Correlative Study Of Cerebral Small Vessel Disease And Circadian Rhythm Disturbances

Objective:This present study aims to investigate whether the circadian biomarkers have changed in cerebral small vessel disease(CSVD)patients and to explore the gray matter volume(GMV)alterations in CSVD patients with and without sleep disturbance.This study also explores the relationships between rest-activity rhythms,sleep assessments,and imaging markers of CSVD among the Chinese community elderly.Methods:Part Ⅰ:CSVD patients and healthy subjects were recruited from the Tongji Hospital.We determined the expression profiles of principal clock genes in the peripheral blood mononuclear cells using quantitative real-time PCR.Serum melatonin and cortisol levels were measured by enzyme-linked immunosorbent assay and chemiluminescent microparticle immunoassay respectively.Sleep quality was measured using the Pittsburgh sleep quality index(PSQI)questionnaire.The correlations among imaging markers of CSVD,sleep quality,and circadian rhythm biomarkers were assessed by partial correlation analysis.Part Ⅱ:CSVD patients were divided into good sleepers(GS)and poor sleepers(PS)subgroups according to their PSQI score.To investigate group differences in GMV,voxel-based morphometry(VBM)analysis was performed.Associations between sleep quality,GMV,and white matter hyperintensities(WMH)were examined using multivariate linear regression.Part Ⅲ:Eligible participants were recruited from communities of Wuhan.The rest-activity rhythm indicators were assessed by the actigraphy.The association between rest-activity rhythms and imaging markers of CSVD was analyzed using multiple linear regression.Part Ⅳ:For the participants recruited in the Wuhan community,the PSQI questionnaire and the Epworth sleepiness scale(ESS)were used to assess sleep quality and excessive daytime sleepiness(EDS),respectively.CSVD participants performed follow-up cognitive assessment 1 year later.Relationships between baseline sleep assessments with CSVD and cognitive performance were assessed using multiple linear regression.For follow-up CSVD participants,linear mixed-effects model was used to assess the relationships between baseline sleep assessments and longitudinal cognitive changes.Results:Part Ⅰ:A total of 69 CSVD patients and 60 healthy controls(HC)were recruited for the present study.Our data showed that the levels of BMAL1,CRY1,CRY2,PER1,and NR1D1 gene expression and the level of serum melatonin were significantly decreased,the serum cortisol level was significantly increased in CSVD patients as compared with that of HC.The levels of BMAL1,CRY2,and NR1D1 gene expression and the level of serum melatonin were negatively associated with imaging markers of CSVD,and the serum cortisol level was positively associated with imaging markers of CSVD.Furthermore,the expression levels of BMAL1,CRY1,NR1D1,and the serum melatonin and cortisol levels were correlated with sleep quality in CSVD patients.Part Ⅱ:CSVD patients were categorized into either the CSVD-GS group(n=23)or the CSVDPS group(n=36)based on the PSQI score.We observed GMV differences between the three groups in the bilateral caudate,right thalamus,bilateral calcarine cortex,left precentral gyrus,right orbitofrontal cortex,left cingulate gyrus,and right sub-gyral temporal lobe.Additionally,the CSVD-PS group exhibited decreased GMV in the bilateral calcarine cortex yet increased GMV in the right caudate compared to the CSVDGS group.In fully adjusted models,GMV of the right caudate and bilateral calcarine cortex was associated with sleep quality in CSVD patients.Part Ⅲ:Rest-activity rhythm data from a total of 160 participants were included.Multiple linear regression analysis showed the sleep fragmentation was significantly correlated with WMH burden,the presence of lacunes and microbleeds.The activity fragmentation was associated with the presence of microbleeds.Furthermore,the intradaily variability was associated with the severity of WMH.Part Ⅳ:A total of 1076 participants were enrolled at baseline,and 149 participants with CSVD were re-assessed cognition 1 year later at follow-up.At baseline,sleep quality was related to the severity of WMH,the presence of lacunes,and moderate to severe enlarged perivascular spaces(EPVS)in basal ganglia;EDS was correlated with the severity of WMH and the presence of lacunes.Sleep quality and EDS were also related to the cognitive performances such as executive function and processing speed.In CSVD participants with follow-up,baseline poor sleep quality was associated with decline in executive function,and baseline EDS was associated with decline in memory.Conclusions:In CSVD patients,the expression levels of clock genes and the level of serum melatonin were decreased,and the serum cortisol level was increased as compared with that of HC.And the circadian rhythm biomarkers were associated with imaging markers of CSVD and sleep quality of CSVD patients.The present study also revealed structural brain alterations in CSVD patients with sleep disturbance.Disrupted restactivity rhythms and sleep problems were associated with imaging markers of CSVD in the community-dwelling elderly Chinese population.For participants with CSVD,baseline sleep quality and EDS were associated with cognitive decline.Our study further highlights the association between CSVD and circadian rhythm disturbances and provides clues for the pathological mechanisms of CSVD.Part Ⅰ:The Relationship Between Cerebral Small Vessel Disease and Circadian Rhythm BiomarkersObjective:This study aimed to explore whether the circadian rhythm biomarkers(clock genes,melatonin,and cortisol)have changed in patients with cerebral small vessel disease(CSVD),as well as their associations with imaging markers of CSVD and sleep quality in patients with CSVD.Methods:CSVD patients and healthy subjects were recruited from the Tongji Hospital.We determined the expression profiles of eight principal clock genes,BMAL1,CLOCK,CRY1,CRY2,PER1,PER2,PER3,and NR1D1,in the peripheral blood mononuclear cells using quantitative real-time PCR.Serum melatonin and cortisol levels were measured by enzyme-linked immunosorbent assay and chemiluminescent microparticle immunoassay respectively.Sleep quality was measured using the Pittsburgh sleep quality index(PSQI)questionnaire.The correlations among imaging markers of CSVD,sleep quality,and circadian rhythm biomarkers were assessed by partial correlation analysis with age serving as a nuisance covariate.Results:A total of 69 CSVD patients and 60 healthy controls(HC)were recruited for the present study.Our data showed that the levels of BMAL1,CRY1,CRY2,PER1,and NR1D1 gene expression and the level of serum melatonin were significantly decreased,the serum cortisol level was significantly increased in CSVD patients as compared with that of HC.The levels of BMAL1,CRY2,and NR1D1 gene expression and the level of serum melatonin were negatively associated with imaging markers of CSVD,and the serum cortisol level was positively associated with imaging markers of CSVD.Furthermore,the expression levels of BMAL1,CRY1,NR1D1,and the serum melatonin and cortisol levels were correlated with sleep quality in CSVD patients.Conclusions:In patients with CSVD,the expression levels of clock genes and the level of serum melatonin were decreased,and the serum cortisol level was increased as compared with that of HC.And the circadian rhythm biomarkers were associated with imaging markers of CSVD and sleep quality of CSVD patients.Part Ⅱ:Differences in Gray Matter Volume in Cerebral Small Vessel Disease Patients with and without Sleep DisturbanceObjective:Recently,there has been increased interest in the relationship between CSVD and circadian rhythm disruption,particularly sleep disturbance.However,the neural mechanism of sleep disturbance in CSVD patients remains poorly understood.The present study aimed to explore the gray matter volume(GMV)alterations in CSVD patients with and without sleep disturbance.Methods:CSVD patients were consecutively recruited from the department of Neurology,Tongji Hospital.And healthy subjects without sleep complaints were also recruited as the control group.CSVD patients were categorized into either the good sleepers group(CSVD-GS)or the poor sleepers group(CSVD-PS)based on the PSQI score.To investigate group differences in GMV,voxel-based morphometry(VBM)analysis was performed.Associations between sleep quality,GMV,and white matter hyperintensities(WMH)were examined using multivariate linear regression.Results:A total of 59 CSVD patients with complete MRI data and 40 healthy controls without sleep complaints were recruited for the present study.There were 23 patients in the CSVD-GS group and 36 patients in the CSVD-PS group.We observed GMV differences between the three groups in the bilateral caudate,right thalamus,bilateral calcarine cortex,left precentral gyrus,right orbitofrontal cortex,left cingulate gyrus,and right sub-gyral temporal lobe.Additionally,the CSVD-PS group exhibited decreased GMV in the bilateral calcarine cortex yet increased GMV in the right caudate compared to the CSVD-GS group.In fully adjusted models,GMV of the right caudate and bilateral calcarine cortex was associated with sleep quality in CSVD patients.Conclusions:The present study revealed structural brain alterations in CSVD patients with sleep disturbance.These findings may provide novel insights into the neural mechanisms of sleep disturbance in CSVD.Part Ⅲ:The Relationship Between 24h Rest-Activity Rhythms Disruption and Cerebral Small Vessel Disease in Community-Dwelling Older AdultsObjective:To explore the relationship between 24h rest-activity rhythms and imaging markers of CSVD among the Chinese community elderly.Methods:Eligible participants were recruited from communities of Wuhan.The restactivity rhythm indicators were calculated from the activity/rest cycle parameters obtained by the actigraphy.The association between rest-activity rhythms and imaging markers of CSVD was assessed using a multiple linear regression model.Results:Rest-activity rhythm data from a total of 160 participants were included.Multiple linear regression analysis showed the sleep fragmentation was significantly correlated with WMH burden,the presence of lacunes,and microbleeds.The activity fragmentation was associated with the presence of microbleeds.Furthermore,the intradaily variability was associated with the severity of WMH.Conclusions:Disrupted rest-activity rhythms were associated with imaging markers of CSVD in the community-dwelling elderly Chinese population.Part Ⅳ:Sleep Quality and Excessive Daytime Sleepiness in CommunityDwelling Elderly Population and Their Association with Cerebral Small Vessel Disease and CognitionObjective:This study aimed to investigate whether self-reported sleep quality and excessive daytime sleepiness(EDS)were related to the imaging markers of CSVD and cognitive performance in the Chinese community elderly,and explored the association between baseline sleep assessment with cognitive decline after 1 year in CSVD participants.Methods:Eligible participants were recruited from communities of Wuhan.The PSQI questionnaire and the Epworth sleepiness scale(ESS)were used to assess sleep quality and EDS,respectively.All participants underwent a comprehensive cognitive assessment at baseline,and CSVD participants performed follow-up cognitive assessment 1 year later.Relationships between baseline sleep assessments with imaging markers of CSVD and cognitive performance were assessed using multiple linear regression.For follow-up CSVD participants,linear mixed-effects model was used to assess the relationships between baseline sleep assessments and longitudinal cognitive changes.Results:A total of 1076 participants were enrolled at baseline,and 149 participants with CSVD were re-assessed cognition 1 year later at follow-up.At baseline,sleep quality was related to the severity of WMH,the presence of lacunes,and moderate to severe enlarged perivascular spaces(EPVS)in basal ganglia;EDS was correlated with the severity of WMH and the presence of lacunes.Sleep quality and EDS were also related to the cognitive performances,such as executive function and processing speed.In CSVD participants with follow-up,baseline poor sleep quality was associated with the decline in executive function,and baseline EDS was associated with the decline in memory.Conclusions:Sleep quality and EDS were related to the imaging markers of CSVD and cognitive performance in the Chinese community elderly.For participants with CSVD,baseline sleep quality and EDS were associated with cognitive decline.Interventions aimed at targeting sleep symptoms may help improve both CSVD and cognition.