Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's.
Specifically neuropathic Gaucher's mutations accelerate cognitive decline in Parkinson's.
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特别是神经性戈谢氏突变会加速帕金森氏症的认知能力下降。
DOI：
10.1002/ana.24781
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发表时间：
2016-11
影响因子：
11.2
通讯作者：
International Genetics of Parkinson Disease Progression (IGPP) Consortium
中科院分区：
文献类型：
--
作者：
Liu G;Boot B;Locascio JJ;Jansen IE;Winder-Rhodes S;Eberly S;Elbaz A;Brice A;Ravina B;van Hilten JJ;Cormier-Dequaire F;Corvol JC;Barker RA;Heutink P;Marinus J;Williams-Gray CH;Scherzer CR;International Genetics of Parkinson Disease Progression (IGPP) Consortium
我们假设，在纯合子中引起神经性戈谢病（GD）的 β-葡萄糖脑苷脂酶基因（GBA）的特定突变会导致杂合子帕金森病（PD）患者的认知能力严重下降，而非神经性 GD 突变则导致中等进展率。对七个队列中总共 2,304 名 PD 患者和 20,868 次长达 12.8 年（中位数为 4.1）的纵向就诊进行了分析。使用混合随机效应和固定效应以及 Cox 比例风险模型评估了 GBA 四种遗传变异对纵向认知能力下降的差异影响。总体而言，10.3% 的 PD 和 GBA 测序患者携带突变。与非携带者相比，神经性 GD 突变携带者（占患者的 1.4%）的整体认知障碍风险比 (HR) 为 3.17（95% 置信区间 [CI]，1.60-6.25），并且简易精神状态检查分数加速下降（p = 0.0009）。复杂 GBA 等位基因的携带者 (0.7%) 的 HR 为 3.22 (95% CI, 1.18–8.73; p = 0.022)。相比之下，常见的非神经性 N370S 突变（1.5% 的患者；HR，1.96；95% CI，0.92–4.18）或非致病性风险变异（6.6% 的患者；HR，1.36；95% CI，0.89–2.05）并未达到显着性。导致神经性 GD 致病的 GBA 基因突变和复杂等位基因将 PD 的纵向认知能力下降转变为“高速”。这些发现表明特定类型的 GBA 突变与侵袭性认知能力下降之间存在关系，并对改进临床试验的设计具有直接影响。安·尼罗尔 2016；80：674–685
We hypothesized that specific mutations in the β‐glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non‐neuropathic GD mutations confer intermediate progression rates. A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60–6.25) and a hastened decline in Mini–Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18–8.73; p = 0.022). By contrast, the common, non‐neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92–4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89–2.05) did not reach significance. Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into “high gear.” These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674–685