Glymphatic Pathway And Its Underlying Mechanism In Patients With Cerebral Small Vessel Disease

Part 1 Relationship between glymphatic function and imaging markers of cerebral small vessel diseaseObjective: Our study aims to analyze the relationship between glymphatic function and imaging markers(including white matter hyperintensities [WMHs],lacunes,microbleeds,enlarged perivascular spaces [EPVS])of cerebral small vessel disease(CSVD)in two cohorts:(1)analyze the relationship between glymphatic function and imaging markers based on the classical detection of glymphatic function in patients receiving intrathecal administration of gadolinium contrast agent;(2)compare the classical detection of glymphatic function and non-invasive diffusion tensor image analysis along the perivascular space(ALPS-index),and analyze the relationship between glymphatic function and imaging markers based on non-invasive ALPS-index in larger sample of patients with CSVD.Methods: Cohort 1: Patients with indications for lumbar puncture were enrolled from July 2018 to January 2020.All patients underwent three-dimensional T1-weighted imaging(3D-T1)before and at 39 hours after intrathecal administration of gadolinium contrast agent.Glymphatic clearance function was defined as percentage changes(PC)in signal unit ratio from baseline to 39 hour on predefined 6 locations on 3D-T1.Cohort 2: Patients with CSVD who underwent 3D-T1,T2-weighted imaging(T2WI),fluid-attenuated inversion recovery(FLAIR),susceptibility weighted imaging(SWI)and diffusion tensor imaging(DTI)were prospectively enrolled in our center from January 2010 to January 2020.ALPS-index was calculated from SWI and DTI.WMHs and EPVS were assessed by semi quantitative scoring,and the presence and number of lacunes and microbleeds were recorded.Results: Cohort 1: Totally,40 patients were included.Severer periventricular and deep WMHs,number of lacunes,number of microbleeds,and severer EPVS in basal ganglia was related to PC in fourth ventricle,third ventricle,lateral ventricle,frontal horn,inferior frontal gyrus and precentral gyrus(all p < 0.05).The degree of EPVS in centrum semiovale was not related to PC in above brain regions(all p > 0.05).38 patients could calculate ALPS-index.The inter-and intra-observer correlation coefficients of ALPS-index were 0.920 and 0.936,respectively.There were negative correlations between ALPS-index and PC in fourth ventricle,third ventricle,lateral ventricle,frontal horn,inferior frontal gyrus and precentral gyrus(Pearson r =-0.871~-0.789,all p < 0.001).Cohort 2: 346 patients were included,with average age of 63 ± 10,and 168(48.6%)were female.Severer periventricular and deep WMHs(? =-0.334,p < 0.001;? =-0.289,p < 0.001),number of lacunes(? =-0.212,p < 0.001),number of microbleeds (? =-0.147,p = 0.005),and severer EPVS in basal ganglia(? =-0.217,p < 0.001)were independent related of low ALPS-index.The degree of EPVS in centrum semiovale was not related to ALPS-index(p = 0.245).Conclusion: Non-invasive ALPS-index was closely related to the classical detection of glymphatic function,which might be applied in clinic in future.WMHs,lacunes,microbleeds and EPVS in basal ganglia were related to glymphatic function,while EPVS in centrum semiovale was not related to glymphatic function.Part 2 Relationship between glymphatic function and cerebral blood flow in patients with cerebral small vessel diseaseObjective: Our study aims to analyze the relationship between glymphatic function and cerebral blood flow(CBF)in patients with cerebral small vessel disease(CSVD).Methods: Patients with CSVD who underwent three-dimensional T1-weighted imaging(3D-T1),T2-weighted imaging,fluid-attenuated inversion recovery,susceptibility weighted imaging(SWI),diffusion tensor imaging(DTI)and arterial spin labeling imaging(ASL)were prospectively enrolled in our center from January 2010 to January 2020.Glymphatic function was defined as ALPS-index,which was calculated from SWI and DTI.The CBF of whole brain(Brain-CBF)was calculated from ASL.Results: 341 patients were included.Brain-CBF was correlated with ALPS-index(Pearson r = 0.187,p = 0.001).In patients with severer white matter hyperintensities(WMHs),presence of lacunes,presence of microbleeds or severer enlarged perivascular spaces(EPVS)in basal ganglia,Brain-CBF was correlated with ALPS-index(Pearson r = 0.242~0.278,all p < 0.05),while in patients without severer WMHs,presence of lacunes,presence of microbleeds or severer EPVS in basal ganglia,Brain-CBF was not correlated with ALPS-index(all p > 0.05).Among them,42 patients underwent follow-up SWI,DTI and ASL.After adjusting for baseline ALPS-index,low baseline Brain-CBF was independent related to follow-up low ALPS-index(? = 0.369,p = 0.006),and after adjusting for baseline Brain-CBF,low baseline ALPS-index was independent related to follow-up low Brain-CBF(? = 0.155,p = 0.015).Conclusion: The glymphatic function was related to CBF in patients with CSVD.The decrease of CBF may lead to the decrease of glymphatic function,and the decrease of glymphatic function may also lead to the decrease of CBF.Part 3 The effect of brain glymphatic pathway on cognitive function in patients with cerebral small vessel diseaseObjective: Our study aims to analyze the effect of brain glymphatic pathway on cognitive function in patients with cerebral small vessel disease(CSVD).Methods: Patients with CSVD who underwent three-dimensional T1-weighted imaging,T2-weighted imaging,fluid-attenuated inversion recovery,susceptibility weighted imaging(SWI),diffusion tensor imaging(DTI)and cognitive function assessment were prospectively enrolled in our center from January 2010 to January 2020.Glymphatic function was defined as ALPS-index,which was calculated from SWI and DTI.The cognitive function was assessed by mini-mental state examination(MMSE).Results: 297 patients were included.After adjusting for age,years of education,history of smoking,severer white matter hyperintensities and microbleeds,low ALPS-index was an independent risk factor of low MMSE(? = 0.118,p = 0.032).In addition,low ALPS-index was an independent risk factor of low score of orientation(? = 0.227,p = 0.001),and was not related to scores of other cognitive functions(all p > 0.05).Conclusion: The glymphatic function was related to cognitive function in patients with CSVD.The glymphatic function was related to orientation,but was not related to other cognitive functions.