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White Matter Tract Abnormalities are Associated with Cognitive Dysfunction in CADASIL1Shanghai Key Laboratory of Magnetic Resonance and Department of Physics, School of Physics and Materials Science, East China Normal University, Shanghai, China, 2Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
Synopsis
This study was to investigate the white matter microstructural abnormalities and the relationship between white matter alterations and cognitive impairment in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), by diffusion tensor imaging (DTI). Patients with CADASIL showed significant extensive reductions in fractional anisotropy (FA), and increases in axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD) compared to healthy controls. Furthermore, these white matter microstructural alterations were significantly correlated with Cognitive scores, and Stroke scale scores. It indicated that damage of white matter play an important role in cognition impairment in CADASIL
Purpose
The cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common familial cerebral small vessel disease (SVD) caused by mutations of the NOTCH3 gene, which is strongly associated with ischemic stroke and dementia1. Patients are characterized by cognitive impairment and widespread white matter lesions2. However, the relationship between white matter lesion and cognitive impairment is not very clear. The aim of this study was to investigate the white matter microstructural abnormalities and the relationship between white matter alterations and cognitive impairment in patients with CADASIL by diffusion tensor imaging (DTI).Materials and Methods
Clinical information including Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA) and modified Rankin scale (mRs) scores were recorded. DTI data were collected from 18 patients with CADASIL (aged 16-72 years, MMSE: 23.8±6.6; MoCA: 21.2±8.5, MRS:1.1±1.1, 10 male) and 18 gender- and age-matched healthy controls. The DTI image was obtained using an axial single‐shot echo planar imaging sequence with the following parameters: TR = 8900 ms, TE = 86 ms, FOV = 256 mm × 256 mm, matrix size = 128 × 128, 70 slices, slice thickness = 12 mm; b-value = 0 and with 1000 s/mm2, diff direction = 64. Image processing and analysis were performed using tract-based spatial statistics (TBSS) by FSL5.0, so as to calculate diffusion tensor metrics including the fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), mean diffusivity (MD). A two-sample t test was performed to assess differences between CADASIL patients and HC. Finally, Pearson correlation analysis was performed between diffuse microstructural indices (FA, AD, RD, MD) and general clinical information (Cognitive score: MMSE and MoCA; Stroke scale: mRS) separately.Results
Compared with healthy controls, patients with CADASIL showed extensive significant reductions in FA, and increased in RD, AD, MD (P<0.01, TFCE and FWE corrected), they were almost all over the brain (including inferior and superior longitidinal fasciculus, inferior fronto-occipital fasciculus, corpus callosum, internal capsule, cerebral peduncle, uncinate fasciculus, corona radiate, thalamic radiation, cingulum), more details see Figure 1. Furthermore, FA values showed significant positive correlation with MMSE and MoCA scores, negative correlation with mRs scores in patients. Conversely, in patients, AD, RD, MD had significant negative correlation with MMSE and MoCA scores, and positive correlation with mRs scores.Discussion
Consistent with our hypothesis, patients with CADASIL showed widespread abnormalities of the white matter, and there were significant correlation between white matter microstructural integrity and cognitive impairment. Mutations in NOTCH3 gene cause axonal damage and myelin demyelination, thereby producing progressive impairment of white matter tract integrity in CADASIL1, 2. White matter is the basis of nerve signal transmission. The impairment of its integrity would directly affect the transmission of neural signals, thus impairing the cognitive and motor functions of the brain. Our results indicated that damage of white matter play an important role in cognition impairment in CADASIL.Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (Nos. 81571658 to X. X. Du)References
1. Di Donato I, Bianchi S, De Stefano N, et al. Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) as a model of small vessel disease: update on clinical, diagnostic, and management aspects. Bmc Med 2017;15.
2. Joutel A, Corpechot C, Ducros A, et al. Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 1996;383:707-710.
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