脑脊液和血液中的犬尿氨酸途径代谢物作为亨廷顿病的潜在生物标志物,Journal of Neurochemistry

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脑脊液和血液中的犬尿氨酸途径代谢物作为亨廷顿病的潜在生物标志物
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2021-04-02 , DOI: 10.1111/jnc.15360
Filipe B Rodrigues ₁ , Lauren M Byrne ₁ , Alexander J Lowe ₁ , Rosanna Tortelli ₁ , Mariette Heins ₂ , Gunnar Flik ₂ , Eileanoir B Johnson ₁ , Enrico De Vita _{3,

4} , Rachael I Scahill ₁ , Flaviano Giorgini ₅ , Edward J Wild ₁

Affiliation

来自多个模型和死后人类脑组织研究的汇聚证据支持犬尿氨酸途径 (KP) 参与亨廷顿病 (HD) 发病机制。定量 HD 生物流体中的 KP 代谢物是可取的，既可以用于研究病理学，也可以作为生物标志物的潜在来源来量化通路功能障碍并评估针对其成分的治疗干预措施的生化影响。在一项标准化收集脑脊液 (CSF)、血液、表型和影像数据的前瞻性单中心对照队列研究中，我们使用高效液相色谱法来测量 KP 代谢物（色氨酸、犬尿氨酸、犬尿酸、3）的水平。 -羟基犬尿氨酸、邻氨基苯甲酸和喹啉酸——存在于 80 名参与者的脑脊液和血浆中（20 名健康对照者、20 名前期 HD 和 40 名明显 HD）。我们研究了短期稳定性、组间差异、与临床和影像学测量的关联，并为未来的研究导出了样本量计算。总体而言，脑脊液和血浆中的 KP 代谢物在 6 周内保持稳定，没有表现出显着的组间差异，并且与临床或影像学测量无关。我们得出的结论是，所研究的代谢物在对照和 HD 基因扩增载体的生物液中都可以轻松可靠地定量。然而，我们发现几乎没有证据支持 HD 中 KP 的显着紊乱，至少在患者来源的生物液中代谢物水平所反映的程度上是这样。

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Kynurenine pathway metabolites in cerebrospinal fluid and blood as potential biomarkers in Huntington's disease

Converging lines of evidence from several models, and post-mortem human brain tissue studies, support the involvement of the kynurenine pathway (KP) in Huntington's disease (HD) pathogenesis. Quantifying KP metabolites in HD biofluids is desirable, both to study pathobiology and as a potential source of biomarkers to quantify pathway dysfunction and evaluate the biochemical impact of therapeutic interventions targeting its components. In a prospective single-site controlled cohort study with standardised collection of cerebrospinal fluid (CSF), blood, phenotypic and imaging data, we used high-performance liquid-chromatography to measure the levels of KP metabolites—tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, anthranilic acid and quinolinic acid—in CSF and plasma of 80 participants (20 healthy controls, 20 premanifest HD and 40 manifest HD). We investigated short-term stability, intergroup differences, associations with clinical and imaging measures and derived sample-size calculation for future studies. Overall, KP metabolites in CSF and plasma were stable over 6 weeks, displayed no significant group differences and were not associated with clinical or imaging measures. We conclude that the studied metabolites are readily and reliably quantifiable in both biofluids in controls and HD gene expansion carriers. However, we found little evidence to support a substantial derangement of the KP in HD, at least to the extent that it is reflected by the levels of the metabolites in patient-derived biofluids.

更新日期：2021-04-02

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