Study On Correlation Between Sleep Quality,APOE Gene Polymorphism And Mild Cognitive Impairment And Association Between Pre-stroke Cognitive Impairment And MRI Markers

Part 1 Study on correlation between sleep quality,APOE gene polymorphism and mild cognitive impairmentBackground and objectiveAt present,the incidence of Alzheimer’s disease（AD）in the world is showing a trend of rapid increase.Mild cognitive impairment（MCI）refers to the occurrence of cognitive impairment that is not related to age and education level but is more severe than normal aging,with a high risk of progression to Alzheimer’s disease（AD）.In clinical practice,MCI patients are more likely to have the chief complaint of "not sleeping well and/or not falling asleep",and are more possible to have sleep disorders.Most research results show that there is a bidirectional relationship between cognitive impairment and sleep quality.This study further investigates the relationship between sleep quality and cognitive function/different cognitive domains.The past studies have discovered many AD susceptibility genes,among which the Apolipoprotein E gene polymorphism located on chromosome 19 is closely related to the pathogenesis of AD,and the ApoEε4 allele is a risk factor for cognitive impairment,while increasing the conversion rate of MCI to AD.With our country population’s average life expectancy increasing,the population structure changing rapidly and tending to be aging,the number of MCI patients and dementia patients is increasing rapidly,which not only brings a serious economic burden to the whole society and patients’ families,but also endangers people’s health and quality of life.It is particularly important to identify and diagnose MCI early,and to reverse or slow the progress of MCI to dementia.The study uses the comprehensive neuropsychological,functional,and behavioral assessment,which also included Pittsburgh Sleep Quality Index（PSQI）to assess sleep quality and cognitive function,in order to further reveal the correlation between sleep quality,ApoE gene polymorphisms and mild cognitive dysfunction,and to analyze the influence of sleep and ApoE gene polymorphisms on cognitive function,so as to be able to identify high-risk populations when cognitive function is normal,and provide a new basis for early prevention and research of MCI patients in the future.Methods492 participants were recruited according to the inclusion criteria,140 subjects were excluded according to the exclusion criteria,and a total of 352 subjects were included in the final study.All participants were divided into the MCI group including 149 cases and the NC group including 203 cases,depending on neuropsychological diagnostic criteria.All participants underwent a comprehensive neuropsychological,functional,and behavioral assessment and a Pittsburgh Sleep Quality Index（PSQI）questionnaire,with 2 ml of peripheral blood for testing ApoE genotype.Clinical data collected included:age,sex,years of education,history of smoking and drinking,past medical history and neuropsychological,cognitive function and behavioral assessment scales,and sleep-related scales.The correlation between individual cognitive domains and sleep quality was analyzed using Person correlation;The incidence of sleep disorders and the scores of each sleep quality dimension were compared in the MCI group and the NC group,and use binary logistics analysis to investigate the sleep risk factors of MCI.;The function of various cognitive domains were compared in MCI patients with sleep disorders and with no sleep disorders;Comparing the SNP distribution and odds ratio,ApoE genotype and allele distribution of ApoE were compared in MCI group and NC group,analysis the influence of ApoE allele on MCI and risk factors for MCI.The study also analyses the functions of various cognitive domains in MCI patients carrying the ε4 allele and the non-carrier group.Results1.Analysis of the relationship between sleep quality and cognitive function showed that there was an inverse correlation between the total PSQI score and overall cognition（MOCAB,ACE）,memory（AVLT,BVMT-R）,attentional executive function（STT-A,SDMT）,and visuospatial ability（CDT）,（P<0.001）.There was no significant correlation with language.Among the 7 dimensions of sleep quality,three dimensions,sleep latency,sleep disturbances,and daytime dysfunction,were inversely correlated with cognitive function and multiple cognitive domain functions（MOCA-B,ACE,AVLT,BVMT-R,DST,DOT,STT-A,SDMT,CDT）（P<0.001）,and were not significantly related to the subjective sleep quality,sleep duration,sleep efficiency,and sleep aids.2.Comparing the sleep quality of MCI group and NC group,the results showed that the incidence of sleep disorder in patients in MCI group was 26.17%,which was significantly higher than that of 9.85%in the control group（P<0.001）.The total score of PSQI and the three dimensions of sleep latency,sleep disturbance and daytime dysfunction of MCI were significantly higher than control group.Further analysis implied sleep latency,sleep disturbances are risk factors for MCI.Among MCI patients,overall cognitive function of the group with sleep disorders was significantly worse than the group without sleep disorders,and the five cognitive domains:memory,language,attentional executive function,and visual spatial ability were significantly worse than the control group（P<0.05）.3.The results of analyzing the correlation between ApoE gene polymorphisms and MCI showed that the TT（rs429358）ratio of MCI was significantly lower than NC,the TC/CC ratio were higher than NC（P<0.05）.It is also showed that the SNP（rs7412）CT ratio was significantly higher than NC（P<0.05）,and the CC/TT type ratio were lower than NC.Further analysis of the allele distribution and odds ratio of SNP rs429358 and rs7412,at SNP（rs429358）,base C is a risk factor for MCI,and at SNP rs7412,there is no significant difference between the allele C and allele T distribution of the two groups.Compared ApoE genotype and allele ε2,ε3,ε4 frequency of the MCI group and the NC group,genotype E3/E3 in the NC group is the most common,and in MCI group is E3/E4;in both groups,the frequency of ApoEε3 allele was the highest,the frequency and carrying rate of the ApoEε4 allele in the MCI were significantly higher than the NC（P<0.05）.Through binary logistics regression analysis,the ApoEε4 allele is a risk factor for MCI disease.Conclusions1.In older people（>55 y）,sleep quality was negatively correlated with multiple cognitive domain functions（memory,attentional executive function,and visuospatial ability）and was not significantly associated with language,among which the three dimensions of sleep quality:sleep latency,sleep disturbance,and daytime dysfunction were significantly associated with impaired cognitive domain function.2.The incidence of sleep disorders in MCI was significantly higher than the NC group,and prolonged sleep latency and sleep disturbance were risk factors for MCI;the cognitive function of MCI with sleep disorder was generally impaired,and the five cognitive domains:memory,language,attention,executive function,and visual spatial ability were more seriously impaired than MCI patients without sleep disorder.3.ApoE gene polymorphisms are closely related to MCI,and in the ApoE gene SNP rs429358,allele C is a risk factor for MCI;ApoEε4 allele is a risk factor for MCI;cognitive function of MCI patients carrying the ApoE ε4 allele is more seriously impaired than noncarrier patients,mainly manifested in three cognitive domains:learning ability,attention executive function,and visual spatial ability.Part 2 Association between pre-stroke cognitive impairment and MRI markers in patients with acute mild ischemic strokeBackground and objectivePre-stroke cognitive impairment（PSCI）refers to the cognitive impairment caused by various etiologies before the onset of stroke in patients,including causing by neurodegenerative disease and vascular diseases.Because it is difficult to screen PSCI,using Informant Questionnaire on Cognitive Decline in the Elderly（IQCODE）completing by caregivers to assessing cognitive function.Different research methods and research subjects reveal prevalence of PSCI ranging from 16.7%to 36%,and 9%of stroke patients have dementia before stroke.Although post-stroke cognitive impairment has received increasing attention,current attention to PSCI remains low.However,PSCI not only significantly increases the incidence of post-stroke dementia,but also has a greater impact on intravenous thrombolysis,endovascular therapy,and overall disease outcomes after stroke.Therefore,early identification and diagnosis of PSCI is of great significance.The research results of risk factors for PSCI are still controversial.The certain risk factors include age,years of education,atrial fibrillation,history of stroke,heart failure,and the use of anticoagulants and antihypertensive drugs before the onset of the disease.In recent years,the imaging changes of brain structure before stroke have attracted attention.Chronic brain structure imaging studies have shown that brain degeneration including Global cortical atrophy（GCA）,medial temporal atrophy（MTA）related to cognitive impairment and imaging signs of cerebral small vessel disease including vasogenic lacunar foci,cerebral microbleeds（CMBs）,enlarged perivascular spaces（EPVS）,and white matter hyperintensities（WMHs）often interact with each other.Using a fast,practical and reliable visual scoring method to analyze the signs of chronic brain structural damage before the onset of acute stroke has the advantages of strong clinical operability and less influence by acute infarction lesions.In this study,useing IQCODE to estimate pre-stroke cognitive function of patients with first onset mild ischemic stroke and collecting the complete clinical and MRI information of the patients,the visual scoring method was used to retrospectively evaluate brain structure relating to PSCI.Then analysing the correlation between pre-stroke cognitive function and MRI signs to provide evidence for early identification of PSCI in clinical practice.MethodsThe Clinical baseline data and imaging infomation of 221 patients with mild acute ischemic stroke,aged≥60 years with first onset were retrospectively analyzed.According to the Informant Questionnaire on Cognitive Decline in the Elderly（IQCODE）,they were divided into pre-stroke cognitive impairment group（IQCODE≥3.31）and pre-stroke normal cognition group（IQCODE<3.31,control group）.Bisection visual score was used to analyze MRI biomarker information of small vascular diseases and degenerative diseases,including white matter hypersignal（WMH）,vasogenic lacunar lesions,microbleeding,perivascular space and total cerebral cortex atrophy,medial temporal lobe atrophy（MTA）,to analyze the differences of clinical baseline data and MRI imaging information between the two groups.Logistics regression model was used to explore the correlation between structural MRI abnormalities and PSCI,and the area under ROC curve of risk factors was calculated.Results1.221 patients were enrolled,77（34.8%）in PSCI group and 144（65.2%）in control group.Univariate analysis showed significant differences in age,years of education,MRI pathologic imaging（MTA and≥1 structural MRI abnormalities）between the two groups.Multivariate logistic regression analysis showed that MTA was a structural MRI marker after adjusting for gender and white matter hypersignal（OR=2.911,95%CI=1.385-6.121;P=0.005）,≥1 structural MRI abnormalities（OR=2.823,95%CI=1.305-5.938;P=0.007）and age（OR=0.089,95%CI1.034-1.146,P=0.001）,total years of education<6（OR=3.134,95%CI=1.534～6.401;P<0.002）was an independent risk factor for PSCI.2.Both of the area under curve ofMTA（AUC=0.595）and≥1 structural MRI abnormalities（AUC=0.584）were lower.The combination of AUC（AUC=0.818）of these three risk factors was the lagest one,with sensitivity 79.90%,and the specificity 71.40%,among MTA,≥1 structural MRI abnormalities and poorly educated individual.ConclusionsPSCI has a high incidence,MTA combined with other MRI biomarker have predictive reference value for PSCI.