Interaction And Related Mechanism Of "ApoE-effect-Syndrome" In The Treatment Of Vascular Dementia With Qi Deficiency And Blood Stasis Syndrome

BackgroundVascular Dementia(VD)is the second most common subtype of dementia after Alzheimer’s disease,and it is currently the only dementia disease that can be prevented.Therefore,the control of risk factors plays an important role in the prevention and treatment of VD.Low high-density lipoprotein cholesterol and high low-density lipoprotein cholesterol in lipids are known risk factors for atherosclerosis,which may lead to cerebral hypoperfusion and subsequent cognitive impairment or cerebral embolism.Previous literature has shown that ApoE gene is an important factor affecting blood lipid regulation,and patients with poor blood lipid control are likely to carry ApoE4 allele.Research in the journal "Nature Medicine" shows that the ApoE4 allele is a major genetic risk factor,and its appearance even increases the probability of cognitive impairment by 12 times,but they have developed a small molecule structure corrector that make ApoE4 structurally and functionally similar to ApoE3.Existing studies have shown that although ApoE genotype can’t change,the adverse effects of ApoE4 gene can be alleviated to a certain extent.The most widely used drugs in blood lipid regulation are statins.A number of existing studies have confirmed that long-term application of statins can prevent and treat VD,and can reduce the risk of VD,delay disease progression,and improve related biological indicators.The previous research results suggest that the application of atorvastatin to VD patients with qi deficiency and blood stasis may lead to a decrease in drug efficacy and the risk of increasing blood lipids.Therefore,ApoE gene and qi deficiency and blood stasis syndrome are two important factors that affect the blood lipid regulation effect of VD patients.Based on the above background,this study proposes three hypotheses:Is there a relationship between different ApoE genotypes-blood lipid regulation effect-qi deficiency and blood stasis syndrome?Whether patients with vascular dementia of qi deficiency and blood stasis type can promote the changes of the body’s syndromes and achieve a state of yin and yang secret after syndrome contrast treatment,thereby improving the efficacy of clinical application of statins and achieving effective control of blood lipids;and whether it can alleviate the adverse effect of ApoE gene on blood lipid regulation in the treatment of VD patients?ObjectPreliminary exploration of whether there is mutual influence among "ApoE genotype-blood lipid regulation effect-qi deficiency and blood stasis syndrome" in VD patients with qi deficiency and blood stasis type after syndrome matching treatment,and conduct a preliminary discussion on the related mechanism based on non-targeted metabolomics,to provide theoretical basis and research ideas for the clinical diagnosis and treatment of vascular dementia.Content1 Efficacy-syndrome study(blood lipid regulation effect-qi deficiency and blood stasis syndrome):To evaluate the changes of cognitive function,syndrome and blood lipids in VD patients with qi deficiency and blood stasis type before and after treatment against syndromes.2 ApoE-effect study(ApoE genotype-blood lipid regulation effect):To evaluate the changes of cognitive function and blood lipids in VD patients with qi deficiency and blood stasis syndrome with different ApoE gene before and after treatment against syndromes.3 ApoE-syndrome study(ApoE genotype-qi-deficiency and blood-stasis syndrome):To evaluate the changes of syndromes before and after treatment against syndrome in different ApoE types VD patients with qi-deficiency and blood-stasis syndrome.4 To analyze the changes of metabolic pathways in patients with vascular dementia of Qi deficiency and blood stasis type before and after syndrome matching treatment based on non-targeted metabolomics technology.MethodThis study was a self-control before and after study.All the enrolled patients were patients with vascular dementia of Qi deficiency and blood stasis type,and they were given basic treatment+symptomatic treatment(Sailuotong Capsules)for a total of 12 weeks.The cognitive function of patients before and after treatment was evaluated by the Mini-Mental State Examination Scale(MMSE);The changes of total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipoprotein cholesterol(LDL-C),and triglyceride(TG)before and after treatment and the lipid-lowering rate were used to evaluate the effect of blood lipid regulation;Syndrome changes refer to the "General Principles of Clinical Research on New Chinese Medicines"(2015)and combine the characteristics of the disease to evaluate the curative effects of fatigue,mental apathy,limb numbness/pain,and dizziness,and compare the symptom disappearance rate;The ApoE genotype of the enrolled patients was detected,and the changes of syndrome,cognitive function and blood lipid before and after treatment were analyzed;Comparative analysis of non-targeted metabolomics among enrolled patients before treatment,after treatment,and healthy people;Safety indicators are laboratory tests(including routine blood,liver and kidney function,creatine kinase,myoglobin)and the occurrence of adverse events.Results1.Baseline situationA total of 33 patients with vascular dementia of Qi deficiency and blood stasis type were included,5 cases were dropped out,and 28 cases were finally included,including 21 males and 7 females,with an average age of 65.96±8.56 years old.2.Changes in cognitive function,syndromes,and blood lipids in VD patients with Qi deficiency and blood stasis type before and after treatmentChanges in cognitive function:VD patients with Qi deficiency and blood stasis type had significant differences in the MMSE scores before and after treatment of the syndrome(P<0.01).Syndrome changes:The disappearance rates of main symptoms of VD patients with Qi deficiency and blood stasis type before and after treatment were fatigue(71.4%),listlessness(64.3%),limb numbness/pain(60.7%),dizziness(57.1%).Changes in blood lipids:VD patients with qi deficiency and blood stasis type had statistically significant differences in the changes of TC,HDL-C,and TG before and after treatment,among which TC(P<0.01),HDL-C(P<0.05),TG(P<0.01).3.Changes in cognitive function,blood lipids and syndromes before and after treatment in VD patients with different ApoE geneApoE classification:2 patients(7%)with ApoE2,21(75%)with ApoE3,and 5(18%)with ApoE4.Since the number of E2 patients is too small,only the patients with ApoE3 and ApoE4 types were used for statistical analysis and difference comparison.Cognitive function:There was no significant difference in MMSE scores between ApoE3 patients and ApoE4 patients before and after syndrome matching treatment(P>0.05).Syndrome changes:The disappearance rates of main symptoms in ApoE3 patients before and after treatment were fatigue(71.4%),listlessness(52.3%),limb numbness/pain(57.1%),and dizziness(52.3%).The disappearance rates of main symptoms in ApoE4 patients before and after treatment were fatigue(80%),listlessness(80%),limb numbness/pain(60%),dizziness(80%).Changes in blood lipids:Before treatment,there were significant differences in LDL-C and TC indexes between the two groups of patients with ApoE3 type and ApoE4 type(P<0.05),and the levels of TG and LDL-C indexes in patients with ApoE4 were higher than those in the ApoE3 group.After treatment,there was no significant difference in the changes of TC,TG,LDL-C and HDLC between the two groups of patients with ApoE3 and ApoE4(P>0.05).The lipid-lowering rates of TC,TG,LDLC,and HDL-C had no significant difference between the groups(P>0.05),but the lipidlowering rates of LDL-C,TC,and HDL-C in ApoE4 patients were higher than those of the ApoE3 patients.4.Results of non-targeted metabonomicsThe results of non-targeted metabolomics univariate analysis showed that the differential metabolites of VD patients with Qi deficiency and blood stasis type before and after treatment were mainly classified as Lipids and lipid-like molecules;the differential metabolites between pre-treatment and healthy people were mainly classified as Lipids and lipid-like molecules,Organic acids and derivatives,Organic nitrogen compounds;the difference metabolites between post-treatment and healthy people are mainly attributed to Lipids and lipid-like molecules,Organic acids and derivatives.The KEGG number pathway enrichment analysis was performed on the screened metabolites with significant differences.The results showed that the metabolic pathways with significant differences before and after treatment were mainly:Protein digestion and absorption,Choline metabolism in cancer,ABC transporters;The metabolic pathways with significant differences were mainly:Basal cell carcinoma,mTOR signaling pathway,Bile secretion;The metabolic pathways with significant differences between post-treatment and healthy people were mainly:Choline metabolism in cancer,Steroid hormone biosynthesis,ABC transporters;The metabolic pathways with significant differences among the before treatment,after treatment and healthy people were mainly as follows:ABC transporters,Central carbon metabolism in cancer,Protein digestion and absorption.Conclusion1.There is mutual influence between "ApoE genotype-blood lipid regulation effect-qi deficiency and blood stasis syndrome" in the clinical treatment of VD patients with qi deficiency and blood stasis.The syndrome can be adjusted by improving the symptoms of fatigue,lethargy,limb numbness/pain,and dizziness to varying degrees,and the safety is good.2.ApoE4 VD patients with qi deficiency and blood stasis may have an effective lipid-lowering pathway different from that of statins before and after symptomatic treatment,which may achieve lipid-lowering effect by increasing HDL-C and reducing TC and LDL-C.3.Preliminary exploration found that before and after the treatment of syndromes may improve cognitive function and affect blood lipid metabolism by regulating Basal cell carcinoma,mTOR signaling pathway,and Bile secretion metabolic pathway in VD patients with qi deficiency and blood stasis type,and the efficacy of the drug may be better exerted by affecting the metabolic pathway of ABC transporters.