Imaging Study Of Abnormal Brain Function In Patients With Spinocerebellar Ataxia Type 3

Spinocerebellar ataxia type 3(SCA3)is a large group of neurodegenerative disorders with ataxia as the main clinical manifestation due to genetic inheritance.In recent years,it has been reported that patients with SCA3 have abnormalities in brain functional activity and connectivity,accompanied by a combination of motor and cognitive symptoms,as the disease progresses and extends from cerebellar atrophy to more areas.However,the pattern of disorders in the functional connectome of SCA3 remains unclear.Therefore,we investigated the abnormal brain function in patients with SCA3 using a combination of gradient approach,dynamic network topography,neurotransmitter density and genetic analysis to explore whether changes in the functional connectome of patients with SCA3 are closely related to their pathological manifestations and to search for possible biomarkers and potential therapeutic targets to slow down the progression of SCA3.The main studies are as follows:1.Previous studies have reported extensive functional connectivity(FC)abnormalities in the cerebellum and cerebellar-cerebral pathways in patients with SCA3,but the way by which the perturbation of the functional connectivity by SCA3 affects the hierarchical functional organization of the cerebellum remains unclear.To address this gap,connectome gradients analysis was used to explore abnormalities in the functional hierarchy of the cerebellum in patients with SCA3 and to link hierarchical abnormalities to clinical symptoms of spinocerebellar ataxia type 3.The results verified that the functional gradient pattern derived from cerebellar connectome of both healthy subjects and patients with SCA3 followed a hierarchical organization from primary to transmodal(default network)regions.Compared to healthy controls,patients with SCA3 exhibited compressed cerebellar principal gradients at both the voxel and network levels,which were associated with increased gradient values in sensorimotor areas and areas involved in early integration and reduced gradient values in transmodal areas.Cluster-specific increases in functional connectivity were found in unimodal and transmodal regions,possibly supporting the disruption of the cerebellar functional hierarchy indicated by the gradients.Further analysis revealed a reasonable correlation between changes in gradients and clinical scores.This study provides new evidence for altered cerebellar functional hierarchy and advances the understanding of the functional hierarchy of the cerebellar connectome in SCA3.2.The abnormal brain functional activity in patients with SCA3 involves multiple regions and networks throughout the cortical cortex,but the abnormal integration patterns of the cortical large-scale networks are unclear.To investigate this issue,time derivative multiplication,community assignment algorithm,neurotransmitter density,and genetic analysis were used to explore abnormal network integration patterns in patients with SCA3.Results revealed that patients with SCA3 had a higher degree of functional integration compared to controls,and areas of elevated mean participation coefficients were observed in the border regions between modules,as well as in the sensorimotor network,the salience network,the visual network,the dorsal attention network,and the cingulo-opercular network.Correlating the altered mean participation coefficients with neurotransmitter density and receptor gene expression maps,respectively,revealed that elevated integration was significantly associated with class-specific neurotransmitter density and gene expression of noradrenergic,serotonergic,and cholinergic receptor subclasses in the cerebral cortex.The study identified imaging features of dynamic network damage associated with specific neurotransmitter density and gene expression in patients with SCA3,highlighting novel potential diagnostic and therapeutic approaches for this disorder.In summary,this paper explores the aberrant brain function in SCA3 from multiple perspectives based on gradient analysis,time-varying network analysis,neurotransmitter density and genetic analysis,and reveals the correlation between brain functional network abnormalities and pathological manifestations.This study contributes to the understanding of the pathophysiological mechanisms of SCA3 and provides new perspectives on potential diagnostic and therapeutic approaches for the disease.