Memory and Aging Center, Department of Neurology, University of California, San Francisco, United States.
Department of Epidemiology and Biostatistics, University of California, San Francisco, United States.
Neuroimage Clin. 2017 Sep 14;16:595-603. doi: 10.1016/j.nicl.2017.09.007. eCollection 2017.
Degradation of white matter microstructure has been demonstrated in frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD). In preparation for clinical trials, ongoing studies are investigating the utility of longitudinal brain imaging for quantification of disease progression. To date only one study has examined sample size calculations based on longitudinal changes in white matter integrity in FTLD.
To quantify longitudinal changes in white matter microstructural integrity in the three canonical subtypes of frontotemporal dementia (FTD) and AD using diffusion tensor imaging (DTI).
60 patients with clinical diagnoses of FTD, including 27 with behavioral variant frontotemporal dementia (bvFTD), 14 with non-fluent variant primary progressive aphasia (nfvPPA), and 19 with semantic variant PPA (svPPA), as well as 19 patients with AD and 69 healthy controls were studied. We used a voxel-wise approach to calculate annual rate of change in fractional anisotropy (FA) and mean diffusivity (MD) in each group using two time points approximately one year apart. Mean rates of change in FA and MD in 48 atlas-based regions-of-interest, as well as global measures of cognitive function were used to calculate sample sizes for clinical trials (80% power, alpha of 5%).
All FTD groups showed statistically significant baseline and longitudinal white matter degeneration, with predominant involvement of frontal tracts in the bvFTD group, frontal and temporal tracts in the PPA groups and posterior tracts in the AD group. Longitudinal change in MD yielded a larger number of regions with sample sizes below 100 participants per therapeutic arm in comparison with FA. SvPPA had the smallest sample size based on change in MD in the fornix (n = 41 participants per study arm to detect a 40% effect of drug), and nfvPPA and AD had their smallest sample sizes based on rate of change in MD within the left superior longitudinal fasciculus (n = 49 for nfvPPA, and n = 23 for AD). BvFTD generally showed the largest sample size estimates (minimum n = 140 based on MD in the corpus callosum). The corpus callosum appeared to be the best region for a potential study that would include all FTD subtypes. Change in global measure of functional status (CDR box score) yielded the smallest sample size for bvFTD (n = 71), but clinical measures were inferior to white matter change for the other groups.
All three of the canonical subtypes of FTD are associated with significant change in white matter integrity over one year. These changes are consistent enough that drug effects in future clinical trials could be detected with relatively small numbers of participants. While there are some differences in regions of change across groups, the genu of the corpus callosum is a region that could be used to track progression in studies that include all subtypes.
额颞叶变性（FTLD）和阿尔茨海默病（AD）中已经证实了白质微观结构的退化。为了进行临床试验，正在进行的研究正在探索使用纵向脑成像来量化疾病进展的效用。迄今为止，只有一项研究基于 FTLD 白质完整性的纵向变化来检查样本量计算。
使用扩散张量成像（DTI）量化三种典型额颞痴呆（FTD）亚型和 AD 的白质微观结构完整性的纵向变化。
研究了 60 名临床诊断为 FTD 的患者，包括 27 名行为变异额颞痴呆（bvFTD）患者、14 名非流利型原发性进行性失语症（nfvPPA）患者和 19 名语义变异型 PPA（svPPA）患者，以及 19 名 AD 患者和 69 名健康对照组。我们使用基于体素的方法，使用大约相隔一年的两个时间点，计算每个组中分数各向异性（FA）和平均扩散系数（MD）的年变化率。在 48 个基于图谱的感兴趣区域中，以及全球认知功能的平均变化率，用于计算临床试验的样本量（80%的功率，α 为 5%）。
所有 FTD 组均显示出统计学上显著的基线和纵向白质退化，bvFTD 组主要涉及额部束，PPA 组涉及额部和颞部束，AD 组涉及后部束。与 FA 相比，MD 的纵向变化产生了更多的样本量低于每个治疗臂 100 名参与者的区域。与 MD 相比，svPPA 的穹窿的样本量最小（每个研究臂 41 名参与者可检测到药物 40%的效果），nfvPPA 和 AD 的左侧上纵束的 MD 变化的样本量最小（nfvPPA 为 49 名，AD 为 23 名）。bvFTD 通常显示出最大的样本量估计（基于胼胝体的 MD，最小 n=140）。胼胝体似乎是一个可以包含所有 FTD 亚型的潜在研究的最佳区域。功能状态全球测量（CDR 框评分）的变化为 bvFTD 提供了最小的样本量（n=71），但与其他组相比，临床指标不如白质变化。
三种典型的 FTD 亚型在一年内均与白质完整性的显著变化相关。这些变化足够一致，以至于在未来的临床试验中，可以用相对较少的参与者来检测药物的效果。虽然各组之间的变化区域存在一些差异，但胼胝体的膝部是一个可以用于追踪所有亚型进展的区域。
