Adam J Schwarz, PhD, Takeda Pharmaceuticals, Ltd., 40 Landsdowne St., Cambridge MA 02139, USA Tel: (+1) 317 282 3557, Email:
J Prev Alzheimers Dis. 2024;11(1):38-47. doi: 10.14283/jpad.2023.92.
Longitudinal changes in volumetric MRI outcome measures have been shown to correlate well with longitudinal changes in clinical instruments and have been widely used as biomarker outcomes in clinical trials for Alzheimer's disease (AD). While instances of discordant findings have been noted in some trials, especially the recent amyloid-removing therapies, the overall relationship between treatment effects on brain atrophy and clinical outcomes, and how it might depend on treatment target or mechanism, clinical instrument or imaging variable is not yet clear.
To systematically assess the consistency and therapeutic class-dependence of treatment effects on clinical outcomes and on brain atrophy in published reports of clinical trials conducted in mild cognitive impairment (MCI) and/or AD.
Quantitative review of the published literature. The consistency of treatment effects on clinical and brain atrophy outcomes was assessed in terms of statistical agreement with hypothesized equal magnitude effects (e.g., 30% slowing of both) and nominal directional concordance, as a function of therapeutic class.
Interventional randomized clinical trials.
MCI or AD trial participants.
Treatments included were those that involved ingestion or injection of a putatively active substance into the body, encompassing both pharmacological and controlled dietary interventions.
Each trial included in the analysis reported at least one of the required clinical outcomes (ADAS-Cog, CDR-SB or MMSE) and at least one of the required imaging outcomes (whole brain, ventricular or hippocampal volume).
Data from 35 trials, comprising 185 pairwise comparisons, were included. Overall, the 95% confidence bounds overlapped with the line of identity for 150/185 (81%) of the imaging-clinical variable pairs. The greatest proportion of outliers was found in trials of anti-amyloid antibodies that have been shown to dramatically reduce the level of PET-detectable amyloid plaques, for which only 13/33 (39%) of observations overlapped the identity line. A Deming regression calculated using all data points yielded a slope of 0.54, whereas if data points from the amyloid remover class were excluded, the Deming regression line had a slope of 0.92. Directional discordance of treatment effects was also most pronounced for the amyloid-removing class, and for comparisons involving ventricular volume.
Our results provide a frame of reference for the interpretation of clinical and brain atrophy results from future clinical trials and highlight the importance of mechanism of action in the interpretation of imaging results.
体积 MRI 测量的纵向变化已被证明与临床仪器的纵向变化密切相关，并已被广泛用作阿尔茨海默病（AD）临床试验中的生物标志物结果。虽然在一些试验中已经注意到不一致的结果，特别是最近的淀粉样蛋白清除疗法，但治疗对脑萎缩和临床结果的影响之间的总体关系，以及它如何取决于治疗靶点或机制、临床仪器或成像变量尚不清楚。
系统评估在轻度认知障碍（MCI）和/或 AD 的临床试验发表报告中，治疗对临床和脑萎缩结果的影响的一致性和治疗类别依赖性。
对已发表文献进行定量综述。根据与假设的同等幅度效应（例如，两者都减慢 30%）和名义方向一致性的统计学一致性，评估治疗对临床和脑萎缩结果的影响的一致性，作为治疗类别的函数。
干预性随机临床试验。
MCI 或 AD 试验参与者。
包括将潜在活性物质摄入或注入体内的治疗方法，包括药理学和受控饮食干预。
纳入分析的每项试验均报告了至少一项必需的临床结果（ADAS-Cog、CDR-SB 或 MMSE）和至少一项必需的成像结果（全脑、脑室或海马体积）。
纳入了 35 项试验的数据，共包含 185 对比较。总体而言，95%置信区间与 150/185（81%）对成像-临床变量对的身份线重叠。在已证明可显著降低 PET 可检测淀粉样斑块水平的抗淀粉样蛋白抗体试验中发现了最多的离群值，其中只有 33/33（39%）的观察结果与身份线重叠。使用所有数据点计算的 Deming 回归得到斜率为 0.54，而如果排除淀粉样蛋白清除剂类别的数据点，则 Deming 回归线的斜率为 0.92。治疗效果的方向不一致也最明显的是淀粉样蛋白清除类，以及涉及脑室体积的比较。
我们的结果为未来临床试验中临床和脑萎缩结果的解释提供了参考框架，并强调了作用机制在解释成像结果中的重要性。
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