背景:APP重复是阿尔茨海默病和脑淀粉样血管病(CAA)的罕见遗传原因。我们旨在评估APP重复携带者的表型。
方法:临床,放射学,回顾性分析了24个法国家庭的43个APP重复携带者的神经病理学特征,将MRI特征和脑脊液(CSF)生物标志物与40例APP阴性的CAA对照进行比较。
结果:在90.2%有症状的APP重复携带者中发现了主要的神经认知障碍,9.7%的突出行为障碍。有症状的脑出血占29.2%,癫痫发作占51.2%。18/19例患者和14/19例患者的CSFAβ42水平异常,符合CAA的MRI放射学标准,而只有5个没有出血特征。我们发现CAA放射学征象与重复大小之间没有相关性。与CAA对照组相比,APP重复携带者表现出较少的播散性皮质浅表铁质沉着症(0%vs37.5%,p=0.004调整了症状发作和MRI之间的延迟)。在两个APP复制载体中发现了深的微出血。除了神经原纤维缠结和老年斑,在所有9例尸检中,CAA弥漫性且严重,软脑膜血管增厚。在黑质中发现了路易体,蓝斑,和2/9患者的皮质结构,一个在基底神经节出现血管淀粉样蛋白沉积。
结论:与APP重复相关的表型与包括痴呆在内的不同临床表现是异质的,出血,癫痫发作和不同的放射学表现,甚至在家庭中。没有发现与重复大小的明显相关性。如MRI和神经病理学数据的出血特征所示,淀粉样蛋白负荷严重且广泛延伸至脑血管。使APP复制成为一种有趣的CAA模型。
APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers.
Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls.
Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia.
Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.