Neurology Clinic, University of Perugia, Perugia, Italy.
Department of Pharmaceutical Sciences, University of Perugia, Perugia, Italy.
Mov Disord. 2017 Oct;32(10):1423-1431. doi: 10.1002/mds.27136. Epub 2017 Aug 26.
Reduced β-glucocerebrosidase activity was observed in postmortem brains of both GBA1 mutation carrier and noncarrier Parkinson's disease patients, suggesting that lower β-glucocerebrosidase activity is a key feature in the pathogenesis of PD. The objectives of this study were to confirm whether there is reduced β-glucocerebrosidase activity in the CSF of GBA1 mutation carrier and noncarrier PD patients and verify if other lysosomal enzymes show altered activity in the CSF.
CSF β-glucocerebrosidase, cathepsin D, and β-hexosaminidase activities were measured in 79 PD and 61 healthy controls from the BioFIND cohort. The whole GBA1 gene was sequenced.
Enzyme activities were normalized according to CSF protein content (specific activity). β-glucocerebrosidase specific activity was significantly decreased in PD versus controls (-28%, P < 0.001). GBA1 mutations were found in 10 of 79 PD patients (12.7%) and 3 of 61 controls (4.9%). GBA1 mutation carrier PD patients showed significantly lower β-glucocerebrosidase specific activity versus noncarriers. β-glucocerebrosidase specific activity was also decreased in noncarrier PD patients versus controls (-25%, P < 0.001). Cathepsin D specific activity was lower in PD versus controls (-21%, P < 0.001). β-Hexosaminidase showed a similar trend. β-Glucocerebrosidase specific activity fairly discriminated PD from controls (area under the curve, 0.72; sensitivity, 0.67; specificity, 0.77). A combination of β-glucocerebrosidase, cathepsin D, and β-hexosaminidase improved diagnostic accuracy (area under the curve, 0.77; sensitivity, 0.71; specificity, 0.85). Lower β-glucocerebrosidase and β-hexosaminidase specific activities were associated with worse cognitive performance.
CSF β-glucocerebrosidase activity is reduced in PD patients independent of their GBA1 mutation carrier status. Cathepsin D and β-hexosaminidase were also decreased. The possible link between altered CSF lysosomal enzyme activities and cognitive decline deserves further investigation. © 2017 International Parkinson and Movement Disorder Society.
在 GBA1 突变携带者和非携带者帕金森病患者的尸检脑组织中均观察到β-葡糖脑苷脂酶活性降低，这表明较低的β-葡糖脑苷脂酶活性是 PD 发病机制的关键特征。本研究的目的是确认 GBA1 突变携带者和非携带者帕金森病患者的 CSF 中是否存在β-葡糖脑苷脂酶活性降低，并验证其他溶酶体酶在 CSF 中的活性是否发生改变。
从 BioFIND 队列中测量了 79 名 PD 患者和 61 名健康对照者的 CSFβ-葡糖脑苷脂酶、组织蛋白酶 D 和β-己糖胺酶活性。整个 GBA1 基因进行了测序。
根据 CSF 蛋白含量（比活性）对酶活性进行了归一化。PD 患者的β-葡糖脑苷脂酶比活性明显低于对照组（-28%，P<0.001）。在 79 名 PD 患者中发现了 10 名（12.7%）和 61 名对照者中的 3 名（4.9%）GBA1 突变。GBA1 突变携带者的 PD 患者与非携带者相比，β-葡糖脑苷脂酶比活性明显降低。非携带者 PD 患者的β-葡糖脑苷脂酶比活性也低于对照组（-25%，P<0.001）。组织蛋白酶 D 比活性在 PD 患者中低于对照组（-21%，P<0.001）。β-己糖胺酶也表现出类似的趋势。β-葡糖脑苷脂酶比活性能较好地区分 PD 患者与对照组（曲线下面积为 0.72；敏感性为 0.67；特异性为 0.77）。β-葡糖脑苷脂酶、组织蛋白酶 D 和β-己糖胺酶的组合提高了诊断准确性（曲线下面积为 0.77；敏感性为 0.71；特异性为 0.85）。较低的β-葡糖脑苷脂酶和β-己糖胺酶比活性与认知功能下降有关。
PD 患者的 CSFβ-葡糖脑苷脂酶活性降低，与 GBA1 突变携带者状态无关。组织蛋白酶 D 和β-己糖胺酶也降低。改变的 CSF 溶酶体酶活性与认知能力下降之间的可能联系值得进一步研究。
