Uro-Coste E, Russano de Paiva G, Guilbeau-Frugier C, Sastre N, Ousset P J, da Silva N A, Lavialle-Guillotreau V, Vellas B, Delisle M-B
Service d'Anatomie Pathologique, CHU Rangueil and Faculté de Médecine Rangueil, France.
Clin Neuropathol. 2010 Jul-Aug;29(4):209-16. doi: 10.5414/npp29209.
After the interruption of the international multicenter Phase 2 clinical trial with active immunotherapy based on synthetic Abeta42 (AN1792), few reports about the neuropathological findings in those patients and those from the Phase 1 clinical trial were published. These reports described some pathological similarities among the patients such as a reduction in the burden of amyloid plaques, the reactions of microglia/macrophages and the persistence of neurofibrillary tangles and neuropil threads. In addition, a lymphocytic inflammatory infiltrate as well as white matter lesions were present in some cases with meningoencephalitis. In both animal models of vaccination, as well as some vaccinated patient samples, there appears to be a correlation between vaccination and hemorrhages. Subsequently, two series reports concerning 8 patients from the Phase 1 initial trial showed that immunization with Abeta42 seemed to result in clearance of amyloid plaques, but did not prevent progressive neurodegeneration and that it increased vessel wall amyloid angiopathy as well as cortical microhemorrhages. Recent clinical data gave further encouraging results regarding vaccination in humans demonstrating that long term follow-up of patients from the second clinical trial revealed reduced functional decline, at least, in antibody responders. Here we describe a patient diagnosed with Alzheimer's disease who also participated in the Phase 2 clinical trial. A neuropathological examination confirmed Alzheimer's disease without meningoencephalitis and revealed a severe amyloid angiopathy with frequent microhemorrhages, the decrease of amyloid load being difficult to ascertain. Our results are in agreement with previous studies and confirm the presence of severe amyloid angiopathy after vaccination. The latter may be a transient phenomenon depending on the degree of immune response and the pathological stage of the disease when the patient underwent treatment. In addition, our vaccinated case also demonstrated microhemorrhages and microinfarcts which were already noticed to occur with a higher density in immunized Alzheimer's disease patients.
基于合成β淀粉样蛋白42（AN1792）的主动免疫疗法的国际多中心2期临床试验中断后，关于这些患者以及1期临床试验患者神经病理学发现的报道很少。这些报道描述了患者之间的一些病理相似性，如淀粉样斑块负担减轻、小胶质细胞/巨噬细胞反应以及神经原纤维缠结和神经毡丝的持续存在。此外，在一些脑膜脑炎病例中存在淋巴细胞炎性浸润以及白质病变。在疫苗接种的动物模型以及一些接种疫苗的患者样本中，疫苗接种与出血之间似乎存在关联。随后，关于1期初始试验中8名患者的两份系列报告显示，用β淀粉样蛋白42免疫似乎导致淀粉样斑块清除，但并未阻止进行性神经变性，并且增加了血管壁淀粉样血管病以及皮质微出血。最近的临床数据给出了关于人类疫苗接种的进一步令人鼓舞的结果，表明对第二次临床试验患者的长期随访显示至少在抗体应答者中功能衰退有所减轻。在此我们描述一名被诊断患有阿尔茨海默病且也参与了2期临床试验的患者。神经病理学检查证实为无脑膜脑炎的阿尔茨海默病，并显示出严重的淀粉样血管病且伴有频繁的微出血，淀粉样蛋白负荷的降低难以确定。我们的结果与先前的研究一致，并证实了疫苗接种后存在严重的淀粉样血管病。后者可能是一种短暂现象，取决于免疫反应的程度以及患者接受治疗时疾病的病理阶段。此外，我们的接种疫苗病例还显示出微出血和微梗死，在接种疫苗的阿尔茨海默病患者中已注意到这些情况以更高的密度出现。
