From the Department of Neurology (G.F.C., R.B., X.C., M.A.S.) and Biostatistics Center, Department of Medicine (E.A.M.), Massachusetts General Hospital; Harvard Medical School (G.F.C., E.A.M., R.B., X.C., A.A., M.A.S.), Boston, MA; Denali Therapeutics Inc. (R.M., J.W., M.M., S.S.D., J.I.A., G.A., S.H.-R.), San Francisco, CA; and Department of Nutrition (A.A.), Harvard T. H. Chan School of Public Health, Boston, MA.
Neurology. 2020 Dec 15;95(24):e3428-e3437. doi: 10.1212/WNL.0000000000010863. Epub 2020 Sep 30.
To identify markers of resistance to developing Parkinson disease (PD) among mutation carriers (+), we carried out metabolomic profiling in individuals with PD and unaffected controls (UC), with and without the mutation.
Plasma from 368 patients with PD and UC in the LRRK2 Cohort Consortium (LCC), comprising 118 +/PD+, 115 +/UC, 70 -/PD+, and 65 /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 and PD status, using analysis of covariance models adjusted by age, study site cohort, and sex, with value corrections for multiple comparisons.
Plasma caffeine concentration was lower in patients with PD vs UC ( < 0.001), more so among + carriers (by 76%) than among - participants (by 31%), with significant interaction between and PD status ( = 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 PD+ compared to UC with significant interaction effect with the mutation ( < 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 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 mutation carriers.
在携带 突变的个体（+）中，确定对帕金森病（PD）发展具有抗性的标志物。我们对 PD 患者和未受影响的对照（UC）个体进行了代谢组学分析，这些个体携带或不携带 突变。
对 LRRK2 队列联盟（LCC）中的 368 名 PD 患者和 UC 个体的血浆（包括 118 名+/PD+、115 名+/UC、70 名-/PD+和 65 名/UC）和 68 名个体的 CSF 进行了分析，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，我们评估了 4 组之间的差异，以及 与 PD 状态之间的相互作用，使用协方差分析模型进行调整，调整了年龄、研究地点队列和性别，对多重比较进行了 值校正。
与 UC 相比，PD 患者的血浆咖啡因浓度更低（<0.001），+携带者的降幅更大（降低了 76%），而非-参与者的降幅较小（降低了 31%），在 与 PD 状态之间存在显著的相互作用（=0.005）。在血浆中咖啡因代谢物（副黄嘌呤、茶碱、1-甲基黄嘌呤）和咖啡消耗的非黄嘌呤标志物（葫芦巴碱），以及相应的 CSF 样本中，也观察到了类似的结果。与 UC 相比，PD+的饮食咖啡因也较低，与 突变的相互作用具有显著的影响（<0.001）。
对 LCC 样本的代谢组学分析确定了咖啡因、其去甲基化代谢物和葫芦巴碱作为抵抗 PD 的显著标志物，这些标志物与致病性 突变的相关性大于与特发性 PD 的相关性。由于这些分析物既是咖啡消耗的相关性，也是动物 PD 模型中的神经保护剂，因此这些发现可能反映了它们在易患 PD 的个体中的回避，或在 突变携带者中的保护作用。
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