Extensive White Matter Alterations and Its Correlations with Ataxia Severity in SCA 2 Patients

Abstract

BackgroundPrevious studies of SCA2 have revealed significant degeneration of white matter tracts in cerebellar and cerebral regions. The motor deficit in these patients may be attributable to the degradation of projection fibers associated with the underlying neurodegenerative process. However, this relationship remains unclear. Statistical analysis of diffusion tensor imaging enables an unbiased whole-brain quantitative comparison of the diffusion proprieties of white matter tracts in vivo.MethodsFourteen genetically confirmed SCA2 patients and aged-matched healthy controls participated in the study. Tract-based spatial statistics were performed to analyze structural white matter damage using two different measurements: fractional anisotropy (FA) and mean diffusivity (MD). Significant diffusion differences were correlated with the patient's ataxia impairment.ResultsOur analysis revealed decreased FA mainly in the inferior/middle/superior cerebellar peduncles, the bilateral posterior limb of the internal capsule and the bilateral superior corona radiata. Increases in MD were found mainly in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Clinical impairment measured with the SARA score correlated with FA in superior parietal white matter and bilateral anterior corona radiata. Correlations with MD were found in cerebellar white matter and the middle cerebellar peduncle.ConclusionOur findings show significant correlations between diffusion measurements in key areas affected in SCA2 and measures of motor impairment, suggesting a disruption of information flow between motor and sensory-integration areas. These findings result in a more comprehensive view of the clinical impact of the white matter degeneration in SCA2.

Brain atrophy measures in preclinical and manifest spinocerebellar ataxia type 2

“…Magnetic resonance imaging (MRI) data are sparse and often comprise only small sample sizes in this orphan disease. The available structural MRI data have so far confirmed the neuropathological findings showing atrophy of the brainstem and cerebellum,6, 7, 8 but there is also some evidence for cortical brain atrophy and microstructural abnormalities in SCA2 patients 9, 10, 11, 12, 13. For preclinical SCA2 mutation carriers, only two structural MRI studies exist.…”

“…26,27 Similarly, microstructural abnormalities measured by diffusion weighted imaging have been detected in the cerebellum and the pons 28 as well as cortical alterations in SCA2 patients. 10,11,29 Functional MRI in resting-state modus further shows changes of cerebellar but also fronto-and parietal connectivity networks related to cognitive and motor performance. 30,31 No multimodal MRI data other than macroanatomical measurements exist for the preclinical stage of the disease.…”

“…The available structural MRI data have so far confirmed the neuropathological findings showing atrophy of the brainstem and cerebellum, [6][7][8] but there is also some evidence for cortical brain atrophy and microstructural abnormalities in SCA2 patients. [9][10][11][12][13] For preclinical SCA2 mutation carriers, only two structural MRI studies exist. The Ataxia Study Group (www.ataxiastudy-group.net) investigates the natural history of the preclinical stages in SCA1, SCA2, SCA3, and SCA6 (RISCA).…”

Neural substrates of motor and cognitive dysfunctions in SCA2 patients: A network based statistics analysis

“…In SCA2 patients microstructural alterations of the cerebellar WM have been reported by Diffusion Tensor Imaging (DTI) studies, showing the prevalent involvement of the main afferent and efferent tracts (i.e. Middle and Superior Cerebellar Peduncle), connecting the cerebellum with both motor and non-motor cortical regions (Mandelli et al, 2007, Della Nave et al, 2008b, Hernandez-Castillo et al, 2015b). Although in the present study structural connectivity has not been specifically investigated, it has to be considered that microstructural abnormalities of the cerebellar WM tracts, typically reported in SCA2 patients, may underlie a deficient structural connectivity that impacts the cerebello-cerebral interplay and results in a lack of functional connectivity.…”

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

“…In neurodegenerative diseases including spinocerebellar ataxias (SCAs), both MD and FA have gained widespread acceptance as sensitive indicators for quantifying microstructural damage to white matter, showing the associations between the white matter integrity and behavioral impairment in some cases. 6,[10][11][12][13] Among several studies using diffusion measurements, only a preliminary study has explored the white matter integrity in a small group of patients with SCA7, 6 reporting significant FA decreases that correlate with the number of years passed from the onset of symptoms. However, the contribution of the degeneration of projection fibers to the patients' impairments was not explored, possibly due to the small number of subjects.…”