A MR Imaging Study Focusing On Brain Iron And Network Analysis In Parkinson’s Disease

BackgroundParkinson’s disease(PD)is the most common movement disorder,with typical clinical manifestations of akinesia,rigidity and resting tremor.As the society in China is getting aging,the number of PD patients has increased year by year,which has placed a heavy burden on the society and families.Current clinical practices are too subjective to reach a stable diagnostic accuracy,therefore,the search for objective biomarkers remains an international challenge.The root cause is supposed to be the absence of effective research methods to study the changes of PD brain from multiple perspectives,and the few attention paid to explain the clinical heterogeneity of PD.Therefore,we believed that,in order to improve the systematical understanding of brain degeneration and provide objective evidence for clinical diagnosis and treatment,the multi-modal magnetic resonance imaging technique can be used to evaluate the iron metabolism and brain network in PD brain integrated with the considerations of clinical heterogeneity of PD patients(e.g.,different clinical stages and clinical subtypes)In view of these two aspects,the research in each chapter of this thesis aimed to achieve the following three purposes:(1)to reveal changes in brain iron metabolism and functional network in different clinical stages of PD patients;(2)to understand the difference of basal ganglia network between PD patients with different motor sub pes;(3)to explore the relationships among nigral iron accumulation,dysfunction of basal ganglia and the changes in topological properties of brain network in PD by taking advantages of multi-modal magnetic resonance imaging,and further elucidate the influence of nigral iron accumulaton on brain network.MethodsExperiment 1:A total of 60 PD patients and 40 normal controls underwent enhanced magnetic sensitivity-weighted angiography(ESWAN)with a 3.0 T MRI scanner(GE Signa EXCITE).According to the Hoehn-Yahr staging,PD patients were divided into early-to-middle stage PD(Hoehn-Yahr staging ≤2.5,n=45)and late stage PD(Hoehn-Yahr staging≥3,n=15).Quantitative susceptibility mapping(QSM)was processed and used to manually meansure the brain iron content(magnetic susceptibility)in the subcortical nuclei.The comparisons of brain iron content among groups were performed.Partial correlation analyses were conducted to test their clinical correlations.Experiment 2:A total of 88 PD patients and 36 normal controls were enrolled.According to Hoehn-Yahr staging,PD patients were divided into early stage PD(Hoehn-Yahr staging=1 or 1.5,n=39)and middle stage PD(Hoehn-Yahr staging=2 or 2.5,n=49).Resting-state functional magnetic resonance imaging(rsfMRI)data were acquired using a 3.0 T MRI scanner(GE 750).First,we constructed large-scale functional connectivity matrices in different oscillation frequencies;then,we used graph theory network analysis method to calculate the nodal properties of functional network in each oscillation frequency;finally,we compared the nodal properties among different oscillation frequencies and different groups,and associated the altered nodal properties with different motor impairments.Experiment 3:106 PD patients and 52 normal controls were enrolled.Patients with PD were divided into tremor-dominant PD(n=57)and akinesia/rigidity-dominant PD(n=49).rsfMRI data were acquired with with a 3.0 T MRI scanner(GE Signa EXCITE).First,we used the independent component analysis method to extract the basal ganglia network in the three groups.Voxel-based and the region of interest-based analyses were conducted to compare functional connectivity among the three groups.At the same time,we calculated the eigenvector centrality of the subcortical neuclei and region of interest-based analysis was used to detect the differences among groups.Finally,the altered nodal properties were correlated with different motor impairments.Experiment 4:90 PD patients and 38 normal controls were included.ESWAN data,rsfMRI data and diffusion tensor imaging data were acquired with a 3.0 T MRI scanner(GE 750).First,we processed the QSM image,normalized the substantia nigra to the template space,and calculated brain iron content in the superior,middle and inferior subregions;then,by using rsfMRI data,we calculated the functional connectivity among striatum,pallidum and thalamus,and the topological properties of bram network based on the graph theory network analysis method;finally,we compared the differences of the above brain attributes between the groups,and partial correlation analysis was used to explore the relationships among substantia nigra iron content,striatal interconnectivity and topological properties of functional network.Further,mediation analysis was performed to determine the mediator effect of striatal interconnectivity on the global functional network.ResultsExperiment 1:Compared with nonnal controls,early-to-middle PD had only significant iron accumulation in the substantia nigra pars compacta,while bram iron accumulation in late PD patients extended to other areas,including iron-rich substantia nigra,red nucleus and globus pallidus.The iron content in the substantia nigra pars compacta and globus pallidus were significantly correlated with disease severity.Experiment 2:Hierarchical distributions of nodal properties among different oscillation frequencies were observed,in other words,the anteroventral neocortex(excluding frontal pole)and deep grey matter had high values within the low oscillation frequencies while the posterodorsal neocortex had high values within the relatively high oscillation frequency.Compared with normal controls,the nodal funcion in early PD patients remained relatively intact,while the middle stage PD patients showed extensive changes in the basal ganglia and neocortex.The disruption of occipital cortex in the high oscillation frequency was associated with akinesia/rigidty score.Experiment 3:Compared with normal controls,patients with different subtypes had similar abnormal dysfunction in the gray matter nucleus(intra-network functional connectivity was impaired,and eigenvector centrality was enhanced).Compared with tremor-dominant PD patients,akinesia/rigidity-dominant PD patients showed significant reductions of functional connectivity in the occipital lobe and posterior cerebellar lobe.These changes were positively correlated with tremor scores and negatively correlated with akinesia/rigidity scores.Experiment 4:Compared with normal controls,PD patients had significant iron accumulation in the inferior substantia nigra,decreased striatal interconnectivity,and abnormal functional network topology.Through partial correlation analyses,nigral iron connent was significantly correlated with the global properties of the functional networks and striatal interconnectivity was significantly correlated with global properties of weighted functional network in PD patients.Moreover,iron contnent in the inferior substantia nigra was significantly correlated with striatal interconnectivity in the whole population.Through mediation analysis,we found that,in PD patients,nigral iron accumulation had an indirect effect on the topological properties of the weighted functional network through striatal interconnectivityConclusionsOur study showed that,(1)as the disease evolved,PD patients had progressive alterations in the brain iron accumulation of subcortical nuclei and nodal properties of functional network;(2)in addition to the conmon changes in the basal ganglia regions,akinesia/rigidity-dominant PD patients had disrupted functional connectivity in occipital lobe and posterior cerebellar lobe compared with tremor-dominant PD;(3)iron accumulation in the inferior substantia nigra light be the core pathological change in PD,and iron-related nigral degeneration had a negative influence on the weigthed functional network mediated by the striatal dysfunction.These findings indicated that,in consideration of the clinical heterogeneity of PD,different modalities of MRI can be used to uncover PD pathogeneisis,and the integration between different modalities can further explore the influence of nigral iron accumulation on the functional network,which provided important objective evidence for validating and deepening the degeneration of the dopaminergic pathway in the PD.