Long-term effects of Aβ42 immunisation in Alzheimer's disease:: follow-up of a randomised, placebo-controlled phase I trial
Long-term effects of Aβ42 immunisation in Alzheimer's disease:: follow-up of a randomised, placebo-controlled phase I trial
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DOI：
10.1016/s0140-6736(08)61075-2
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发表时间：
2008-07-19
期刊：
影响因子：
168.9
通讯作者：
Nicoll, James A. R.
中科院分区：
文献类型：
--
作者：
Holmes, Clive;Boche, Delphine;Nicoll, James A. R.
背景
用全长β - 淀粉样肽（Aβ(42)）对阿尔茨海默病患者进行免疫接种可清除大脑中的淀粉样斑块。我们的目的是评估Aβ(42)免疫反应、斑块清除程度和长期临床结果之间的关系。
方法
2000年9月，80名患者（或其护理人员）参加了用Aβ(42)（AN1792，爱尔兰Elan制药公司）进行的I期随机、安慰剂对照免疫试验。2003年6月，征求这些患者（或其护理人员）同意进行长期临床随访、死后神经病理学检查，或两者皆进行。随访研究于2006年9月完成。通过Aβ免疫染色的皮质面积百分比（Aβ负荷）以及反映斑块清除的特征性组织学特征来评估斑块。用Cox比例风险模型评估所有80名个体直至严重痴呆或死亡的生存情况。
结果
20名参与者——AN1792组15名，安慰剂组5名——在随访开始前死亡。另有22名患者——AN1792组19名，安慰剂组3名——在随访期间死亡。9名死亡患者（均来自AN1792组）同意进行死后分析；其中1名并非死于阿尔茨海默病的患者被排除。在其余8名接受免疫接种并进行神经病理学检查的参与者中，平均Aβ负荷低于年龄匹配的未免疫对照组（接受治疗的参与者为2.1%[标准误0.7]，对照组为5.1%[0.9]；平均差异3.0%，95%置信区间0.6 - 5.4；p = 0.02）。尽管免疫接种的参与者之间Aβ负荷和斑块清除程度存在相当大的差异，但斑块清除程度与治疗研究期间达到的平均抗体反应显著相关（Kruskal - Wallis检验，p = 0.02）。8名接受免疫接种并进行死后评估的患者中，有7名（包括那些斑块几乎完全清除的患者）在死亡前患有严重的终末期痴呆。在整个队列中，没有证据表明AN1792组相对于安慰剂组生存情况有所改善（风险比0.93，95%置信区间0.43 - 3.11；p = 0.86），或发展至严重痴呆的时间有所改善（1.18，0.45 - 3.11；p = 0.73）。
解释
尽管用Aβ(42)进行免疫接种可导致阿尔茨海默病患者的淀粉样斑块清除，但这种清除并不能阻止进行性神经退行性变。
Background Immunisation of patients with Alzheimer's disease with full-length amyloid-beta peptide (A beta(42)) can clear amyloid plaques from the brain. Our aim was to assess the relation between A beta(42) immune response, degree of plaque removal, and long-term clinical outcomes.Methods In June, 2003, consent for long-term clinical follow-up, post-mortem neuropathological examination, or both, was sought from 80 patients (or their carers) who had entered a phase I randomised, placebo-controlled trial of immunisation with A beta(42) (AN1792, Elan Pharmaceuticals) in September, 2000. The follow-up study was completed in September, 2006. Plaques were assessed in terms of the percentage area of the cortex with A beta immunostaining (A beta load) and in terms of characteristic histological features reflecting plaque removal. Survival of all 80 individuals until severe dementia or death was assessed with a Cox proportional hazard model.Findings 20 participants-15 in the AN1792 group, five in the placebo group-died before follow-up started. A further 22 patients-19 in the AN1792 group, three in the placebo group-died during follow-up. Nine of the deceased patients, all in the AN1792 group, had given consent for post-mortem analysis; one of these who did not die with Alzheimer's disease was excluded. in the remaining eight participants who received immunisation and who were examined neuropathologically, mean A beta load was lower than in an unimmunised control group that was matched for age at death (2.1% [SE 0.7] in treated participants vs 5.1% [0.9] in controls; mean difference 3.0%, 95% CI 0.6-5.4; p=0.02). Although there was considerable variation in A beta load and degree of plaque removal among immunised participants, the degree of plaque removal varied significantly with mean antibody response attained during the treatment study period (Kruskal-Wallis p=0.02). Seven of the eight immunised patients who underwent post-mortem assessment, including those with virtually complete plaque removal, had severe end stage dementia before death. In the whole cohort, there was no evidence of improved survival (hazard ratio 0.93, 95% CI 0.43-3.11; p=0.86) or of an improvement in the time to severe dementia (1.18, 0.45-3.11; p=0.73) in the AN1792 group versus the placebo group.Interpretation Although immunisation with A beta(42) resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.