Department of Neurology and CNR-MAJ, Univ Rouen Normandie, U1245 and CHU Rouen, 76000, Rouen, France.
Department of Neurology, Rouen University Hospital, Rouen Cedex, 76031, France.
Alzheimers Res Ther. 2023 May 11;15(1):93. doi: 10.1186/s13195-023-01172-2.
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.
APP 基因重复是阿尔茨海默病和脑淀粉样血管病（CAA）的罕见遗传病因。我们旨在评估 APP 重复携带者的表型。
回顾性分析了来自 24 个法国家族的 43 名 APP 重复携带者的临床、影像学和神经病理学特征，并将 MRI 特征和脑脊液（CSF）生物标志物与 40 名 APP 阴性 CAA 对照进行了比较。
90.2%有症状的 APP 重复携带者出现了主要的神经认知障碍，其中 9.7%有明显的行为障碍。29.2%的患者报告了症状性颅内出血，51.2%的患者出现了癫痫。18/19 名患者的 CSF Aβ42 水平异常，14/19 名患者符合 CAA 的 MRI 影像学标准，而仅有 5 名患者没有出血特征。我们发现 CAA 影像学征象与重复大小之间没有相关性。与 CAA 对照组相比，APP 重复携带者的皮质表面铁沉积分布更为局限（0% vs 37.5%，p = 0.004，校正症状出现和 MRI 之间的时间延迟）。两名 APP 重复携带者发现了深部微出血。除了神经纤维缠结和老年斑外，所有 9 例尸检标本均显示 CAA 弥漫且严重，软脑膜血管增厚。2/9 例患者的黑质、蓝斑和皮质结构中发现了 Lewy 体，1 例患者基底节有血管淀粉样沉积物。
与 APP 重复相关的表型具有异质性，临床表现包括痴呆、出血和癫痫，影像学表现也不同，甚至在家族内也不同。未发现与重复大小有明显相关性。淀粉样蛋白负荷严重，广泛扩展到脑血管，这提示 MRI 和神经病理学数据的出血特征，使 APP 重复成为 CAA 的一个有趣模型。
