Introduction

Multiple system atrophy (MSA) is a sporadic, adult-onset neurodegenerative disease characterized by autonomic failure, parkinsonism, and cerebellar ataxia [1]. Freezing of gait（FOG）was defined as “Brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk [2]. Epidemiological studies reveal about 65.93% of MSA patients had experienced FOG [3]. As one of the disabling gait disorders, FOG may cause falls and in turn contributes to lower quality of life. Identification of the neurological mechanism underpinning FOG will help clinicians better understand FOG pathophysiology and potentially select effective treatments to alleviate symptoms. Neuroimaging studies found that the cerebellum, in addition to pedunculopontine nucleus, is widely involved in fog regulation in patients with Parkinson's disease [3]. A recent study further found that patients with the damaged cerebellar locomotor region had gait-freezing-like symptoms [4], suggesting that the cerebellum may be involved in the occurrence and development of FOG symptoms. Due to the key role of the cerebellum impairment in MSA, the current study was to explore whether atrophy of cerebellar gray matter volume and cerebellum-cerebral circuit related to FOG in multiple system atrophy patients.

Materials and Methods

43 MSA patients with FOG and 27 MSA patients without FOG diagnosed by clinic doctors who specifies in Parkinson's disease and confirmed by the follow-up study were included in this study,42 HCs were recruited through advertisements but excluded after assessed exist of brain lesions based on medical history and conventional MRI. All patients underwent the resting state function magnetic resonance BOLD sequence and T1 BRAVO structural image 3.0T MRI scanner (Discovery MR750W, GE Healthcare). Volumes of cerebellum subregions and cerebellum atrophy secondary cerebellum-cerebral circuit were analyzed by SPM12 software embed in MATLAB. The relationship between these changes and the severity of FOG score was further analyzed.

Results

The volume shrinkage in the right cerebellum VIII and left cerebellum VI were the main manifestations in MSA patients with FOG injury, an negative correlation was found between FOG-Q scores and left cerebellum VI (Figure 1). A secondary FC analysis based on the right cerebellum VIII and left cerebellum VI as seeds revealed an increased FC between lobule VIII and the left inferior parietal lobule and left cerebellum crus I; an increased FC between lobule VI and the bilateral superior temporal gyrus, right medial frontal gyrus, left rectus, left insula, right superior frontal gyrus, left middle occipital gyrus and left middle cingulum cortex.

Discussion

MSA patients with or without fog showed significant different cerebellar gray matter volume after controlling the interference of motor and non-motor covariates. This suggested that cerebellar atrophy may be involved in the regulation of FOG symptoms in MSA patients. MSA patients are distinct from idiopathic PD patients with FOG injury. Our results were inconsistent with the finding for patients with FOG of the abnormal cerebellar function rather than cerebellar gray matter structure alteration. In present study, MSA patients with FOG symptoms showed more widely damaged cerebellum subregions, including right cerebellum VIII and cerebellum VI, than those without FOG. left cerebellum VI was the only cerebellum region related to FOG severity in MSA patients. Furthermore, a second seed-based functional connectivity method revealed the decreased cerebellar-cortical “executive-control” and “visual-auditory” cortex. The relationship between the FOG severity and decreased the cerebellum volume as well as weaker cerebellum-cerebral circuit in the present study may explain that disturbances of executive control in loading tasks can exacerbate the gait freezing.

Conclusions

This study suggested that the cerebellum volume atrophy may be involved in FOG development in MSA patients and subsequently induce functional abnormality in the cerebellum-cerebral circuit. This study provided neuroimaging evidence for clinical understanding of cerebellum role in MSA patients with FOG injury.

Acknowledgements

With special thanks to Professor Xiaoguang Luo for her guidance on the conception of the manuscript.

References

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