Center of Neurology, Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
German Center for Neurodegenerative Diseases, University of Tübingen, Tuebingen, Germany.
Mov Disord. 2021 May;36(5):1216-1228. doi: 10.1002/mds.28472. Epub 2021 Feb 6.
With pathway-specific trials in PD associated with variants in the glucocerebrosidase gene (PD ) under way, we need markers that confirm the impact of genetic variants in patient-derived biofluids in order to allow patient stratification merely based on genetics and that might serve as biochemical read-out for target engagement.
To explore GBA-pathway-specific biomarker profiles cross-sectionally (TUEPAC-MIGAP, PPMI) and longitudinally (PPMI).
We measured enzyme activity of the lysosomal glucocerebrosidase, CSF levels of glucosylceramides (upstream substrate of glucocerebrosidase), CSF levels of ceramides (downstream product of glucocerebrosidase), lactosylceramides, sphingosines, sphingomyelin (by-products) and CSF levels of total α-synuclein in PD patients compared to PD patients.
Cross-sectionally in both cohorts and longitudinally in PPMI: (1) glucocerebrosidase activity was significantly lower in PD compared to PD . (2) CSF levels of upstream substrates (glucosylceramides species) were higher in PD compared to PD . (3) CSF levels of total α-synuclein were lower in PD compared to PD . All of these findings were most pronounced in PD with severe mutations (PD ). Cross-sectionally in TUEPAC-MIGAP and longitudinally in PPMI, CSF levels of downstream-products (ceramides) were higher in PD . Cross-sectionally in TUEPAC-MIGAP by-products sphinganine and sphingosine-1-phosphate and longitudinally in PPMI species of by-products lactosylceramides and sphingomyelin were higher in PD .
These findings confirm that GBA mutations have a relevant functional impact on biomarker profiles in patients. Bridging the gap between genetics and biochemical profiles now allows patient stratification for clinical trials merely based on mutation status. Importantly, all findings were most prominent in PD with severe variants. © 2021 International Parkinson and Movement Disorder Society.
随着与葡萄糖脑苷脂酶基因（PD）变异相关的 PD 通路特异性试验的进行，我们需要标志物来确认遗传变异在患者衍生生物流体中的影响，以便仅基于遗传学对患者进行分层，并且可以作为靶标结合的生化读出。
探索 GBA 通路特异性生物标志物谱的横断面（TUEPAC-MIGAP、PPMI）和纵向（PPMI）。
我们测量了溶酶体葡萄糖脑苷脂酶的酶活性、CSF 中葡萄糖脑苷脂（葡萄糖脑苷脂酶的上游底物）、CSF 中神经酰胺（葡萄糖脑苷脂酶的下游产物）、乳糖脑苷脂、神经酰胺、神经酰胺、鞘氨醇（副产物）和 CSF 中总α-突触核蛋白的水平，与 PD 患者相比。
在两个队列的横断面和 PPMI 的纵向研究中：（1）PD 患者的葡萄糖脑苷脂酶活性明显低于 PD 患者。（2）CSF 中上游底物（葡萄糖脑苷脂种类）水平在 PD 患者中高于 PD 患者。（3）PD 患者的 CSF 中总α-突触核蛋白水平低于 PD 患者。所有这些发现都在 PD 严重突变患者中最为明显（PD 患者）。在 TUEPAC-MIGAP 的横断面和 PPMI 的纵向研究中，CSF 中下游产物（神经酰胺）水平在 PD 患者中较高。在 TUEPAC-MIGAP 的横断面中，副产物神经鞘氨醇和神经鞘氨醇-1-磷酸以及在 PPMI 的纵向研究中，副产物乳糖脑苷脂和神经鞘磷脂的种类在 PD 患者中较高。
这些发现证实了 GBA 突变对患者生物标志物谱具有相关的功能影响。弥合遗传学和生化谱之间的差距，现在允许仅基于突变状态对临床试验进行患者分层。重要的是，所有发现都在 PD 严重变异患者中最为突出。© 2021 国际帕金森病和运动障碍协会。
