| Background:Cerebral white matter lesions (WMLs), also known as leukoaraiosis, are frequentlyobserved on neuroimaging in the brains of elderly patients. They are defined as diffuse,confluent white matter abnormalities, often with irregular margins. On magnetic resonanceimaging (MRI), they are seen as hypointensities on T1-weighted imaging andhyperintensities on T2-weighted imaging and fluid-attenuated inversion recovery sequences(FLAIR). FLAIR is now the preferred imaging modality to assess the presence and severityof WMLs because of clear distinction between WMLs and lacunes. WMLs aremanifestation of cerebral small vessel disease and reflect multiple pathologic changes,including loss and deformation of myelin sheath, changes in vessel wall permeability,disruption of the blood-brain barrier, hypoperfusion attributable to altered cerebrovascularautoregulation and gliosis. WMLs are often divided into two categories: periventricularWMLs (PVWMLs) and deep WMLs (DWMLs), with a possible dissimilarity in pathogenicmechanisms and clinical relevance. The human brain contains multiple networks of neuronsthat serve not only motor and sensation but also neurobehavioral functions such as attention,memory, language, visuospatial ability, and emotion. Damage to white matter might disrupthigher cortical functions and be related to various neurobehavioral syndromes, especially inelderly people. The clinical and pathologic significance of WMLs has been investigated byseveral studies over the last30years. Although considered as benign changes at first,WMLs have been proven by accumulated evidence to predict an increased risk of stroke,cognitive decline, dementia, depression, disability, and all-cause mortality. Whereasadvanced age and hypertension are the most widely accepted risk factors for WMLs, thecurrent understanding of other risk factors for WMLs remains less clear. Given thedetrimental impact of WMLs on individuals and healthcare systems, knowledge of the risk factors for WMLs, especially modifiable ones, is becoming more important. Furthermore,environmental risk factors account for only a part of the variance in the formation of WMLs,and twins and family studies have shown that genetic factors are contributory. Studying thegenetics of WMLs may be very helpful in early diagnosis and individual treatment ofWMLs and related diseases, such as stroke or dementia.Therefore, the aim of the present study was to investigate the associations of WMLswith metabolic syndrome and serum lipids in middle aged and elderly patients, which havenot fully elucidated in former studies. And the other aim was to explore the relationshipbetween WMLs and single nucleotide polymorphisms (SNPs) of adiponectin gene, whichhas never been investigated before.Section One Assotiation between WMLs and metabolic syndromeBackgroud:Metabolic syndrome (MetS) is a constellation of modifiable vascular risk factorsincluding abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. It has beenrelated to silent lacunar infarction, which is another manifestation of cerebral small vesseldisease and has similar pathogenesis to WMLs. However, little is known about therelationship between MetS and the prevalence of WMLs. The aim of the study was toinvestigate the association between MetS, its components and WMLs in middle-aged andelderly patients.Methods:Consecutive inpatients aged50years and older were prospectively enrolled in thisstudy. All participants underwent MRI scans to assess the presence and severity ofPVWMLs and DWMLs using the4-point modified Fazekas’method. The MetS was definedaccording to the updated National Cholesterol Education Program’s Adult Treatment PanelIII criteria. Multivariate logistic regression analyses were performed to examine therelationship between MetS, its components, and WMLs. Further sex-specific analyses wereconducted. Finally, a multinomial logistic regression model was performed to evaluate theassociation between MetS and the severity of PVWMLs and DWMLs.Results:1. From June2012to January2013, a total of852consecutive patients were enrolledin the study. The mean age was66.0±9.4years;52.0%were female. Mild periventricular WMLs (PVWMLs) was found in311(36.5%), moderate in77(9.0%), and severe in71(8.3%), while mild deep WMLs (DWMLs) was found in298(35.0%), moderate in116(13.6%) and severe in66(7.7%). According to the updated NCEP-ATP III criteria, MetSwas present in38.4%of the total population,43.8%of females and32.5%of males. Theprevalence of PVWMLs and DWMLs increased with increasing age and number of MetScomponents ((Ptrend<0.001).2. In logistic regression model adjusted for age and sex, MetS was associated with anincreased risk of PVWMLs and DWMLs. Further adjustment for current smoking, dailydrinking, coronary heart disease (CHD), and prior stroke attenuated the ORs slightly, butthe association remained significant (OR:3.21,95%CI:2.26-4.55for PVWMLs; OR:2.93,95%CI:2.09-4.09for DWMLs). Moreover, in sex-stratified analyses, the results remainedsignificant in both men and women.3. There was a clear trend towards an increased prevalence of PVWMLs and DWMLswith increasing number of MetS components ((Ptrend<0.001). Compared to patients withoutany MetS components, those having4or5components were almost6.5times more likelyto have PVWMLs and3.7times to have DWMLs.4. When all the five components were entered simultaneously into the logistic model,with multivariable adjustment for age, sex, current smoking, daily drinking, CHD and priorstroke, the independent risk factor of PVWMLs were elevated blood pressure (BP)(OR:2.69,95%CI:1.91-3.78), elevated fasting blood glucose (FBG)(OR:1.55,95%CI:1.08-2.23) and low high-density lipoprotein cholesterol (HDL-C)(OR:1.42,95%CI:1.01-2.00), while elevated BP (OR:2.59,95%CI:1.86-3.60) and low HDL-C (OR:1.51,95%CI:1.09-2.09) showed an increased risk of DWMLs. In the sex-stratified analyses,elevated BP was an independent risk factor of PVWMLs and DWMLs in both sexes.However, the association between elevated FBG and PVWMLs was observed only in menand the impact of low HDL-C on DWMLs was observed only in women.5. A multinomial logistic regression was performed with adjustment for age, sex,current smoking, daily drinking, CHD and prior stroke to evaluate the association of MetSwith the severity of PVWMLs and DWMLs. The adjusted ORs were2.97(95%CI:2.07-4.26) for mild,4.14(95%CI:2.35-7.28) for moderate and5.44(95%CI:2.86-10.35)for severe PVWMLs, while the adjusted ORs for increasing grades of DWMLs were2.44 (95%CI:1.72-3.47) for mild,5.09(95%CI:3.05-8.48) for moderate, and6.31(95%CI:3.30-12.06) for severe, respectively. The ORs increased with the advancing grades ofPVWMLs and DWMLs, showing a dose effect.Conclusions:1. The presence of MetS was associated with an approximate3times increased risk ofPVWMLs and DWMLs in middle-aged and elderly patients, after adjustment forconfounding factors. This effect was observed in both sexes. Apart from MetS, age andprior stroke were independent risk factors of PVWMLs and DWMLs as well.2. The number of MetS components was associated with the presence of PVWMLsand DWMLs. Those having4or5components were almost6.5times more likely to havePVWMLs and3.7times to have DWMLs.3. the independent risk factor of PVWMLs were elevated BP, elevated FBG and lowHDL-C, while elevated BP and low HDL-C showed an increased risk of DWMLs.4. The presence of MetS was associated with the severity of PVWMLs and DWMLs inmultinomial logistic regression models. Patients with MetS were almost5.4times morelikely to have severe PVWMLs and6.3times more likely to have severe DWMLs,compared with those without MetS..Section Two Assotiation between WMLs and levels of serum lipidsBackground:The relationship between WMLs and levels of serum lipids is controversial in formerstudies. Thus, the aim of this study was to investigate the association of serum lipids withthe presence of PVWMLs and DWMLs in middle-aged and elderly subjects.Methods:Consecutive inpatients aged50years and older of our department were prospectivelyenrolled in this study. All participants underwent MRI scans to assess the presence andseverity of PVWMLs and DWMLs using the4-point modified Fazekas’ method.Multivariate logistic regression analyses were performed to examine the association ofWMLs with serum lipids including total cholesterol (TC), triglyceride (TG), HDL-C,low-density lipoprotein cholesterol (LDL-C), apolipoprotein A-I (ApoA-I), apolipoproteinB (ApoB) and ApoB/ApoA-I. The levels of the lipid profile were divided into four quartilesand the highest quartile was used as the reference. Results:1. From June2012to June2013, a total of1282consecutive patients (606men and676women,65.9±9.4years) were enrolled in the study. Mild PVWMLs was found in469(36.6%), moderate in110(8.6%), and severe in99(7.7%), while mild DWMLs was foundin486(37.9%), moderate in147(11.5%) and severe in91(7.1%). The prevalence ofPVWMLs and DWMLs increased with advancing age ((Ptrend<0.001).2. Patients with PVWMLs were older (70.0±8.9VS61.3±7.5，P <0.001) andshowed significantly higher proportion of male sex, hypertension, diabetes mellitus, priorstroke, and CHD, and higher levels of systolic/diastolic BP and FBG (P <0.05). Thesmoking and drinking status and body mass index (BMI) were not different between groups(P>0.05). The differences between patients with DWMLs and without DWMLs weresimilar to those with and without PVWMLs, except for levels of FBG (P=0.386).3. The distribution of serum TC, HDL-C, LDL-C, ApoA-I and ApoB levels weresignificantly different between four grades of PVWMLs (P <0.05). The distribution ofserum TC, HDL-C and ApoA-I levels were significantly different between four grades ofDWMLs (P <0.05)4. After adjustment for age, sex, prior stroke, CHD, hypertension, and diabetes,patients with the lowest HDL-C (Ptrend=0.044) or apoA-I (Ptrend=0.019) quartile wereapproximately1.5times more likely to have PVWMLs, compared with those with thehighest quartile. Likewise, patients with the lowest HDL-C (Ptrend=0.013) or apoA-I (Ptrend=0.002) quartile were approximately1.5or1.8times more likely to have DWMLs. Noneof other lipids were related to WMLs.5. After adjustment for age, sex, prior stroke, CHD, hypertension, and diabetes, thelowest HDL-C (OR:1.39,95%CI:1.01-1.93) or apoA-I (OR:1.50,95%CI:1.09-2.07)quartile were related to the severity of PVWMLs in ordinal regression models, while thelowest apoA-I (OR:1.49,95%CI:1.09-2.05) quartile was related to the severity ofDWMLs.6. In sex-specific analyses, the lower levels of HDL-C and ApoA-I predicted higherrisk of PVWMLs and DWMLs only in women.Conclusions:1. Decreased serum levels of HDL-C and ApoA-I were associated with an increased risk of PVWMLs and DWMLs independent of other risk factors.2. In odinal logistic regression models, serum levels of HDL-C and ApoA-I wererelated to the severity of PVWML, while levels of ApoA-I were related to the severity ofDWML.3. In sex-specific analyses, the lower levels of HDL-C and ApoA-I were associatedwith higher risk of PVWMLs and DWMLs only in women.Section Three Assotiation between WMLs and adiponectin gene polymorphismsBackground:Adiponectin manifests anti-atherosclerosis and anti-inflammatory effects. Singlenucleotide polymorphisms (SNPs) in adiponectin gene have been related to MetS,hypertension, diabetes, stroke and levels of HDL-C. However, the association of SNPs inadiponectin gene with WMLs has never been studied before. Therefore, the aim of thisstudy was to investigate the association between adiponectin gene SNPs and WML inmiddle aged and elderly subjects, using the cross-sectional design method.Methods:Consecutive inpatients aged50years and older of our department were prospectivelyenrolled in this study. All participants underwent MRI scans to assess the presence andseverity of WMLs using the4-point modified Fazekas’ method. For statistical analyses,WMLs severity, defined as the sum of the scores of PVWMLs and DWMLs, wasdichotomized into scores0-1(controls) versus2-6(cases). Multivariate logistic regressionanalyses were performed to examine the association of WMLs with SNPs.Results:1. From June2012to January2013, a total of811consecutive subjects were enrolledin the study. The mean age was66.4±9.1,47.6%were males. Among the participants,419were cases and392were controls. The cases were older (P <0.05), and showedsignificantly higher proportion of hypertension, diabetes mellitus, prior stroke, and CHD (P<0.05), and higher levels of systolic/diastolic BP and FBG (P <0.05) whereas lower levelsof TC, HDL-C and ApoA-I (P <0.05).2. More than97%samples were genotyped successfully for each SNP. Every groupconformed to the Hardy-Weinberg equilibrium (P>0.05).3. As for rs7649121, the AA, AT and TT genotype frequency were50.6%,41.7%and 7.7%in the case group respectively, whereas61.5%,35.2%and3.3%in the control group.The distribution of genotypes was different between the two groups significantly (χ2=13.407，P=0.001). The A and T allele frequency were71.5%and28.5%in cases whereas79.1%and20.9%in controls, showing significant difference (χ2=12.562，P <0.001). Nodifferences in genotype or allele frequency were observed in rs1063539, rs2241767,rs1501299, rs16861194, rs12495941, rs182052and rs266729between cases and controls.4. After adjustment for age, sex, prior stroke, CHD, hypertension, diabetes and HDL-Clevels, AT (OR:1.59,95%CI:1.01-2.50) and TT (OR:3.44,95%CI:1.18-10.03) wereassociated with higher risk of WMLs independently. In dominant model, AT/TT genotypewas1.7times more likely to have WMLs than AA genotype.Conclusions:1. Among the middle aged and elderly subjects, the present study firstly found thatrs7649121in adiponectin gene might be associated with WMLs, and T allele was probablya susceptible allele of WMLs.2. We failed to found any association between WMLs and other SNPs in adiponectingene including rs1063539, rs2241767, rs1501299, rs16861194, rs12495941, rs182052andrs266729. |
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