GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease.
GBA Variants are associated with a distinct pattern of cognitive deficits in Parkinson's disease.
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DOI：
10.1002/mds.26359
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Zabetian CP
中科院分区：
文献类型：
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作者：
Mata IF;Leverenz JB;Weintraub D;Trojanowski JQ;Chen-Plotkin A;Van Deerlin VM;Ritz B;Rausch R;Factor SA;Wood-Siverio C;Quinn JF;Chung KA;Peterson-Hiller AL;Goldman JG;Stebbins GT;Bernard B;Espay AJ;Revilla FJ;Devoto J;Rosenthal LS;Dawson TM;Albert MS;Tsuang D;Huston H;Yearout D;Hu SC;Cholerton BA;Montine TJ;Edwards KL;Zabetian CP
GBA基因的功能缺失突变与PD中更严重的认知功能障碍相关，但这些缺陷的性质尚不清楚，并且常见的GBA多态性是否会影响PD的认知表现尚不清楚。我们在PD认知遗传学联盟8个研究中心招募的1，369名PD患者中筛查了GBA编码区的突变和E326 K多态性。参与者接受了学习和记忆（霍普金斯言语学习测试修订版），工作记忆/执行功能（字母-数字排序和线索制作A和B），语言处理（语义和音素言语流畅性），视觉空间能力（本顿判断行方向）和整体认知功能（蒙特利尔认知评估）的评估。我们使用线性回归来检验基因型和认知表现之间的关联，并对重要的协变量进行调整，并使用Bonferroni校正进行多重检验。突变携带者（n = 60; 4.4%）和E326K携带者（n = 65; 4.7%）的痴呆患病率较高（突变，比值比= 5.1; p = 9.7 × 10 − 6; E326K，比值比= 6.4; p = 5.7 × 10 − 7）和字母-数字测序的较低性能（突变，校正的p [pc]= 9.0 × 10 − 4; E326K，pc = 0.036）、Trail Making B-A（突变，pc = 0.018; E326K，pc = 0.018）和Benton判断线方向（突变，pc = 0.0045; E326K，pc = 0.0013）。GBA突变和E326 K均与PD患者的不同认知特征相关，其特征为工作记忆/执行功能和视觉空间能力受损更严重。E326K对认知表现产生负面影响的发现使我们现在认识到的PD患者的比例增加了一倍，这些患者有更严重的GBA相关认知缺陷的风险。
Loss-of-function mutations in the GBA gene are associated with more severe cognitive impairment in PD, but the nature of these deficits is not well understood and whether common GBA polymorphisms influence cognitive performance in PD is not yet known. We screened the GBA coding region for mutations and the E326K polymorphism in 1,369 PD patients enrolled at 8 sites from the PD Cognitive Genetics Consortium. Participants underwent assessments of learning and memory (Hopkins Verbal Learning Test–Revised), working memory/executive function (Letter-Number Sequencing and Trail Making A and B), language processing (semantic and phonemic verbal fluency), visuospatial abilities (Benton Judgment of Line Orientation), and global cognitive function (Montreal Cognitive Assessment). We used linear regression to test for association between genotype and cognitive performance with adjustment for important covariates and accounted for multiple testing using Bonferroni corrections. Mutation carriers (n=60; 4.4%) and E326K carriers (n=65; 4.7%) had a higher prevalence of dementia (mutations, odds ratio =5.1; p=9.7 × 10−6; E326K, odds ratio =6.4; p=5.7 × 10−7) and lower performance on Letter-Number Sequencing (mutations, corrected p[pc]=9.0 × 10−4; E326K, pc=0.036), Trail Making B-A (mutations, pc=0.018; E326K, pc=0.018), and Benton Judgment of Line Orientation (mutations, pc=0.0045; E326K, pc=0.0013). Both GBA mutations and E326K are associated with a distinct cognitive profile characterized by greater impairment in working memory/executive function and visuospatial abilities in PD patients. The discovery that E326K negatively impacts cognitive performance approximately doubles the proportion of PD patients we now recognize are at risk for more severe GBA-related cognitive deficits.