Resting-state functional MRI reveals altered brain connectivity and its correlation with motor dysfunction in a mouse model of Huntington\u2019s disease

Qiang Li,Wenzhen Duan,Christopher A Ross,Zhipeng Hou,Yihong Yang,Gang Li,Dan Wu,Jiangyang Zhang,Hanbing Lu

doi:10.1038/s41598-017-17026-5

Abstract

Huntington’s disease (HD) is an autosomal dominant inherited neurodegenerative disorder, and no cure is available currently. Treatment of HD is likely to be most beneficial in the early, possibly pre-manifestation stage. The challenge is to determine the best time for intervention and evaluate putative efficacy in the absence of clinical symptoms. Resting-state functional MRI may represent a promising tool to develop biomarker reflecting early neuronal dysfunction in HD brain, because it can examine multiple brain networks without confounding effects of cognitive ability, which makes the resting-state fMRI promising as a translational bridge between preclinical study in animal models and clinical findings in HD patients. In this study, we examined brain regional connectivity and its correlation to brain atrophy, as well as motor function in the 18-week-old N171-82Q HD mice. HD mice exhibited significantly altered functional connectivity in multiple networks. Particularly, the weaker intra-striatum connectivity was positively correlated with striatal atrophy, while striatum-retrosplenial cortex connectivity is negatively correlated with striatal atrophy. The resting-state brain regional connectivity had no significant correlation with motor deficits in HD mice. Our results suggest that altered brain connectivity detected by resting-state fMRI might serve as an early disease biomarker in HD.

Highlights

Huntington disease (HD) is a neurodegenerative disorder resulting from a trinucleotide repeat expansion in the huntingtin gene
These networks were consistently detected in both control and Huntington’s disease (HD) mouse brains, aligned well with anatomical boundaries, and were comparable with the networks reported in previous resting-state fMRI (rs-fMRI) studies of rodent models[23,24,25,26]
In this study we investigated rs-fMRI signals among functionally connected brain regions and used two complementary analysis approaches, independent components analysis showed that stable network interconnectivity in mouse brain, and seed-based analysis revealed patterns of weakened striatal connections and strengthened striatal to the retrosplenial cortex connections in the HD mice

Summary

Introduction

Huntington disease (HD) is a neurodegenerative disorder resulting from a trinucleotide repeat expansion in the huntingtin gene. Measurements of brain connectivity can add the dimension of brain function and may be sensitive to early functional changes in HD. It has been shown that altered functional brain connectivity detected by rs-fMRI in prodromal and early manifest HD subjects[15,16,17,18,19,20,21], and a recent study demonstrated that an abnormal functional connectivity of the default mode network precedes brain atrophy and is sensitive to a drug treatment, may indicate a biomarker of dysfunction in HD21. No study has examined the resting-state functional networks in HD mouse models yet, and it is unknown whether the functional connectivity changes are correlated with brain pathology and behavioral phenotypes in HD mice. We investigated the functional connectivity by rs-fMRI and analyzed the relationship between functional connectivity and striatal atrophy, as well as motor function in a well-characterized HD mouse model- N171-82Q9,22

Methods

Results

Conclusion