GBA1突变携带者血糖脑苷酶活性和α-突触核蛋白水平的联合评估：一种新的潜在生物标志物

IF 3.1 3区医学 Q2 CLINICAL NEUROLOGY

Parkinsonism & related disorders Pub Date : 2025-04-29 DOI:10.1016/j.parkreldis.2025.107854

M. Avenali , S.P. Caminiti , M. Gegg , S. Cerri , P. Mitrotti , L. Bandirali , M. Toffoli , D. Hughes , C. Cerami , C. Tassorelli , E.M. Valente , A.H.V. Schapira , F. Blandini

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引用次数: 0

摘要

编码糖脑苷酶（GCase）的GBA1基因的杂合变异体是帕金森病（PD）最常见的遗传危险因素。然而，只有少数GBA1携带者最终会发展为显性PD，而且这种外显率降低的机制仍未被广泛探索。GCase降低和α-突触核蛋白水平升高被单独认为是有希望的GBA-PD预后血液生物标志物。在这里，我们的目的是评估GCase活性降低和α-突触核蛋白水平升高作为GBA1人群预后较差的潜在生化标志的联合作用。方法对98例患者（30例gba -non - pd、29例GBA-PD和39例健康对照）进行详细的临床评估，并测定外周血单个核细胞（PBMCs） GCase活性和总α-突触核蛋白水平。采用ROC曲线分析和两步聚类分析，根据受试者的GCase和α-synuclein生化谱进行分类。临床评分进行跨组分析。结果基于α-synuclein/GCase活性比的roc曲线分析能够将GBA1阳性个体与健康对照区分开。我们确定了两个独立的生化集群-良性集群（高GCase/中低α-synuclein）和恶性集群（低GCase/高α-synuclein）。所有健康对照均属于良性集群，而59%的GBA-PD和47%的gba -非pd属于恶性集群。恶性集群中的gba -非pd有更大的抑郁症状，GBA-PD表现出更差的认知表现。我们首次报道了血液GCase活性和α-突触核蛋白水平的联合评估可以定义两个不同的生化簇，能够区分具有较大临床前非运动症状的gba -非pd患者和具有较差认知特征的GBA-PD患者。需要进行纵向研究来确认这种潜在生物标志物的准确性。

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Combined assessment of blood glucocerebrosidase activity and α-synuclein levels in GBA1 mutation carriers: A novel potential biomarker

Introduction

Heterozygous variants in the GBA1 gene encoding the glucocerebrosidase enzyme (GCase) are the most frequent genetic risk factor for Parkinson's Disease (PD). Yet, only a minority of GBA1 carriers will eventually develop overt PD, and the mechanisms underlying such reduced penetrance are still largely unexplored.

Decreased GCase and increased α-synuclein levels are individually considered promising prognostic blood biomarkers for GBA-PD. Here, we aim to assess the combined role of decreased GCase activity and increased α-synuclein levels as a potential biochemical signature of worse outcome in GBA1 population.

Methods

Ninety-eight subjects (30 GBA-nonPD, 29 GBA-PD and 39 healthy controls) underwent a detailed clinical assessment, as well as measurement of GCase activity and total α-synuclein levels in peripheral blood mononuclear cells (PBMCs). ROC curve analysis and a two-step clustering analysis were performed to classify subjects based on their combined GCase and α-synuclein biochemical profile. Clinical scores were analysed across clusters.

Results

ROC curve analysis based on α-synuclein/GCase activity ratio was able to discriminate GBA1 positive individuals from healthy controls. We identified two separate biochemical clusters – a benign (high GCase/mid-low α-synuclein) and a malignant (low GCase/high α-synuclein) cluster. All healthy controls belonged to the benign cluster, while 59% of GBA-PD and 47% of GBA-nonPD fell into the malignant cluster. GBA-nonPD within the malignant cluster had greater depressive symptoms, and GBA-PD showed worse cognitive performance.

Conclusions

We report for the first time that the combined assessment of blood GCase activity and α-synuclein levels can define two distinctive biochemical clusters able to discriminate GBA-nonPD subjects with greater preclinical non-motor symptoms and GBA-PD patients with a worse cognitive profile. Longitudinal studies are needed to confirm the accuracy of this potential biomarker.

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来源期刊

Parkinsonism & related disorders 医学-临床神经学

CiteScore

6.20

自引率

4.90%

发文量

292

审稿时长

39 days

期刊介绍： Parkinsonism & Related Disorders publishes the results of basic and clinical research contributing to the understanding, diagnosis and treatment of all neurodegenerative syndromes in which Parkinsonism, Essential Tremor or related movement disorders may be a feature. Regular features will include: Review Articles, Point of View articles, Full-length Articles, Short Communications, Case Reports and Letter to the Editor.