Magnetic Resonance Imaging of Mouse Cerebral Cavernomas Reveal Differential Lesion Progression and Variable Permeability to Gadolinium.
Magnetic Resonance Imaging of Mouse Cerebral Cavernomas Reveal Differential Lesion Progression and Variable Permeability to Gadolinium.
复制标题
小鼠脑海绵状血管瘤的磁共振成像揭示了不同的病变进展和对钆的可变渗透性。
DOI：
10.1161/atvbaha.122.318938
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Tvrdik,Petr
中科院分区：
文献类型：
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作者：
Fisher,DelaneyG;Sharifi,KhadijehA;Ulutas,EZeynep;Kumar,JeyanS;Kalani,MYasharS;Miller,GWilson;Price,RichardJ;Tvrdik,Petr
研究背景脑海绵状血管畸形（cavernous malformations），又称海绵状血管瘤，是一种由大量毛细血管组成的血管异常。一般人群（包括无症状病例）的患病率估计为0.5%。一些患者出现严重症状，包括癫痫发作和局灶性神经功能缺损，而另一些患者则无症状。这种显着的介绍异质性的主要单基因疾病的原因仍然知之甚少。MethodsWe建立了一个慢性小鼠模型的脑海绵状血管畸形，诱导出生后消融Krit 1 with Pdgfb-CreERT 2，并检查病变进展在这些小鼠T2加权7 T磁共振成像（MRI）。我们还建立了一个修改后的协议，动态增强MRI和钆示踪剂钆贝葡胺的定量地图。终端成像后，脑切片染色抗体对小胶质细胞，星形胶质细胞和内皮细胞。ResultsThese小鼠发展脑海绵状血管畸形病变逐渐超过4至5个月的年龄在整个大脑。对单个病灶的精确体积分析显示非单调行为，一些病灶暂时变小。然而，累积病灶体积总是随时间增加，约2个月后呈幂趋势。使用动态增强MRI，我们制作了病变中钆的定量图，表明病变渗透性的高度异质性。病变的MRI特征与内皮细胞、星形胶质细胞和小胶质细胞的细胞标志物相关。病变的MRI特性与内皮细胞和神经胶质细胞的细胞标记物的多变量比较显示，病变周围细胞密度的增加与稳定性相关，结论我们的研究结果为更好地了解个体病变特性奠定了基础，并为测试新的药物和基因治疗提供了一个全面的临床前平台，控制脑海绵状畸形
BackgroundCerebral cavernous malformations, also known as cavernous angiomas, are blood vessel abnormalities comprised of clusters of grossly enlarged and hemorrhage-prone capillaries. The prevalence in the general population, including asymptomatic cases, is estimated to be 0.5%. Some patients develop severe symptoms, including seizures and focal neurological deficits, whereas others remain asymptomatic. The causes of this remarkable presentation heterogeneity within a primarily monogenic disease remain poorly understood.MethodsWe established a chronic mouse model of cerebral cavernous malformations, induced by postnatal ablation ofKrit1withPdgfb-CreERT2, and examined lesion progression in these mice with T2-weighted 7T magnetic resonance imaging (MRI). We also established a modified protocol for dynamic contrast-enhanced MRI and produced quantitative maps of gadolinium tracer gadobenate dimeglumine. After terminal imaging, brain slices were stained with antibodies against microglia, astrocytes, and endothelial cells.ResultsThese mice develop cerebral cavernous malformations lesions gradually over 4 to 5 months of age throughout the brain. Precise volumetric analysis of individual lesions revealed nonmonotonous behavior, with some lesions temporarily growing smaller. However, the cumulative lesional volume invariably increased over time and after about 2 months followed a power trend. Using dynamic contrast-enhanced MRI, we produced quantitative maps of gadolinium in the lesions, indicating a high degree of heterogeneity in lesional permeability. MRI properties of the lesions were correlated with cellular markers for endothelial cells, astrocytes, and microglia. Multivariate comparisons of MRI properties of the lesions with cellular markers for endothelial and glial cells revealed that increased cell density surrounding lesions correlates with stability, whereas denser vasculature within and surrounding the lesions may correlate with high permeability.ConclusionsOur results lay a foundation for better understanding individual lesion properties and provide a comprehensive preclinical platform for testing new drug and gene therapies for controlling cerebral cavernous malformations.