Prodromal substantia nigra sonography undermines suggested association between substrate accumulation and the risk for GBA-related Parkinson's disease
Prodromal substantia nigra sonography undermines suggested association between substrate accumulation and the risk for GBA-related Parkinson's disease
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DOI：
10.1111/ene.13927
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发表时间：
2019-07-01
影响因子：
5.1
通讯作者：
Zimran, A.
中科院分区：
文献类型：
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作者：
Arkadir, D.;Dinur, T.;Zimran, A.
背景和目的携带GBA（葡萄糖脑苷脂酶）突变的个体患帕金森病（PD）的风险增加。然而，这种风险增加是否是由葡萄糖脑苷脂酶活性受损导致底物蓄积引起的仍有争议。比较GBA突变携带者和戈谢病（GD）患者（其中底物积累广泛）中前驱PD标志物的存在有助于澄清这一问题。方法在这项横断面研究中，我们比较了GBA突变携带者（n = 71）和GD患者（n = 145）的黑质高回声区，一种前驱PD标志物。我们的对照人群为健康、非携带者（n = 49）和GBA相关PD患者（n = 11）。根据葡萄糖基鞘氨醇的干血斑水平评估底物蓄积。结果我们的研究结果表明，没有贡献的底物积累，因为高回声的面积是类似的扩大相对于健康对照GBA突变携带者和GD患者。此外，当仅比较N370S（c.1226A>G）突变的携带者（n = 38）与相同突变的纯合子的未经治疗的GD患者（n = 47）时，GBA携带者和GD患者之间的这种相似性仍然存在。此外，高回声区的测量与未治疗的GD患者的葡萄糖鞘氨醇水平无关。结论在GBA突变人群中，前驱PD（黑质强回声）标志物的存在与底物蓄积无关。虽然需要进一步的纵向研究来确定该标记物对GBA相关PD的精确预测价值，但我们的研究结果对物质减少策略对PD预防的贡献提出了质疑。
Background and purpose Individuals with GBA (glucocerebrosidase) mutations are at increased risk of Parkinson's disease (PD). It is still debated, however, whether this increased risk results from impaired glucocerebrosidase activity leading to substrate accumulation. Comparing the presence of prodromal PD marker in GBA mutation carriers and patients with Gaucher disease (GD) (in which substrate accumulation is extensive) can assist in clarifying this issue. Methods In this cross-sectional study, we compared the hyperechogenic area of the substantia nigra, a prodromal PD marker, in large cohorts of GBA mutation carriers (n = 71) and patients with GD (n = 145). Our control populations were healthy, non-carriers (n = 49) and patients with GBA-related PD (n = 11). Substrate accumulation was assessed from dry blood spot levels of glucosylsphingosine. Results Our findings indicate no contribution of substrate accumulation, as the area of hyperechogenicity is similarly enlarged relative to healthy controls in both GBA mutation carriers and patients with GD. Moreover, this similarity between GBA carriers and patients with GD persists when comparing only carriers of the N370S (c.1226A>G) mutation (n = 38) with untreated patients with GD who were homozygotes for the same mutation (n = 47). In addition, measurements of hyperechogenic area did not correlate with levels of glucosylsphingosine in the untreated patients with GD. Conclusion The presence of a marker of prodromal PD (substantia nigra hyperechogenicity) is independent of substrate accumulation in a population with mutated GBA. Although further longitudinal studies are needed to determine the precise predictive value of this marker for GBA-related PD, our findings raise doubts regarding the contribution of substance reduction strategies to PD prevention.