Translational Imaging Department, Merck & Co., Inc., Rahway, NJ, USA.
Mallinckrodt Institute of Radiology, Washington University in St. Louis, St. Louis, MO, United States.
Neuroimage. 2024 Sep;298:120794. doi: 10.1016/j.neuroimage.2024.120794. Epub 2024 Aug 22.
Robust methods are needed for preclinical evaluation of novel Alzheimer Disease (AD) therapies to accelerate drug discovery. Quantitative Gradient Recalled Echo (qGRE) MRI has shown promise to provide insight into neurodegeneration in AD prior to atrophy development in humans, highlighting areas of low neuronal density. In this study a novel qGRE method (20 echoes, TE=2-40ms) is shown to non-invasively measure the longitudinal neuronal loss in the hippocampus of a mouse model of AD tauopathy Tg4510. Tg4510 (n=10) and wild type (WT, n=6) mice underwent MRI (7T field strength) at 3-7 months old. 3D qGRE approach was used to generate brain-specific R* maps free of magnetic field inhomogeneity artifacts. Light-sheet microscopy of the brains stained with NeuN and MBP served to visualize neuronal nuclei and myelin content respectively. Significant decrease in NeuN staining between 3mo and 5mo was observed in the hippocampus of Tg4510, validating the mouse AD model. Longitudinal analysis showed clear decreases in R* metric of qGRE signal in the Tg4510 mice hippocampus undergoing neurodegeneration between 3 and 5 months old. Histogram analysis revealed an upward trend in patterns of low R* value (Dark Matter, DM), and broadening of R* distribution. These were quantified as significant increase in both DM Volume Fraction (DMVF) and R* Standard Deviation (SD) in Tg4510 mice (p=0.004/p=0.016 DMVF/SD) but not in WT controls (p>0.25). Further monotonical increase was also observed in both metrics in time. A significant negative correlation was observed between the DMVF and myelin content (p=0.01, r=-0.76), suggesting sensitivity of the technique to the loss of myelinated axons. The presented qGRE technique, validated by histological measurements, can be readily applied as in vivo tool in preclinical models of neurodegeneration for pharmacodynamics and mechanism of action assessment.
需要稳健的方法来对新型阿尔茨海默病 (AD) 疗法进行临床前评估，以加速药物发现。定量梯度回波 (qGRE) MRI 已显示出在人类出现萎缩之前提供 AD 神经退行性变见解的潜力，突出了低神经元密度区域。在这项研究中，展示了一种新的 qGRE 方法（20 个回波，TE=2-40ms），可无创性测量 AD tau 病模型 Tg4510 小鼠海马体中的纵向神经元丢失。Tg4510（n=10）和野生型（WT，n=6）小鼠在 3-7 个月大时接受 MRI（7T 场强）检查。使用 3D qGRE 方法生成无磁场不均匀伪影的大脑特异性 R图。用 NeuN 和 MBP 染色的大脑的光片显微镜分别用于可视化神经元核和髓鞘含量。在 Tg4510 海马体中观察到 3mo 至 5mo 之间 NeuN 染色明显减少，验证了小鼠 AD 模型。纵向分析显示，在经历神经退行性变的 3 至 5 个月大的 Tg4510 小鼠海马体中，qGRE 信号的 R 测量值明显下降。直方图分析显示，低 R* 值（暗物质，DM）的模式呈上升趋势，R* 分布变宽。在 Tg4510 小鼠中，DM 体积分数（DMVF）和 R* 标准差（SD）均显著增加（p=0.004/p=0.016 DMVF/SD），而在 WT 对照组中则没有增加（p>0.25）。随着时间的推移，这两个指标也呈现出单调递增的趋势。DMVF 与髓鞘含量之间观察到显著负相关（p=0.01，r=-0.76），表明该技术对有髓轴突丢失敏感。通过组织学测量验证的所提出的 qGRE 技术可以作为神经退行性变临床前模型中的体内工具，用于药效学和作用机制评估。
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