基于载脂蛋白E等位基因多态性的健康青年携带者脑功能连接密度的静息态功能MRI研究

Apolipoprotein E polymorphism affects brain functional connectivity density in healthy young adults： a resting-state functional MRI

目的 采用功能连接密度（FCD）算法探索载脂蛋白E（APOE）等位基因ε2、ε3和ε4对健康青年携带者静息态脑功能影响.方法2013年4月至12月对213名健康青年志愿者进行静息态fMRI扫描和神经心理学评估,并采集外周静脉血进行APOE基因型检测.根据基因分型结果分别纳入性别、年龄差异无统计学意义的31例APOE ε4/ε3携带者（APOE ε4组）、31例APOE ε3/ε3携带者（APOE ε3组）及14例APOE ε2/ε3携带者（APOE ε2组）,通过去协变量单因素方差分析方法,观察3组全脑长程及短程FCD的差异,并采用post-hoc检验进行组内两两比较,所有结果经高斯随机场校正,校正水平取体素P〈0.01,簇群P〈0.05,双尾校正;进而提取方差分析改变显著脑区的FCD均值与神经心理学量表结果做相关性分析.结果 与APOE ε3组相比,APOE ε2组短程及长程FCD在额叶显著增高,尤其是在内侧前额叶（体素=37,t=3.54）、前扣带回（体素=36,t=3.19）及眶额回脑区（体素=41,t=3.72）,而APOE ε4组短程FCD在双侧楔叶显著减低（体素=38,t=-3.68）.与APOE ε2组相比,APOE ε4组长程FCD在右侧眶额回显著减低（体素=46,t=-4.56）,而在右侧顶下小叶显著增加（体素=31,t=3.49）;双侧前额叶、楔叶及右侧前扣带回、顶下小叶的FCD值与神经心理学量表结果未呈显著相关.结论 APOE ε4青年携带者的楔叶和顶下小叶的改变可能是早期脑功能减弱和功能代偿表现,而额叶功能连接增加可能是APOE ε4青年携带者延缓阿尔茨海默病发生的早期保护机制.

Objective To explore the aberrance of brain activity in healthy young adults with apolipoprotein E （APOE） ε2, ε3 and ε4 allele by the method of functional connectivity density（FCD）. Method Two hundred and thirteen young healthy adults underwent the 3 T resting-state functional MRI, the neuropsychological tests and genotype testing for ε2, ε3 and ε4 allele. Age-and gender-matched individuals,including 14 subjects with APOE ε2,31 subjects with APOE ε4 and 31 subjects with APOE ε3 were enrolled for final analysis.FCD mapping was used to compare the brain functional connective networks among the three groups.All results were corrected with a Gaussian random field（GRF）（voxel-level of P〈0.01 and joint cluster-level of P〈0.05）. Correlation analysis was performed between abnormal short-and long-range FCD values and neuropsychological scores. Results Compared with APOE ε3 carriers, the short-and long-range FCD values of APOE ε2 carriers were increased in the frontal lobe,particularly in the medial prefrontal lobe（37 voxels,t=3.54）,anterior cingulate cortex（36 voxels,t=3.19）and orbital frontal cortex（41 voxels, t=3.72）, while APOE ε4 carriers showed decreased short-range FCD in the bilateral cuneus（38 voxels, t=-3.68）. Moreover, the long-range FCD values of APOE ε4 group were decreased in right orbital frontal cortex（46 voxels,t=-4.56）and increased in the right inferior parietal lobe（31 voxels,t=3.49）compared with that of APOE ε2 group. No significant correlation was detected with Bonferroni correction. Conclusions The opposite FCD alteration in cuneus and inferior parietal lobe might be the early existence of inhibitory and compensatory mechanism modulated by the ε4 allele in the young age, while the increased FCD in frontal lobe might be the underlying protective mechanism of delaying the onset of Alzheimer＇s disease.