Clinical Heterogeneity In Parkinson’s Disease Based On Brain Connectomics

Objectives:To explore the clinical subtypes of PD by applying cluster analysis;and to clarify the stability of the clinical subtypes and their predictive value for disease progression through longitudinal follow-up.To acquire multimodal MRI data to explore the imaging features of different PD subtypes and to use their specific alterations to explain the underlying neural mechanisms of different subtypes.Methods:ninety-two PD patients and 38 healthy controls were recruited,complete baseline clinical data of the subjects were collected and cluster analysis was applied to determine the clinical subtypes of PD at baseline,and patients were followed up longitudinally for 2.7 years,the stability of clinical staging and the predictive value of disease progression.At the same time,baseline multimodal MRI data,including resting-state functional MRI imaging,high-resolution T1-weighted images and diffusion tensor imaging(DTI)data,were acquired to investigate the patterns of brain network alterations in different PD subtypes.Finally,the effects of altered volume and functional connectivity in cerebellar subregions on the clinical symptoms of patients with different PD motor subtypes were analysed.Results:(1)The clinical subtypes of PD were identified at baseline by applying cluster analysis based on age at onset,duration of disease,motor impairment at diagnosis,autonomic impairment,cognitive dysfunction and RBD as key variables for typing:"mild" PD and "moderate" PD."The "mild" PD was further divided into"mild motor-dominant" PD and "mild diffuse " PD.In addition,at a mean follow-up of 2.7 years,non-motor symptoms were significantly worse in both the mild diffuse PD and moderate PD groups;at the same time,patients in the mild diffuse PD group had a significantly higher rate of motor complications and more rapid symptom progression.(2)Alterations in the functional brain network differed among patients with different PD subtypes and had unique clinical characteristics,with alterations in Degree centrality(DC)and functional connectivity(FC)correlating with clinical symptoms in PD patients.In addition,changes in baseline DC predict the severity of clinical symptom progression in different PD subtypes.(3)Different clinical subtypes of PD have different degrees of disruption in the white matter network:PD patients have disrupted global network properties and reduced local efficiency;"moderate" PD patients have significant nodal efficiency changes in the sensorimotor network,default network and significant network;"mild diffuse" PD patients have significant nodal efficiency changes in the left inferior parietal network;and "mild diffuse" PD patients have significant nodal efficiency changes in the left inferior parietal network." PD group had significant nodal efficiency changes in the left inferior parietal lobule,left middle frontal gyrus and left superior temporal gyrus;also,nodal efficiency changes in brain regions correlated with clinical symptoms in PD patients at baseline and predicted the progression of motor and non-motor symptoms in patients after 2.7 years of follow-up.(4)Based on motor symptoms,the postural instability and gait disorder dominant(PIGD-PD)and tremor-dominant(TD-PD)types were classified.In the PIGD-PD group,the FC between the right motor cerebellum and the left postcentral gyrus was elevated and associated with PIGD;in the TD-PD group,the FC in the right dentate nucleus and the left posterior lateral nucleus of the ventral thalamus was reduced and associated with tremor.Conclusions:(1)The subtypes identified based on cluster analysis represent different clinical subtypes of PD that have different rates of progression.(2)Different clinical subtypes of PD have different degrees of abnormalities in functional brain activity and changes in functional brain network connectivity.The application of rs-fMRI for DC and seed point-based whole brain FC analysis methods can help to provide new perspectives on the mechanisms of neural network alterations in clinical subtypes of PD,and also provide new ideas for clinical progression.(3)Structural connectivity patterns in the brain are altered in the early stages of PD and correlate with disease progression.Microstructural differences in DTI measurements between different PD subtypes largely elucidate the heterogeneity of clinical manifestations of PD subtypes.(4)Different cerebellar subregions are involved in the pathophysiology of tremor and PIGD in PD,respectively,elucidating the neural mechanisms of cerebellar involvement in motor subtypes of PD.