Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer's disease
Persistent neuropathological effects 14 years following amyloid-β immunization in Alzheimer's disease
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DOI：
10.1093/brain/awz142
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发表时间：
2019-07-01
期刊：
影响因子：
14.5
通讯作者：
Boche, Delphine
中科院分区：
文献类型：
--
作者：
Nicoll, James A. R.;Buckland, George R.;Boche, Delphine
我们对首次试验β淀粉样蛋白免疫疗法治疗阿尔茨海默病的患者进行了15年的死后神经病理学随访。研究了活性淀粉样蛋白β（42）免疫（AN 1792，Elan Pharmaceuticals）或安慰剂的临床试验的22名参与者。在试验后4个月至15年进行了全面的死后神经病理学评估。我们分析了从大脑皮质去除淀粉样蛋白β的地形分布与tau病理学、脑血管区域、血浆抗AN 1792抗体滴度和晚期认知状态之间的关系。22名参与者中有17名（77%）患有阿尔茨海默氏神经病理学变化，而22名参与者中有5名（23%）患有痴呆症的替代原因（进行性核上性麻痹= 1，路易体病= 1，血管性脑损伤= 1，额颞叶变性= 2）。22名参与者中有19名接受了活性药物，3名接受了安慰剂。16例接受活性剂治疗的阿尔茨海默病患者中有14例（88%）有斑块清除的证据（非常广泛清除= 5例，中度清除= 4例，非常有限清除= 5例，未清除= 2例）。特别值得注意的是，两名在免疫接种后14年死亡的阿尔茨海默病患者在所有检查的区域中只有非常稀疏或不可检测的斑块。接种后外周血抗AN 1792抗体滴度与死后斑块评分之间存在显著负相关（rho =-0.664，P = 0.005）。清除斑块的皮质病灶比保留斑块的皮质含有更少的tau，但缠结的总体分布广泛（Braak V/VI）。总之，阿尔茨海默病患者积极免疫β淀粉样蛋白可以保持14年几乎没有斑块。斑块清除的程度与免疫反应有关。这种长时间的有效性对于支持主动免疫方案作为治疗或潜在预防神经变性相关蛋白质积累是重要的。在阿尔茨海默病治疗试验中纳入无阿尔茨海默病的患者是评估治疗效果的一个问题。尽管阿尔茨海默病的病理改变，但大多数患者已经进展为严重痴呆，特别是包括五名具有非常广泛的斑块去除的患者，这可能是由于持续的tau传播。治疗试验中患者的神经病理学随访提供了有关痴呆症病因和治疗效果的有价值信息。
We performed a 15-year post-mortem neuropathological follow-up of patients in the first trial of amyloid-beta immunotherapy for Alzheimer's disease. Twenty-two participants of a clinical trial of active amyloid-beta(42) immunization (AN1792, Elan Pharmaceuticals) or placebo were studied. Comprehensive post-mortem neuropathological assessments were performed from 4 months to 15 years after the trial. We analysed the relationships between the topographical distribution of amyloid-beta removal from the cerebral cortex and tau pathology, cerebrovascular territories, plasma anti-AN1792 antibody titres and late cognitive status. Seventeen of 22 (77%) participants had Alzheimer's neuropathological change, whereas 5 of 22 (23%) had alternative causes for dementia (progressive supranuclear palsy = 1, Lewy body disease = 1, vascular brain injury = 1, and frontotemporal lobar degeneration = 2). Nineteen of the 22 participants had received the active agent, three the placebo. Fourteen of 16 (88%) patients with Alzheimer's disease receiving the active agent had evidence of plaque removal (very extensive removal = 5, intermediate = 4, very limited = 5, no removal = 2). Of particular note, two Alzheimer's patients who died 14 years after immunization had only very sparse or no detectable plaques in all regions examined. There was a significant inverse correlation between post-vaccination peripheral blood anti-AN1792 antibody titres and post-mortem plaque scores (rho = - 0.664, P = 0.005). Cortical foci cleared of plaques contained less tau than did cortex with remaining plaques, but the overall distribution of tangles was extensive (Braak V/VI). In conclusion, patients with Alzheimer's disease actively immunized against amyloid-beta can remain virtually plaque-free for 14 years. The extent of plaque removal is related to the immune response. This long duration of efficacy is important in support of active immunization protocols as therapy for, or potentially prevention of, neurodegeneration-associated protein accumulations. Inclusion of patients without Alzheimer's disease in Alzheimer's therapy trials is a problem for assessing the efficacy of treatment. Despite modification of Alzheimer's pathology, most patients had progressed to severe dementia, notably including the five with very extensive plaque removal, possibly due to continued tau propagation. Neuropathology follow-up of patients in therapeutic trials provides valuable information on the causes of dementia and effects of treatment.