Blennow Kaj, Zetterberg Henrik, Rinne Juha O, Salloway Stephen, Wei Jenny, Black Ronald, Grundman Michael, Liu Enchi
Clinical Neurochemistry Laboratory, Sahlgrenska Academy, University of Gothenburg, Mölndal, Sweden.
Arch Neurol. 2012 Aug;69(8):1002-10. doi: 10.1001/archneurol.2012.90.
Given the slow and variable clinical course of Alzheimer disease, very large and extended clinical trials are needed to identify a beneficial clinical effect of disease-modifying treatments. Therefore, biomarkers are essential to prove that an anti-β-amyloid (Aβ) drug candidate affects both Aβ metabolism and plaque load as well as downstream pathogenic mechanisms.
To evaluate the effect of the anti-Aβ monoclonal antibody bapineuzumab on cerebrospinal fluid (CSF) biomarkers reflecting Aβ homeostasis, neuronal degeneration, and tau-related pathology in patients with Alzheimer disease.
Two phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trials of 12-month duration.
Academic centers in the United States (Study 201) and England and Finland (Study 202).
Forty-six patients with mild to moderate Alzheimer disease.
Patients received either placebo (n = 19) or bapineuzumab (n = 27) in 3 or 4 ascending dose groups.
Changes between end of study and baseline in the exploratory CSF biomarkers Aβ1-42, AβX-42, AβX-40; total tau (T-tau); and phosphorylated tau (P-tau).
Within the bapineuzumab group, a decrease at end of study compared with baseline was found both for CSF T-tau (-72.3 pg/mL) and P-tau (-9.9 pg/mL). When comparing the treatment and placebo groups, this difference was statistically significant for P-tau (P = .03), while a similar trend for a decrease was found for T-tau (P = .09). No clear-cut differences were observed for CSF Aβ.
To our knowledge, this study is the first to show that passive Aβ immunotherapy with bapineuzumab results in decreases in CSF T-tau and P-tau, which may indicate downstream effects on the degenerative process. Cerebrospinal fluid biomarkers may be useful to monitor the effects of novel disease-modifying anti-Aβ drugs in clinical trials. TRIAL REGISTRATIONS clinicaltrials.gov Identifier: NCT00112073, EudraCT Identifier: 2004-004120-12, and isrctn.org Identifier: ISRCTN17517446.
鉴于阿尔茨海默病临床病程缓慢且多变，需要开展规模非常大且持续时间长的临床试验来确定疾病修饰治疗的有益临床效果。因此，生物标志物对于证明抗β淀粉样蛋白（Aβ）候选药物对Aβ代谢、斑块负荷以及下游致病机制均有影响至关重要。
评估抗Aβ单克隆抗体巴匹纽单抗对反映阿尔茨海默病患者Aβ稳态、神经元变性和tau相关病理的脑脊液（CSF）生物标志物的影响。
两项为期12个月的2期多中心随机双盲安慰剂对照临床试验。
美国的学术中心（研究201）以及英国和芬兰（研究202）。
46例轻度至中度阿尔茨海默病患者。
患者按3个或4个递增剂量组接受安慰剂（n = 19）或巴匹纽单抗（n = 27）治疗。
研究结束时与基线相比，探索性CSF生物标志物Aβ1-42、AβX-42、AβX-40；总tau蛋白（T-tau）；以及磷酸化tau蛋白（P-tau）的变化。
在巴匹纽单抗组内，研究结束时CSF T-tau（-72.3 pg/mL）和P-tau（-9.9 pg/mL）与基线相比均有所下降。在比较治疗组和安慰剂组时，P-tau的这种差异具有统计学意义（P = 0.03），而T-tau也呈现出类似的下降趋势（P = 0.09）。CSF Aβ未观察到明显差异。
据我们所知，本研究首次表明，巴匹纽单抗被动Aβ免疫疗法可使CSF T-tau和P-tau降低，这可能表明对退行性过程有下游效应。脑脊液生物标志物可能有助于在临床试验中监测新型疾病修饰抗Aβ药物的效果。试验注册 clinicaltrials.gov标识符：NCT00112073，EudraCT标识符：2004-004120-12，以及isrctn.org标识符：ISRCTN17517446。
