Holmes Clive, Boche Delphine, Wilkinson David, Yadegarfar Ghasem, Hopkins Vivienne, Bayer Anthony, Jones Roy W, Bullock Roger, Love Seth, Neal James W, Zotova Elina, Nicoll James A R
Division of Clinical Neurosciences, University of Southampton, Southampton, UK; Moorgreen Hospital, Hampshire Partnership Trust, Southampton, UK.
Lancet. 2008 Jul 19;372(9634):216-23. doi: 10.1016/S0140-6736(08)61075-2.
Immunisation of patients with Alzheimer's disease with full-length amyloid-beta peptide (Abeta(42)) can clear amyloid plaques from the brain. Our aim was to assess the relation between Abeta(42) immune response, degree of plaque removal, and long-term clinical outcomes.
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 Abeta(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 Abeta immunostaining (Abeta 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.
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 Abeta 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 Abeta 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.
Although immunisation with Abeta(42) resulted in clearance of amyloid plaques in patients with Alzheimer's disease, this clearance did not prevent progressive neurodegeneration.
用全长β-淀粉样肽（Aβ42）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Aβ42免疫反应、斑块清除程度与长期临床结局之间的关系。
2003年6月，我们向80名患者（或其护理人员）征求了长期临床随访、死后神经病理学检查或两者的同意，这些患者于2000年9月参加了一项用Aβ42（AN1792，伊兰制药公司）进行免疫接种的I期随机、安慰剂对照试验。随访研究于2006年9月完成。根据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对斑块进行评估。使用Cox比例风险模型评估所有80名个体直至出现严重痴呆或死亡的生存率。
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名已故患者均在AN1792组，他们已同意进行死后分析；其中一名并非死于阿尔茨海默病的患者被排除。在其余8名接受免疫接种并接受神经病理学检查的参与者中，平均Aβ负荷低于与死亡年龄匹配的未免疫对照组（治疗参与者为2.1%[标准误0.7]，对照组为5.1%[0.9]；平均差异3.0%，95%可信区间0.6 - 5.4；p = 0.02）。尽管免疫接种参与者的Aβ负荷和斑块清除程度存在很大差异，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名接受死后评估的免疫接种患者中有7名，包括那些几乎完全清除斑块的患者，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组与安慰剂组相比生存率有所提高（风险比0.93，95%可信区间0.43 - 3.11；p = 0.86）或出现严重痴呆的时间有所改善（1.18，0.45 - 3.11；p = 0.73）。
尽管用Aβ42进行免疫接种可使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。
