BACKGROUND Parkinson's disease (PD) is the second most common neurodegenerative disease and the most common movement disorder characterized by motor impairments resulting from midbrain dopamine neuron loss. Abnormalities in small pial arteries and arterioles, which are the primary pathways of local delivery of nutrients and oxygen in brain tissue, have been reported in many neurodegenerative diseases including PD. Mutations in LRRK2 cause genetic PD and contribute to sporadic PD. The most common PD-linked mutation LRRK2 G2019S contributes 20-47% of genetic forms of PD in Caucasian populations. The human LRRK2 G2019S transgenic mouse model displays PD-like movement impairment and was used to identify novel LRRK2 inhibitors, which provides a useful model for studying microvascular abnormalities in PD. OBJECTIVES To investigate abnormalities in arteriolar cerebral blood volume (CBVa) in various brain regions using the inflow-based vascular-space occupancy (iVASO) MRI technique in LRRK2 mouse models of PD. METHODS Anatomical and iVASO MRI scans were performed in 5 female and 7 male nontransgenic (nTg), 3 female and 4 male wild-type (WT) LRRK2, and 5 female and 7 male G2019S-LRRK2 mice of 9 months of age. CBVa was calculated and compared in the substantia nigra (SN), olfactory cortex, and prefrontal cortex. RESULTS Compared to nTg mice, G2019S-LRRK2 mice showed decreased CBVa in the SN, but increased CBVa in the olfactory and prefrontal cortex in both male and female groups, whereas WT-LRRK2 mice showed no change in CBVa in the SN (male and female), the olfactory (female), and prefrontal (female) cortex, but a slight increase in CBVa in the olfactory and prefrontal cortex in the male group only. CONCLUSIONS Alterations in the blood volume of small arteries and arterioles (CBVa) were detected in the G2019S-LRRK2 mouse model of PD. The opposite changes in CBVa in the SN and the cortex indicate that PD pathology may have differential effects in different brain regions. Our results suggest the potential value of CBVa as a marker for clinical PD studies.

中文翻译：

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突变体 G2019S-LRRK2 导致小鼠大脑小动脉脑血容量异常：MRI 研究

背景帕金森病(PD)是第二常见的神经变性疾病和最常见的运动障碍，其特征在于由中脑多巴胺神经元丢失引起的运动障碍。在包括 PD 在内的许多神经退行性疾病中，已经报道了小软脑膜动脉和小动脉的异常，它们是脑组织中局部输送营养物质和氧气的主要途径。LRRK2 突变导致遗传性 PD 并导致散发性 PD。最常见的 PD 相关突变 LRRK2 G2019S 占白种人人群 PD 遗传形式的 20-47%。人类 LRRK2 G2019S 转基因小鼠模型显示出 PD 样运动障碍，并被用于鉴定新型 LRRK2 抑制剂，这为研究 PD 微血管异常提供了有用的模型。目的 使用基于流入的血管空间占用 (iVASO) MRI 技术在 PD 的 LRRK2 小鼠模型中研究不同大脑区域的小动脉脑血容量 (CBVa) 的异常。方法 对 9 个月大的 5 只雌性和 7 只雄性非转基因 (nTg)、3 只雌性和 4 只雄性野生型 (WT) LRRK2 以及 5 只雌性和 7 只雄性 G2019S-LRRK2 小鼠进行解剖和 iVASO MRI 扫描。在黑质 (SN)、嗅觉皮层和前额叶皮层中计算和比较 CBVa。结果 与 nTg 小鼠相比，G2019S-LRRK2 小鼠的 SN 中的 CBVa 降低，但雄性和雌性组的嗅觉和前额叶皮层中的 CBVa 增加，而 WT-LRRK2 小鼠的 SN（雄性和雌性）中的 CBVa 没有变化。 ），嗅觉（女性）和前额叶（女性）皮层，但仅男性组的嗅觉和前额叶皮层的 CBVa 略有增加。结论 在 PD 的 G2019S-LRRK2 小鼠模型中检测到小动脉和小动脉 (CBVa) 的血容量变化。SN 和皮质中 CBVa 的相反变化表明 PD 病理可能在不同的大脑区域具有不同的影响。我们的结果表明 CBVa 作为临床 PD 研究的标志物的潜在价值。