Study On Plasma BDNF Concentration And Its Val66Met Polymorphism In Ischemic Stroke And Rs-fMRI Characteristics Related To Motor Function

Objectives:On one aspect,to explore the relationship between plasma brain derived neurotrophic factor（BDNF）concentration and its Val66Met polymorphism in subacute ischemic stroke（IS）and the degree of neurological impairment.On another aspect,based on the dynamic indicators（dALFF,dfALFF,dReHo）of resting state functional magnetic resonance imaging（rs-fMRI）,we characterize the pathophysiological mechanism of the dynamic separation of brain network and the proportional recovery of motor function in capsular stroke（CS）longitudinally.In addition,exploring whether the change of dynamic indicators is related to the clinical behavior or genetic factor of CS patients.Methods:A total of 102 patients with subacute ischemic stroke admitted to the Department of Neurology,the First Affiliated Hospital of Guangxi Medical University from August 2019 to December 2020,including 39 patients with CS,were enrolled consecutively.98 healthy controls were matched in this study.All patients underwent MRI examination within 7 days（baseline）and 30 days(Day30^th)after infarct onset,meanwhile the control group performed just once.For each patient,National Institutes of Health Stroke Scale（NIHSS）,simple Fugl-Meyer assessment（FM）,Barthel Index（BI）were used to evaluate the neurological deficits,motor function and daily living ability 2 hours before the MRI examination.The mRs score was used to evaluate the patients’neurological function recovery after 30 days.The plasma BDNF concentration and it’s polymorphism of rs6265 was employed by enzyme linked immunoassay technique（ELISA）and the Sanger sequencing method.Compared the differences in plasma BDNF concentration and genotype distribution frequency of rs6265locus at different groups,and the relationship with the severity of the neurological motor deficits.Furthermore,three dynamic indicators of fMRI was calculated for all subjects.Spearman correlations were analyzed between the three signal extraction values of indicators and clinical outcome in CS group.Results:1)Compared with the traditional risk factors of cerebrovascular disease,hypertension,hyperlipidemia,diabetes,smoking and drinking in IS and CS group was higher than that in the controls（P<0.05）.The difference in plasma BDNF concentration between two groups was statistically significant（P<0.001）,and IS group was lower than controls.The distribution frequency of TT genotype in the IS was higher than that in the controls,and the difference was statistically significant（χ²=7.507,P=0.023）.Compared with CC+CT genotype,TT genotypes have increased the risk of IS（P=0.006,OR=3.043,95%CI:1.335-6.938）.And after logistic regression,hypertension is an independent risk factor for IS,what’s more,the T allele difference is still significant（P=0.042,OR=1.783,95%CI:1.015-3.098）.2)According to the NIHSS score of 4-5,there were 72 cases in the mild group and 30 cases in the severe group.There were no significant differences with regard to Val66Met genotype and allele frequencies between the two groups（P>0.05）.The difference of plasma BDNF level between the two groups was statistically significant（P=0.038）,and the mild group was lower.In addition,plasma BDNF concentration were negatively correlated with FMA scores（r_s=-0.276,P=0.006）.3)After adjusting for the multivariate analysis of susceptibility to ischemic stroke,hypertension is an independent risk factor for IS,and carrying the T allele is also an independent risk factor for the onset of IS.4)Compared with controls,CS had significant increased dALFF in the right lingual gyrus,the right fusiform gyrus and the right inferior occipital gyrus,increased dfALFF in the middle cingulum gyrus and the right paracentral lobule were increased,and decreased dReHo in the right precentral gyrus,the right middle frontal gyrus,the right postcentral gyrus and the right inferior parietal gyrus（voxel p<0.05,cluster p<0.05,two tailed）.5)Compared with baseline,patients in D30^th had significant increased dALFF in the left medial superior frontal gyrus and bilateral anterior cingulate,increased dReHo in the bilateral precentral gyrus,the left inferior parietal gyrus,the left superior superior temporal gyrus were increased.But no changes of dfALFF for any brain regions（voxel p<0.05,cluster p<0.05,two tailed）.6)Compared with controls,there was a negative correlation between dALFF values in right lingual gyrus and the plasma BDNF concentration（r_s=0.-579,P=0.045）.Compared with baseline,the dALFF values of left medial superior frontal gyrus was negatively correlated with the plasma BDNF concentration（r_s=-0.560,P=0.046）and positively correlated with the motor function after Day30^th（r_s=0.609,P=0.009）.In addition,changes in plasma BDNF concentration were positively correlated with MOCA score（r_s=0.612,P=0.026）,suggesting that plasma BDNF concentration was related to cognitive and motor functions.Conclusions:The SNP of BDNF Val66Met and plasma BDNF concentration are involved in the occurrence of ischemic stroke.TT genotype may increase the susceptibility to ischemic stroke,and T allele may be an independent risk factor of IS.However,the genotype of BDNF Val66Met may not be correlated with the degree of neuromotor impairment of IS in subacute stage,while the level of plasma BDNF correlated with the degree of neuromotor impairment.Furthermore,fMRI results show the changes in local brain network in CS are related to the destruction of motor and non-motor cortical areas in the hemispheres,leading to the loss of corresponding functions.Follow-up results demonstrate the mechanism of local dynamic network remodeling and its correlation with plasma BDNF concentration and clinical outcomes.This provides valuable spatial and temporal information for the dynamic separation of brain networks in different stage of CS,and reflects the potential biological mechanism of proportional recovery.Proving the possibility of exogenous stem cell therapy（e.g.,NPC injection to increase BDNF concentration）and clinical stimulation target therapy in CS rehabilitation.