In Parkinson’s disease (PD), GBA1- and LRRK2-mutations are associated with different clinical phenotypes which might be related to differential involvement of the cholinergic system. We investigated cholinergic integrity in 149 asymptomatic GBA1 and 169 asymptomatic LRRK2 mutation carriers, 112 LRRK2 and 60 GBA1 carriers with PD, 492 idiopathic PD, and 180 controls from the PPMI cohort. Basal forebrain volumes were extracted and white matter pathways from nucleus basalis of Meynert (NBM) to cortex and from pedunculopontine nucleus (PPN) to thalamus were assessed with a free water-corrected DTI model. Bayesian ANCOVAs were conducted for group comparisons and Bayesian linear mixed models to assess associations with cognitive decline. Basal forebrain volumes were increased in asymptomatic GBA1 (Bayes Factor against the null hypothesis (BF₁₀) = 75.2) and asymptomatic LRRK2 (BF₁₀ = 57.0) compared to controls. Basal forebrain volumes were increased in LRRK2- compared to GBA1-PD (BF₁₀ = 14.5) and idiopathic PD (BF₁₀ = 3.6*10⁷), with no difference between idiopathic PD and PD-GBA1 (BF₁₀ = 0.25). Mean diffusivity along the medial NBM pathway was decreased in asymptomatic GBA1 compared to controls (BF₁₀ = 30.3). Over 5 years, idiopathic PD and PD-GBA1 declined across all cognitive domains whereas PD-LRRK2 patients only declined in processing speed. We found an interaction between basal forebrain volume and time in predicting multiple cognitive domains in idiopathic PD and PD-GBA1, but not in PD-LRRK2. While LRRK2 and GBA1 mutations are both associated with increased basal forebrain volume at asymptomatic stages, this increase persists at the symptomatic PD stage only in LRRK2 and might be related to slower cognitive decline in these patients.

在帕金森病 (PD) 中，GBA1 和 LRRK2 突变与不同的临床表型相关，这可能与胆碱能系统的不同参与有关。我们调查了 149 名无症状 GBA1 和 169 名无症状 LRRK2 突变携带者、112 名 LRRK2 和 60 名患有 PD 的 GBA1 携带者、492 名特发性 PD 以及来自 PPMI 队列的 180 名对照者的胆碱能完整性。提取基底前脑体积，并使用自由水校正的 DTI 模型评估从 Meynert 基底核 (NBM) 到皮质以及从脚桥核 (PPN) 到丘脑的白质通路。采用贝叶斯协方差分析进行组间比较，并使用贝叶斯线性混合模型来评估与认知能力下降的关联。与对照组相比，无症状 GBA1（针对原假设的贝叶斯因子 (BF ₁₀ ) = 75.2）和无症状 LRRK2 (BF ₁₀ = 57.0) 的基础前脑体积增加。与GBA1-PD (BF ₁₀ = 14.5) 和特发性PD (BF ₁₀ = 3.6*10 ⁷ ) 相比，LRRK2- 的基础前脑体积增加，特发性PD 和PD-GBA1 (BF ₁₀ = 0.25) 之间没有差异。与对照组相比，无症状 GBA1 沿内侧 NBM 通路的平均扩散率降低 (BF ₁₀ = 30.3)。 5 年来，特发性 PD 和 PD-GBA1 在所有认知领域均有所下降，而 PD-LRRK2 患者仅处理速度下降。我们发现基础前脑体积和时间在预测特发性 PD 和 PD-GBA1 的多个认知域方面存在交互作用，但在 PD-LRRK2 中则不然。 虽然 LRRK2 和 GBA1 突变均与无症状阶段基础前脑体积增加相关，但这种增加仅在 LRRK2 的有症状 PD 阶段持续存在，并且可能与这些患者认知能力下降较慢有关。