acetyl aspartate glutamate and glycerophosphocholine + phosphocholine was lower in cerebellum regions in the patients with gluten ataxia compared to healthy controls. A significant reduction in the white matter of (total brain, cerebellum, and cerebrum); reduction in the volumes of cerebellum lobe (X) and thalamus while lateral ventricles were increased in the patients with gluten ataxia compared to healthy controls. The reduced neuronal metabolites along with structural changes in the brain suggested neuronal degeneration in the patients with gluten ataxia. Our preliminary findings may be useful in understanding the gluten-induced cerebral damage and indicated that MRI and MRS may serve as a non-invasive useful tool in the early diagnosis, thereby enabling better management of these patients.

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Ataxia Severity Correlates with White Matter Degeneration in Spinocerebellar Ataxia Type 7

Cited by 11 publications

References 32 publications

In vivoassessment of neurodegeneration in Spinocerebellar Ataxia type 7

In vivoassessment of neurodegeneration in Spinocerebellar Ataxia type 7

Longitudinal MRI and 1H-MRS study of SCA7 mouse forebrain reveals progressive multiregional atrophy and early brain metabolite changes indicating early neuronal and glial dysfunction

Cerebellar Abnormalities on Proton MR Spectroscopy and Imaging in Patients With Gluten Ataxia: A Pilot Study

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