Microstructural Alterations in Asymptomatic and Symptomatic Patients with Spinocerebellar Ataxia Type 3: A Tract-Based Spatial Statistics Study

Abstract

ObjectiveSpinocerebellar ataxia type 3 (SCA3) is the most commonly occurring type of autosomal dominant spinocerebellar ataxia. The present study aims to investigate progressive changes in white matter (WM) fiber in asymptomatic and symptomatic patients with SCA3.MethodsA total of 62 participants were included in this study. Among them, 16 were asymptomatic mutation carriers (pre-SCA3), 22 were SCA3 patients with clinical symptoms, and 24 were normal controls (NC). Group comparison of tract-based spatial statistics was performed to identify microstructural abnormalities at different SCA3 disease stages.ResultsDecreased fractional anisotropy (FA) and increased mean diffusivity (MD) were found in the left inferior cerebellar peduncle and superior cerebellar peduncle (SCP) in the pre-SCA3 group compared with NC. The symptomatic SCA3 group showed brain-wide WM tracts impairment in both supratentorial and infratentorial networks, and the mean FA value of the WM skeleton showed a significantly negative correlation with the International Cooperative Ataxia Rating Scale (ICARS) scores. Specifically, FA of the bilateral posterior limb of the internal capsule negatively correlated with SCA3 disease duration. We also found that FA values in the right medial lemniscus and SCP negatively correlated with ICARS scores, whereas FA in the right posterior thalamic radiation positively correlated with Montreal Cognitive Assessment scores. In addition, MD in the middle cerebellar peduncle, left anterior limb of internal capsule, external capsule, and superior corona radiate positively correlated with ICARS scores in SCA3 patients.ConclusionWM microstructural changes are present even in the asymptomatic stages of SCA3. In individuals in which the disease has progressed to the symptomatic stage, the integrity of WM fibers across the whole brain is affected. Furthermore, abnormalities in WM tracts are closely related to SCA3 disease severity, including movement disorder and cognitive dysfunction. These findings can deepen our understanding of the neural basis of SCA3 dysfunction.

MR Imaging of SCA3/MJD

“…DTI studies with TBSS have revealed a widespread decrease in FA accompanied by increased AD, RD, and MD in the WM across the whole brain, especially the cerebellum and the brainstem, as well as some supratentorial areas, such as the bilateral frontal, parietal, temporal, and occipital lobes and thalamus, in patients with SCA3/MJD compared with those in controls, as shown in Figure 3 ( Guimarães et al, 2013 ; Nunes et al, 2015 ; Jao et al, 2019 ). What is more, MD increases showed a similar pattern as FA decreases ( Kang et al, 2014 ; Wu et al, 2017 ; Jao et al, 2019 ), and these findings were in line with the results from the multi-atlas segmented findings ( Rezende et al, 2018 ). WM abnormalities were also identified in some fiber pathways that were mostly in the cerebellar connecting tracts, including the pyramidal tract, thalamic radiations, medial lemnisci, corticospinal tract, corticobulbar tract, and corticopontocerebellar tract in patients with SCA3/MJD ( Rezende et al, 2018 ; Jao et al, 2019 ).…”

“…The discovery of the microstructural changes of preclinical SCA3/MJD is helpful to find neuroimaging markers and even predict the clinical onset of disease. Wu et al (2017) identified decreased FA values and increased MD in the cerebellar peduncles of preclinical SCA3/MJD patients. A multi-atlas analysis in another study revealed that all DTI-based parameters were abnormal in the cerebellar peduncles of asymptomatic SCA3/MJD gene carriers ( Rezende et al, 2018 ).…”

“…Abnormal TBSS results were inversely correlated with SARA scores, ICARS scores, and neuropsychological assessment results of SCA3/MJD patients, which indicated that damage to the WM tracts across specific regions may be closely related to disease severity in SCA3/MJD patients, including the severity of movement disorders (Kang et al, 2014;Peng et al, 2019) and cognitive dysfunction (Lopes et al, 2013;Wu et al, 2017). WM plays a vital role in connecting various brain regions and coordinating the communication between them, while no significant correlation was found between any of the DTI parameters and the number of CAG repeats in expanded alleles (Guimarães et al, 2013;Kang et al, 2014;Peng et al, 2019).…”

Sensorimotor and pain‐related alterations of the gray matter and white matter in Type 2 diabetic patients with peripheral neuropathy

“…Using TBSS, we identified a pattern of lower FA and higher MD and RD throughout the altered WM tracts. The lower FA and higher MD might indicate abnormal myelin structure, although there are indications that these measures alone are insufficient (Hasan, ; Wu et al, ). In addition, experimental evidence indicates that an increase in RD might reflect myelin damage (Wheeler‐Kingshott & Cercignani, ).…”

In vivomolecular signatures of cerebellar pathology in spinocerebellar ataxia type 3

“…Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a polyQ disease caused by an expanded CAG repeat in the ATXN3 gene 12 that leads to selective dysfunction and loss of neurons of specific nuclei in the cerebellum, brain stem, midbrain, spinal cord, and peripheral nerves [9][10][11][13][14][15][16][17][18][19][20][21] . This central and peripheral nervous system pathology manifests in patients with SCA3 as ataxia and a variable degree of other symptoms, such as extrapyramidal signs, neuropathy, ophthalmoplegia, visual impairment and muscle atrophy [22][23][24][25][26] .…”