Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy.
J Alzheimers Dis. 2012;28(4):941-50. doi: 10.3233/JAD-2011-111541.
Primary progressive aphasia (PPA) is a heterogeneous disorder characterized by progressive language impairment. Polymorphisms within forkhead box P2 gene (FOXP2) gene have been associated with speech and language impairment. Apolipoprotein E (APOE) genotype and PRNP 129 codon status have been demonstrated to increase the risk of PPA, but with contrasting results. In the present study, we have evaluated the impact of FOXP2, APOE and PRNP genetic variations as risk factors and/or disease-modulators in PPA. 94 PPA patients and 200 age-matched healthy controls were considered and FOXP2 polymorphisms (rs1456031, rs17137124), APOE genotype, and PRNP codon 129 polymorphism analyzed. In 34 PPA patients, SPECT imaging data were analyzed by Statistical Parametric Mapping (SPM8). Genetic distributions and allele frequencies of FOXP2 and PRNP polymorphisms did not differ between groups while APOE ε4 was more represented in PPA as compared to controls. PPA patients carrying at-risk FOXP2 polymorphisms (rs1456031 and/or rs17137124) showed greater hypoperfusion in the frontal areas, namely the left inferior frontal gyrus and the right cingulated gyrus compared to non-carriers (p < 0.005). PPA patients carrying at least one ε4 allele had greater hypoperfusion in orbitofrontal regions (superior frontal gyrus and orbital gyrus) as compared to non-carriers ε4 (p < 0.005). PRNP codon 129 homozigosity correlated with left frontotemporal hypoperfusion (p < 0.005). Genetic variations within FOXP2, APOE, and PRNP modulate PPA disease, leading to a specific regional hypoperfusion according to different molecular pathways. APOE ε4 is overrepresented in PPA, thus likely acting as genetic risk factor on disease development.
原发性进行性失语症（PPA）是一种以进行性语言障碍为特征的异质性疾病。叉头框 P2 基因（FOXP2）基因内的多态性与言语和语言障碍有关。载脂蛋白 E（APOE）基因型和 PRNP 129 密码子状态已被证明会增加 PPA 的风险，但结果相反。在本研究中，我们评估了 FOXP2、APOE 和 PRNP 遗传变异作为 PPA 的风险因素和/或疾病调节剂的影响。考虑了 94 名 PPA 患者和 200 名年龄匹配的健康对照者，并分析了 FOXP2 多态性（rs1456031、rs17137124）、APOE 基因型和 PRNP 密码子 129 多态性。在 34 名 PPA 患者中，通过统计参数映射（SPM8）分析 SPECT 成像数据。FOXP2 和 PRNP 多态性的遗传分布和等位基因频率在组间没有差异，而 APOE ε4 在 PPA 中比对照组更为常见。携带风险 FOXP2 多态性（rs1456031 和/或 rs17137124）的 PPA 患者与非携带者相比，额叶区域（左额下回和右扣带回）的灌注减少更大（p <0.005）。与非携带者 ε4 相比，携带至少一个 ε4 等位基因的 PPA 患者眶额区域（额上回和眶回）的灌注减少更大（p <0.005）。PRNP 密码子 129 纯合性与左额颞叶灌注减少相关（p <0.005）。FOXP2、APOE 和 PRNP 内的遗传变异调节 PPA 疾病，导致根据不同的分子途径出现特定的区域性灌注减少。APOE ε4 在 PPA 中过度表达，因此可能作为疾病发展的遗传风险因素。
