From the The Norwegian Centre for Movement Disorders (L.O., J.M.-G., K.F.P., G.A., J.L.), Stavanger University Hospital, Norway; Department of Chemistry, Bioscience and Environmental Engineering (J.M.-G., G.A., J.L.), University of Stavanger, Norway; Department of Research (I.D.), Section of Biostatistics, Stavanger University Hospital, Norway; Department of Neurology (O.-B.T.), Haukeland University Hospital, Bergen; Department of Clinical Medicine (O.-B.T.), University of Bergen, Norway; and Department of Neurology (K.F.P., G.A.), Stavanger University Hospital.
Neurology. 2023 Jan 24;100(4):e388-e395. doi: 10.1212/WNL.0000000000201418. Epub 2022 Oct 17.
Variations in the glucocerebrosidase gene () are common risk factors for Parkinson disease (PD) and dementia in PD (PDD) and cause a reduction in the activity of the lysosomal enzyme glucocerebrosidase (GCase). It is anticipated that GCase dysfunction might contribute to a more malignant disease course and predict cognitive impairment in PD, although evidence is lacking. We aimed to discover whether CSF GCase activity is altered in newly diagnosed patients with PD and associated with future development of dementia.
Patients with PD were participants of the ongoing population-based longitudinal ParkWest study in Southwestern Norway and were followed prospectively for up to 10 years. CSF was collected at diagnosis, and carrier status was obtained. Control samples were from persons without neurodegenerative disorders. GCase activity was measured using a validated assay. PD dementia diagnosis was set according to the Movement Disorder Society criteria, and parametric accelerated failure time models were applied to analyze the association of GCase activity with dementia-free survival.
This study enrolled 117 patients with PD (mean age 67.2 years, including 12 non-synonymous variant carriers) and 50 control participants (mean age 64 years). At the time of diagnosis, GCase activity was reduced in patients with PD with (mean ± SD, 0.92 ± 0.40 mU/mg, n = 12) or without variations (1.00 ± 0.37 mU/mg, n = 105) compared with controls (1.20 ± 0.35, n = 50). GCase activity at the time of diagnosis was lower in patients with PD who developed dementia within 10 years (0.85 ± 0.27 mU/mg, n = 41) than in those who did not (1.07 ± 0.40 mU/mg, n = 76, = 0.001). A 0.1-unit reduction in baseline GCase activity was associated with a faster development of PDD (hazard ratio 1.15, 95% CI 1.03-1.28, = 0.014).
The association of early CSF GCase activity with long-term progression to PD dementia will have important implications for the design of clinical trials for GCase targeting therapies and patient management.
This study provides Class III evidence that reduced CSF GCase activity at the time of PD diagnosis is associated with an increased risk for later development of PDD.
葡萄糖脑苷脂酶基因 () 的变异是帕金森病 (PD) 和 PD 伴痴呆 (PDD) 的常见危险因素，导致溶酶体酶葡萄糖脑苷脂酶 (GCase) 的活性降低。预计 GCase 功能障碍可能导致更恶性的疾病进程，并预测 PD 中的认知障碍，尽管证据不足。我们旨在发现新诊断的 PD 患者的 CSF GCase 活性是否发生改变，并与未来痴呆的发生相关。
PD 患者是挪威西南部正在进行的基于人群的纵向 ParkWest 研究的参与者，并进行了长达 10 年的前瞻性随访。在诊断时采集 CSF，并获得 携带者状态。对照样本来自无神经退行性疾病的个体。使用经过验证的测定法测量 GCase 活性。根据运动障碍协会的标准诊断 PD 痴呆，应用参数加速失效时间模型分析 GCase 活性与无痴呆生存的关系。
这项研究纳入了 117 例 PD 患者（平均年龄 67.2 岁，包括 12 名非同义变异携带者）和 50 名对照参与者（平均年龄 64 岁）。在诊断时，与对照组（n = 50）相比，携带 变异的 PD 患者（n = 12）或不携带 变异的 PD 患者（n = 105）的 GCase 活性降低，分别为（均值 ± 标准差，0.92 ± 0.40 mU/mg）和（1.00 ± 0.37 mU/mg）。在 10 年内发生痴呆的 PD 患者（n = 41）的 GCase 活性低于未发生痴呆的患者（n = 76），诊断时的 GCase 活性较低（0.85 ± 0.27 mU/mg， = 0.001）。基线 GCase 活性降低 0.1 单位与 PDD 的快速进展相关（危险比 1.15，95%置信区间 1.03-1.28， = 0.014）。
PD 诊断时 CSF GCase 活性的早期变化与长期进展为 PD 痴呆有关，这对设计 GCase 靶向治疗的临床试验和患者管理具有重要意义。
本研究提供了 III 级证据，表明 PD 诊断时 CSF GCase 活性降低与以后发生 PDD 的风险增加相关。
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