Abdullah Laila, Crawford Fiona, Tsolaki Magda, Börjesson-Hanson Anne, Olde Rikkert Marcel, Pasquier Florence, Wallin Anders, Kennelly Sean, Ait-Ghezala Ghania, Paris Daniel, Hendrix Suzanne, Blennow Kaj, Lawlor Brian, Mullan Michael
Roskamp Institute, Sarasota, FL, United States.
Archer Pharmaceuticals, Sarasota, FL, United States.
Front Neurol. 2020 Mar 6;11:149. doi: 10.3389/fneur.2020.00149. eCollection 2020.
We examined the effects of a dihydropyridine calcium channel blocker nilvadipine with anti-inflammatory properties on cognition and cerebrospinal fluid (CSF) biomarkers by baseline Alzheimer's disease (AD) severity. Exploratory analyses were performed on the dataset ( = 497) of a phase III randomized placebo-controlled trial to examine the response to nilvadipine in AD subjects stratified by baseline AD severity into very mild (MMSE ≥ 25), mild (MMSE 20-24) and moderate AD (MMSE < 20). The outcome measures included total and subscale scores of the Alzheimer's Disease Assessment Scale Cognitive 12 (ADAS-Cog 12), the Clinical Dementia Rating Scale sum of boxes (CDR-sb) and the AD composite score (ADCOMS). Cerebrospinal fluid biomarkers Aβ38, Aβ40, Aβ42, neurofilament light chain (NFL), neurogranin, YKL-40, total tau and P181 tau (ptau) were measured in a subset of samples ( = 55). Regression analyses were adjusted for confounders to specifically examine the influence of nilvadipine and baseline AD severity on cognitive outcomes over 78-weeks. Compared to their respective placebo-controls, nilvadipine-treated, very mild AD subjects showed less decline, whereas moderate AD subjects showed a greater cognitive decline on the ADAS-Cog 12 test and the ADCOMS. A lower decline was observed after nilvadipine treatment for a composite memory trait in very mild AD subjects and a composite language trait in mild AD subjects. Cerebrospinal fluid Aβ42/Aβ40 ratios were increased in mild AD and decreased in moderate AD patients treated with nilvadipine, compared to their respective controls. Among moderate AD subjects, levels of ptau, total tau, neurogranin and YKL-40 increased in subjects treated with nilvadipine compared to placebo. These studies suggest that baseline AD severity influenced the treatment outcome in the NILVAD trial and that future clinical trials of nilvadipine should be restricted to mild and very mild AD patients. NCT02017340 Registered 20 December 2013, https://clinicaltrials.gov/ct2/show/NCT02017340 EUDRACT Reference Number 2012-002764-27 Registered 04 February 2013, https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27.
我们根据阿尔茨海默病（AD）的基线严重程度，研究了具有抗炎特性的二氢吡啶类钙通道阻滞剂尼伐地平对认知和脑脊液（CSF）生物标志物的影响。对一项III期随机安慰剂对照试验的数据集（n = 497）进行探索性分析，以检查按基线AD严重程度分层为极轻度（MMSE≥25）、轻度（MMSE 20 - 24）和中度AD（MMSE < 20）的AD受试者对尼伐地平的反应。结局指标包括阿尔茨海默病评估量表认知部分12项（ADAS - Cog 12）的总分和子量表分数、临床痴呆评定量表框和（CDR - sb）以及AD综合评分（ADCOMS）。在一部分样本（n = 55）中测量了脑脊液生物标志物Aβ38、Aβ40、Aβ42、神经丝轻链（NFL）、神经颗粒素、YKL - 40、总tau和P181 tau（ptau）。进行回归分析以调整混杂因素，从而专门研究尼伐地平及基线AD严重程度对78周认知结局的影响。与各自的安慰剂对照相比，接受尼伐地平治疗的极轻度AD受试者衰退较少，而中度AD受试者在ADAS - Cog 12测试和ADCOMS上显示出更大的认知衰退。在极轻度AD受试者的复合记忆特征和轻度AD受试者的复合语言特征方面，尼伐地平治疗后观察到衰退较低。与各自的对照相比，接受尼伐地平治疗的轻度AD患者脑脊液Aβ42/Aβ40比值升高，中度AD患者则降低。在中度AD受试者中，与安慰剂相比，接受尼伐地平治疗的受试者ptau、总tau、神经颗粒素和YKL - 40水平升高。这些研究表明，基线AD严重程度影响了尼伐地平试验的治疗结果，并且未来尼伐地平的临床试验应限于轻度和极轻度AD患者。NCT02017340于2013年12月20日注册，https://clinicaltrials.gov/ct2/show/NCT02017340；欧盟临床试验注册号2012 - 002764 - 27于2013年2月4日注册，https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-002764-27。
