Association of caffeine and related analytes with resistance to Parkinson disease among LRRK2 mutation carriers: A metabolomic study.
Association of caffeine and related analytes with resistance to Parkinson disease among LRRK2 mutation carriers: A metabolomic study.
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DOI：
10.1212/wnl.0000000000010863
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发表时间：
2020-12-15
期刊：
影响因子：
9.9
通讯作者：
Schwarzschild MA
中科院分区：
文献类型：
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作者：
Crotty GF;Maciuca R;Macklin EA;Wang J;Montalban M;Davis SS;Alkabsh JI;Bakshi R;Chen X;Ascherio A;Astarita G;Huntwork-Rodriguez S;Schwarzschild MA
为了确定LRRK 2突变携带者（LRRK 2+）对帕金森病（PD）发展的抗性标志物，我们在有和没有LRRK 2突变的PD和未受影响的对照（UC）个体中进行了代谢组学分析。LRRK 2队列联盟（LCC）中368例PD和UC患者的血浆，包括118例LRRK 2 +/PD+、115例LRRK 2 +/UC、70例LRRK 2 −/PD+和65例LRRK 2 −/UC，以及其中68例患者的CSF，通过液相色谱-质谱法进行分析。对于血浆和CSF中定量的282种分析物，我们使用按年龄、研究中心队列和性别调整的协方差模型分析评估了4组之间的差异以及LRRK 2和PD状态之间的相互作用，并对多重比较进行了p值校正。PD患者的血浆咖啡因浓度低于UC患者（p < 0.001），LRRK 2+携带者（76%）比LRRK 2 −参与者（31%）更低，LRRK 2和PD状态之间存在显著的相互作用（p = 0.005）。咖啡因代谢物（副黄嘌呤、茶碱、1-甲基黄嘌呤）和咖啡消耗的非黄嘌呤标记物（胡芦巴碱）在血浆中以及相应CSF样本的子集中发现了类似的结果。与LRRK 2 +/UC相比，LRRK 2 +/PD+中的膳食咖啡因也较低，与LRRK 2+突变具有显著的相互作用效应（p < 0.001）。LCC样本的代谢组学分析确定咖啡因、其去甲基化代谢物和胡芦巴碱是与致病性LRRK 2突变相关的PD耐药的突出标志物，而不是与特发性PD相关。由于这些分析物既被认为是咖啡消费的相关因素，又被认为是动物PD模型中的神经保护剂，因此这些发现可能反映了那些易患PD的人对它们的回避，或者它们在LRRK 2突变携带者中的保护作用。
To identify markers of resistance to developing Parkinson disease (PD) among LRRK2 mutation carriers (LRRK2+), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the LRRK2 mutation. Plasma from 368 patients with PD and UC in the LRRK2 Cohort Consortium (LCC), comprising 118 LRRK2+/PD+, 115 LRRK2+/UC, 70 LRRK2−/PD+, and 65 LRRK2−/UC, and CSF available from 68 of them, were analyzed by liquid chromatography with mass spectrometry. For 282 analytes quantified in plasma and CSF, we assessed differences among the 4 groups and interactions between LRRK2 and PD status, using analysis of covariance models adjusted by age, study site cohort, and sex, with p value corrections for multiple comparisons. Plasma caffeine concentration was lower in patients with PD vs UC (p < 0.001), more so among LRRK2+ carriers (by 76%) than among LRRK2− participants (by 31%), with significant interaction between LRRK2 and PD status (p = 0.005). Similar results were found for caffeine metabolites (paraxanthine, theophylline, 1-methylxanthine) and a nonxanthine marker of coffee consumption (trigonelline) in plasma, and in the subset of corresponding CSF samples. Dietary caffeine was also lower in LRRK2+/PD+ compared to LRRK2+/UC with significant interaction effect with the LRRK2+ mutation (p < 0.001). Metabolomic analyses of the LCC samples identified caffeine, its demethylation metabolites, and trigonelline as prominent markers of resistance to PD linked to pathogenic LRRK2 mutations, more so than to idiopathic PD. Because these analytes are known both as correlates of coffee consumption and as neuroprotectants in animal PD models, the findings may reflect their avoidance by those predisposed to develop PD or their protective effects among LRRK2 mutation carriers.