| Background:Parkinson’s disease(PD)is one of the most common neurodegenerative disorder,and age is one of the biggest risk factors for PD.With the aggravation of the aging population in China,the number of PD patients is gradually increasing,which brings heavy pressure and burden to the family and society.Pathologically,PD is characterized by the hypo-dopaminergic neurotransmission within the nigrostriatal dopamine pathway,leading to classic motor deficits,such as akinesia,rigidity and resting tremor.Levodopa acts as a dopamine precursor protein,thus increasing dopamine availability and restoring,and contributing to an immediate and dramatic motor improvement in PD.Though the remarkable clinical efficacy of levodopa is unquestionable,its detailed mechanisms of action in the brain are still matter of debate and its use still presents some controversies.Furthermore,PD patients often present various of non-motor symptoms,such as hypoosmia,sleep disturbance,depression and cognitive decline.Taken together,the clinical features of PD are complex and heterogenous.However,due to the lack of effective methods to investigate the pathophysiological mechanism of PD,the underlying brain changes behind the complex clinical features are poor understood.Current research has confirmed that PD pathology involves whole brain,in which the brain network is damaged and reconstructed.Taking advantage of multimodal magnetic resonance imaging technology,and combining with the analyses of brain network as well as brain pathways,we could explore the potential brain alterations underlying the complex manifestations of PD,which will provide an important objective basis for understanding the pathogenesis of PD.In this study,we intend to use multimodal magnetic resonance imaging technology to analyze the brain alterations underlying the clinical symptoms as well as the heterogeneity of PD,aiming to achieve the following purpose:(1)clarifying the hierarchy characteristics of functional brain network in PD patients and the specific mechanism of levodopa on the brain;(2)exploring the specific brain mechanism of motor symptoms and non-motor symptoms(rapid eye movement sleep behavior disorder)in PD patients from the view of brain network and pathways;(3)revealing the characteristics of heterogeneous PD subtypes and their potential neural substrate.Methods:Experiment 1: Sixty-one PD patients and 89 normal controls were included in this study.All PD patients underwent magnetic resonance imaging(MRI)scanning(including T1 weighted MRI and resting-state functional MRI,rs-f MRI)and clinical assessment in OFF-medication(>12 h after last dopaminergic medication).Additionally,motor symptoms were re-evaluated in an ON-medication condition defined as one hour following anti-parkinsonian treatment(one tablet of immediate release carbidopa/levodopa 50/200 mg)immediately after initial clinical assessment and MRI scanning,and rs-f MRI was rescanned subsequently.All normal controls underwent T1 weighted MRI scanning and rs-f MRI scanning.We constructed functional brain network using preprocessed rs-f MRI images for all participants.We analyzed the general topological organization(rich-club and diverse-club)in PD patients and classified the whole brain into three hierarchical types(rich-club subnetwork,feeder subnetwork,and peripheral subnetwork).We further analyzed the properties of hierarchical subnetworks in PD patients and the levodopa effect on brain properties.Experiment 2: A total of 39 PD patients and 55 normal controls were recruited for this study.All participants underwent T1 weighted MRI scanning,single shell and multi shell diffusion MRI scanning.Probabilistic tractography was used to reconstruct the motor pathways(nigrostriatal and basal ganglia-motor cortex pathways)and limbic pathway(amygdala-accumbens-pallidum pathway)according to the anatomical connections.Microstructural alterations of these pathways were evaluated by the fractional anisotropy(FA),mean diffusivity(MD),axial diffusivity(AD),radial diffusivity(RD),neurite density index(NDI),and orientation dispersion index(ODI).Pearson or Spearman correlation was used to explore the relationships between the variables.Experiment 3: A total of 191 PD patients,including 51 patients with RBD(PD-RBD)and 140 patients without RBD(PD-n RBD),and 76 normal controls were included in the present study.All participants underwent T1 weighted MRI scanning.Structural brain networks were constructed by thresholding gray matter volume correlation matrices of 116 regions and analyzed using graph theoretical approaches.Experiment 4: One hundred and thirty-four PD patients and 77 normal controls were enrolled in this study.All participants underwent T1 weighted MRI scanning,diffusion tensor imaging(DTI)scanning,and rs-f MRI scanning.Canonical correlation analysis was performed to define the clinically relevant connectivity features,which were then used in the hierarchical clustering analysis to identify the distinct subtypes of PD patients.Multimodal neuroimaging analyses were further used to explore the neurophysiological basis of these subtypes.Results:Experiment 1: This study revealed decreased connection strength and global efficiency within rich-club subnetwork,while the function of diverse club was preserved in PD.Specifically,we observed disrupted function within rich-club subnetwork and feeder subnetwork,and decreased degree centrality in rich-club nodes and feeder nodes,along with increased degree centrality in peripheral nodes in PD patients.After levodopa administration,abnormal network properties were normalized.Experiment 2: Compared with normal controls,PD patients showed decreased ODI as well as increased MD and AD in the bilateral nigrostriatal,decreased FA in left basal ganglia-motor cortex pathway,and decreased ODI in left limbic pathway.MD and AD in the left nigrostriatal pathway was negatively correlated with FA in left basal ganglia-motor cortex pathway.MD in the left nigrostriatal pathway was significantly correlated with ODI in the left limbic pathway.FA in the left limbic pathway was correlated with motor symptoms in PD patients.Experiment 3: Significant enhanced regional nodal measures in limbic system,frontal-temporal regions,and occipital regions and decreased nodal measures in cerebellum were found in PD patients with RBD(PD-RBD)compared with PD patients without RBD.Besides,nodes in frontal lobe,temporal lobe,and limbic system were served as hubs in both two PD groups,and PD-RBD exhibited additionally recruited hubs in limbic regions.Experiment 4: Canonical correlation analysis revealed two significant clinically relevant patterns(motor-related pattern and depression-related pattern)among PD patients,and hierarchical clustering analysis identified three neurophysiological subtypes(“mild” subtype,“severe depression-dominant” subtype and “severe motordominant” subtype).Multimodal neuroimaging analyses suggested that the patients in the “severe depression-dominant” subtype exhibited widespread disruptions both in function and structure,while the other two subtypes exhibited relatively mild abnormalities in brain function.Conclusions:Our study revealed that,(1)PD patients showed differentiated brain organization:the function of rich-club organization was disrupted while the function of diverse-club remained preserved;further,different types of nodes showed a distinct pattern under PD pathology,characterized by disrupted function in topological central nodes along with the compensatory effect in topological peripheral nodes;and dopaminergic therapy could modulate the brain architecture to make it reach a normal state;(2)aberrant fiber coherence of the amygdala-accumbens-pallidum pathway was related to the disorganized nigrostriatal pathway and may jointly lead to the motor disruptions in PD patients,indicating that limbic system was potentially relevant to the motor disruption in PD patients;(3)the increased nodal properties of limbic brain regions may be the potential mechanism of the presence of RBD symptoms in PD patients;(4)based on the objective brain network features,data-driven methods could identified heterogeneous subtypes of PD patients,specially,depression symptoms have a considerable impact on brain damage in patients with PD.These findings suggested that,multimodal MRI technology could reveal the neural substrate of PD related clinical symptoms from the view of brain network and brain pathways,and identified heterogenous PD subtypes,which provide important information for understanding the mechanism of complex clinical symptoms as well as the heterogenous subtypes in PD patients. |
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