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Altered structural and functional connectivity in CSF1R-related leukoencephalopathy

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Abstract

CSF1R-related leukoencephalopathy is a rare white-matter encephalopathy characterized by motor and neuropsychiatric symptoms due to colony-stimulating factor 1 receptor (CSF1R) gene mutation. Few studies have investigated the intrinsic brain alternations of patients with CSF1R-related leukoencephalopathy. We aim to evaluate the structural and functional changes in those patients. Seven patients with CSF1R-related leukoencephalopathy and 15 age-matched healthy controls (HCs) underwent multimodal magnetic resonance imaging (MRI), including high-resolution T1-weighted imaging, T2-weighted fluid attenuated inversion recovery imaging, diffusion-weighted imaging, diffusion kurtosis imaging (DKI) and resting-state functional MRI. First, to detect structural alterations, the gray matter volumes were compared using voxel-based morphometry analyses. Second, DKI parametric maps were used to evaluate the white matter (WM) connectivity changes. Finally, we constructed a seed-based resting-state functional connectivity matrix based on 90 regions of interest and examined the functional network changes of CSF1R-related leukoencephalopathy. Unlike the HCs, patients with CSF1R-related leukoencephalopathy predominantly had morphological atrophy in the bilateral thalamus and left hippocampus. In addition, the abnormal diffusivity was mainly distributed in the splenium of the corpus callosum, periventricular regions, centrum semiovale, subcortical U-fibers and midline cortex structures. Moreover, the patients had significantly reduced functional connectivity between the bilateral caudate nucleus and their contralateral hippocampus. Therefore, in addition to hyperintensity on the T2-weighted images, CSF1R-related leukoencephalopathy also showed abnormal structural and functional alterations, including subcortical atrophy and reduced functional connectivity, as well as altered diffuse parameters in the WM and subcortical regions. These findings expand our understanding of the potential pathophysiologic mechanism behind this hereditary disease.

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Abbreviations

CSF1R :

colony-stimulating factor 1 receptor

MRI:

magnetic resonance imaging

DKI:

diffusion kurtosis imaging

ALSP:

adult-onset leukoencephalopathy with neuroaxonal spheroids and pigmented glia

HDLS:

hereditary diffuse leukoencephalopathy with spheroids

POLD:

pigmented orthochromatic leukodystrophy

WM:

white matter

DWI:

diffusion-weighted imaging

GM:

gray matter

fMRI:

Functional MRI

FC:

functional connectivity

HCs:

healthy controls

MMSE :

Mini-Mental State Examination

MoCA:

Montreal Cognitive Assessment

T2-FLAIR:

T2-weighted fluid attenuated inversion recovery imaging

TR :

repetition time

TE :

echo time

FOV :

field of view

NEX :

number of excitations

EPI :

echo planar imaging

VBM :

voxel-based morphometry

CSF:

cerebrospinal fluid

MNI :

Montreal Neurological Institute

MK :

mean kurtosis

AK :

axial kurtosis

RK :

radial kurtosis

FA:

fractional anisotropy

MD:

mean diffusivity

AD:

axial diffusivity

RD:

radial diffusivity

DKE:

Diffusion Kurtosis Estimator

VBA :

voxel-based analysis

TIV:

total intracranial volume

FDR:

false discovery rate

ROIs:

regions of interest

NBS :

network-based statistic

DTI:

diffusion tensor imaging

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Study funding

This work was supported by National Natural Science Foundation of China (81,571,086, 81,870,889 and 81,400,888), National Key R&D Program of China (2017YFC1310200), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20161401) and Interdisciplinary Project of Shanghai Jiao Tong University (YG2016MS64).

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  1. Fei-Xia Zhan and Ze-Yu Zhu contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Rui Jin Hospital & Rui Jin Hospital North, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Fei-Xia Zhan, Ze-Yu Zhu, Hai-Yan Zhou, Xing-Hua Luan, Xiao-Jun Huang, Wo-Tu Tian, Shi-Ge Wang, Xiao-Xuan Song, Guang Chen, Ming-Liang Zhao, Ying Wang, Hui-Dong Tang, Sheng-Di Chen, Bin-Yin Li & Li Cao

  2. Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CAMS & PUMC), Beijing, 100032, China

    Qing Liu

  3. Department of Neurology, Shanghai Fengxian District Central Hospital, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus, Shanghai, 201406, China

    Xiao-Li Liu

  4. Department of Hematology, Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China

    Jiong Hu

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Contributions

Dr. Zhan: data acquisition, analysis and interpretation of data, statistical analysis, drafting the manuscript.

Dr. Zhu: data acquisition, analysis and interpretation of data.

Dr. Liu: data acquisition.

Dr. Zhou: data acquisition.

Dr. Luan: data acquisition.

Dr. Huang: data acquisition.

Dr. Liu: data acquisition.

Dr. Tian: data acquisition.

Dr. SG Wang: data acquisition.

Dr. Song: data acquisition.

Dr. Chen: data acquisition.

Dr. Zhao: data acquisition.

Dr. Y Wang: data acquisition.

Dr. Tang: data acquisition.

Dr. Chen: data acquisition.

Dr. Hu: data acquisition.

Dr. Li: funding, analysis and interpretation of data, drafting the manuscript, manuscript revision.

Prof. Cao: funding, study design and conceptualization, data acquisition, analysis and interpretation of data, statistical analysis, manuscript revision.

Corresponding authors

Correspondence to Bin-Yin Li or Li Cao.

Ethics declarations

Dr. BY Li is in charge of National Natural Science Foundation of China (81400888).

Prof. L Cao is in charge of National Natural Science Foundation of China (81571086 and 81870889), Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant (20161401) and Interdisciplinary Project of Shanghai Jiao Tong University (YG2016MS64).

The other co-authors report no disclosures relevant to the manuscript.

Conflict of interest

None of the authors have potential conflicts of interest to be disclosed. The authors alone are responsible for the content and writing of this paper.

Ethical approval

The study was approved by the ethics committee of Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China and was registered at http://www.chictr.org.cn (registration number: ChiCTR1800015295). All participants or their guardians provided written informed consent.

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Zhan, FX., Zhu, ZY., Liu, Q. et al. Altered structural and functional connectivity in CSF1R-related leukoencephalopathy. Brain Imaging and Behavior 15, 1655–1666 (2021). https://doi.org/10.1007/s11682-020-00360-0

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