Association Study Between Plasma Neurotrophic Factor Levels, Genetic Polymorphisms Correlated With Cognitive Function And Late Onset Depressive Patients

Part1: The correlations and its clinical significance betweenplasma brain-derived neurtrophic factor (BDNF), glial cellline-derived neurotrophic factor (GDNF) levels and cognitivefunctions in late onset depressive patientsObjective:The aim of the present study was to explore the correlations between plasmalevels of neurotrophic factor and pathophysiology of depression and cognitivefunction in late onset depressive patients (LOD), and further predict LOD patientswho may be progress to dementia and provide biological marker in periphery blood.Methods:In this study, we measured the plasma BDNF levels in late onset depressive (LOD)patients (n=34) before antidepressant treatment and normal controls (n=32) with theELISA method. And the plasma GDNF levels were measured in27LOD patientsand28normal controls. The Hamilton Depression Scale (HAMD) andneuropsychologic tests were used to assess depressive severity and cognitivefunction of all subjects, respectively.Results:1. There were no significant differences in age, gender and year of educationbetween LOD and health control group. However, LOD patients in neuropsychologictests showed significant poorer performance than controls. Moreover, the plasma BDNF level in LOD patients [(3.24±2.67) μg/L] were significantly lower than that incontrols [(6.71±3.16) μg/L](P<0.01), and the plasma GDNF levels in LOD patients[(3.85±2.91) μg/L] were significantly increased compared to control subjects[(2.24±1.64)μg/L](P<0.05).2. Correlation analysis suggested that the plasma BDNF level was not related tothe total scores of HAMD and cognitive function in LOD patients, but the increaseof plasma GDNF level was significantly positively correlated with Digit Span Testbackward score in LOD patients, and negatively associated with TMT-Bperformance.Conclusions:The findings suggest that LOD patients in acute phase have extensive impairmentsof cognitive function, and lower plasma BDNF and higher plasma GDNF might beinvolved in the pathogenesis of LOD. Additionally, our study indicates that theBDNF plays no important role in cognitive function, and higher plasma GDNF maybe associated with the cognitive dysfunction in LOD. Part2: Association study between APOE、BDNF、ACE、COMT、MTHFR、TPH2genetic polymorphisms and cognitivefunction in LOD patientsObjective:The aim of this study was to investigate the association of candidate gene forcognition including APOE, BDNF, ACE, COMT, MTHFR, and TPH2withcognitive function in late onset depressive (LOD) patients, further understandingpathogenic mechanism of cognitive dysfunction in LOD.Methods:Case-control study and polymerase chain reaction-restriction fragment lengthpolymorphism (PCR-RFLP) method were used to detect the polymorphisms ofCOMT Val108/158Met, MTHFR C677T, APOE, BDNF Val66Met, ACE I/D, TPH2TPH2rs4290270, TPH2rs7305115in97LOD patients and44healthy controls. TheHamilton Depression Scale (HAMD) and neuropsychologic tests were examined foreach subject. Linkage disequilibrium statistics, allele and genotype frequencies werecalculated by using SHEsis program.Results:1. The performances of neuropsychologic tests in LOD guoup except TMT B weresignificantly poorer than those in control group (P<0.01). Correlation analysisindicated that the total scores of HAMD were negatively associated with Digit SpanTest forward score in LOD patients.2. The distribution of APOE、BDNF、ACE genotypes followed Hardy-Weinbergequilibrium among patients and control subjects. There were no significantdifferences between LOD and controls on genotype and allele frequencies of APOE,BDNF and ACE. A significant main effect of BDNF genotype (F=7.368, P<0.01)and interaction of BDNF×diagnosis on SDTM test performance (F=9.961, P<0.01)were found. However, the current study did not demonstrate any significant maineffect of APOE and ACE on any neuropsychological test performance.3. The distribution of COMT and MTHFR genotypes followed Hardy-Weinbergequilibrium among LOD patients and control subjects (P>0.05for each comparison). Our data showed that the distribution of COMT and MTHFR alleles and genotypeswere not significantly different in patients compared with controls. No main effectsof COMT or MTHFR genotype on any neuropsychological test performance wereobserved. There was a significant interactive effect of COMT Val158Met andMTHFR C677T polymorphisms on SDTM independent of diagnosis ((F=10.542,P<0.01). After controlling for covariates, the subjects with COMT Met/Met andMTHFR C/C genotype had better SDTM performance.4. The distribution of TPH2rs4290270, rs7305115genotypes followedHardy-Weinberg equilibrium among patients and control subjects. There were nosignificant differences in the frequencies of the single alleles and genotypes of twopolymorphisms between two groups. A significant main effect of rs4290270genotype on VFT test performance were found (F=4.504, P<0.05), and there was ainteractive effect of rs7305115and diagnosis on SDTM (F=8.656, P<0.01).Furthermore, the presence of TG haplotype of TPH2rs4290270-rs7305115wassignificantly more frequent in cases than in controls [P<0.05; OR2.135;95%CI1.183-3.851]. The other haplotypes did not show significant difference betweenpatients and controls, and there was no significant difference in neuropsychologicaltest performance between TG haplotype carriers and TG haplotype noncarriersConclusions:1. LOD patients in acute phase have extensive impairments of cognitive functionand the severity of depressive symptoms was significantly negatively correlated withworking momery function.2. APOE、BDNF、ACE polymorphism may be play no role in the pathogenesis ofLOD. BDNF polymorphism may be associated with cognition function in LOD.3. COMT、MTHFR SNPs might not be risk factors for LOD. An interaction ofCOMT Val158Met and MTHFR C677T polymorphisms may be associated to the cognitive function.4. TG haplotype of TPH2rs4290270-rs7305115might influence the susceptibilityfor LOD and TPH2polymorphism may be involved in cognitive dysfunction inLOD.