White matter damage is related to ataxia severity in SCA3

Abstract

Spinocerebellar ataxia type 3 (SCA3) is the most frequent inherited cerebellar ataxia in Europe, the US and Japan, leading to disability and death through motor complications. Although the affected protein ataxin-3 is found ubiquitously in the brain, grey matter atrophy is predominant in the cerebellum and the brainstem. White matter pathology is generally less severe and thought to occur in the brainstem, spinal cord, and cerebellar white matter. Here, we investigated both grey and white matter pathology in a group of 12 SCA3 patients and matched controls. We used voxel-based morphometry for analysis of tissue loss, and tract-based spatial statistics (TBSS) on diffusion magnetic resonance imaging to investigate microstructural pathology. We analysed correlations between microstructural properties of the brain and ataxia severity, as measured by the Scale for the Assessment and Rating of Ataxia (SARA) score. SCA3 patients exhibited significant loss of both grey and white matter in the cerebellar hemispheres, brainstem including pons and in lateral thalamus. On between-group analysis, TBSS detected widespread microstructural white matter pathology in the cerebellum, brainstem, and bilaterally in thalamus and the cerebral hemispheres. Furthermore, fractional anisotropy in a white matter network comprising frontal, thalamic, brainstem and left cerebellar white matter strongly and negatively correlated with SARA ataxia scores. Tractography identified the thalamic white matter thus implicated as belonging to ventrolateral thalamus. Disruption of white matter integrity in patients suffering from SCA3 is more widespread than previously thought. Moreover, our data provide evidence that microstructural white matter changes in SCA3 are strongly related to the clinical severity of ataxia symptoms.

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

“…Some studies reported that SCA3 patients could have extracerebellar involvements (Rüb et al, 2008, Rezende et al, 2015, Yamada et al, 2004). Other studies found the degeneration of cerebral regions, basal ganglia, brain stem, spinal cord and white matter in SCA3 is also correlated with SARA score or ICARS score (D'Abreu et al, 2012, Fahl et al, 2015, Kang et al, 2014, Rezende et al, 2015, Schulz et al, 2010). These results indicate that not only the atrophy of cerebellum but also the degeneration of any brain region in the central nervous loop that modulates motor function may arise in ataxia symptoms (Rüb et al, 2008, Schmahmann and Pandya, 2008).…”

Reconstructing the History of Machado-Joseph Disease

“…Since then and until recently, many clinician-researchers have examined members of the Drew family of Walworth [20]. With a clear autosomal dominant pattern of inheritance (for details, see Kang et al [18]) and pleomorphic clinical characteristics among patients (euphoria, emotional instability, and without cognitive impairment; vertical ophthalmoparesis, nystagmus, and lid retraction; pyramidal signs; sensitive disturbances; extrapyramidal manifestations -including parkinsonism; dysarthria; altered control of sphincters; and cerebellar ataxia) [21], the members of the family were examined through decades by others including T. Grainger Stewart, James Collier, Kinnier-Wilson, Aldren Turner, Worster-Drought, Fergunson and Critchley (1929), J. Brown (1975), Anita Harding (1982 and1984) and Giunti, and Sweeney and Harding (1995) [20].…”

“…In the beginning, even in presymptomatic stages, the first neuroradiological alteration found is cervical spinal atrophy. As the disease evolves, imaging tends to show diffuse cerebral atrophy [17][18][19].…”

Supratentorial and Infratentorial Lesions in Spinocerebellar Ataxia Type 3

“…Diffusion tensor imaging (DTI) can facilitate the visualization and characterization of white matter (WM), and DTI is also an efficient method for study of SCA3 (15). SCA3 had been verified as a WM dominant atrophy neurodegenerative disease (16). Previous studies showed patients with SCA3 demonstrate decreases in fractional anisotropy (FA) in the areas of cerebellum and brainstem, but increases in radial diffusivity (RD) in the cerebellum, brainstem, thalamus, and frontal and temporal lobes (17).…”

“…Previous studies showed patients with SCA3 demonstrate decreases in fractional anisotropy (FA) in the areas of cerebellum and brainstem, but increases in radial diffusivity (RD) in the cerebellum, brainstem, thalamus, and frontal and temporal lobes (17). Another DTI study identified widespread FA reduction in the bilateral cerebral-frontal, -parietal, -temporal, and -occipital WM; cerebellar WM; the thalamus; and the brainstem in patients with SCA3 (16). Moreover, mean diffusivity (MD) increases were detected in a similar, widely overlapping pattern in bilateral cerebral-frontal, -parietal, -temporal, and -occipital WM; cerebellar WM; the thalamus; and the brainstem (16).…”