Mandino Francesca, Shen Xilin, Desrosiers-Grégoire Gabriel, O'Connor David, Mukherjee Bandhan, Owens Ashley, Qu An, Onofrey John, Papademetris Xenophon, Chakravarty M Mallar, Strittmatter Stephen M, Lake Evelyn M R
Department of Radiology and Biomedical Imaging, Yale School of Medicine, New Haven, CT, 06520, USA.
Computational Brain Anatomy Laboratory, Cerebral Imaging Center, Douglas Mental Health University Institute, Montreal, QC, H4H 1R3, Canada.
Mol Psychiatry. 2025 May;30(5):1730-1745. doi: 10.1038/s41380-024-02779-z. Epub 2024 Oct 18.
Amyloid accumulation in Alzheimer's disease (AD) is associated with synaptic damage and altered connectivity in brain networks. While measures of amyloid accumulation and biochemical changes in mouse models have utility for translational studies of certain therapeutics, preclinical analysis of altered brain connectivity using clinically relevant fMRI measures has not been well developed for agents intended to improve neural networks. Here, we conduct a longitudinal study in a double knock-in mouse model for AD (App/hMapt), monitoring brain connectivity by means of resting-state fMRI. While the 4-month-old AD mice are indistinguishable from wild-type controls (WT), decreased connectivity in the default-mode network is significant for the AD mice relative to WT mice by 6 months of age and is pronounced by 9 months of age. In a second cohort of 20-month-old mice with persistent functional connectivity deficits for AD relative to WT, we assess the impact of two-months of oral treatment with a silent allosteric modulator of mGluR5 (BMS-984923/ALX001) known to rescue synaptic density. Functional connectivity deficits in the aged AD mice are reversed by the mGluR5-directed treatment. The longitudinal application of fMRI has enabled us to define the preclinical time trajectory of AD-related changes in functional connectivity, and to demonstrate a translatable metric for monitoring disease emergence, progression, and response to synapse-rescuing treatment.
阿尔茨海默病（AD）中的淀粉样蛋白积累与突触损伤及脑网络连接性改变有关。虽然小鼠模型中淀粉样蛋白积累和生化变化的测量方法对某些治疗方法的转化研究有用，但对于旨在改善神经网络的药物，使用临床相关功能磁共振成像（fMRI）测量方法对改变的脑连接性进行临床前分析尚未得到充分发展。在此，我们在AD双敲入小鼠模型（App/hMapt）中进行了一项纵向研究，通过静息态fMRI监测脑连接性。虽然4个月大的AD小鼠与野生型对照（WT）小鼠没有区别，但相对于WT小鼠，AD小鼠在6个月大时默认模式网络中的连接性下降就很明显，到9个月大时则更为显著。在第二组相对于WT存在持续性AD功能连接缺陷的20个月大小鼠中，我们评估了用已知可挽救突触密度的mGluR5沉默变构调节剂（BMS - 984923/ALX001）进行两个月口服治疗的影响。针对mGluR5的治疗逆转了老年AD小鼠的功能连接缺陷。fMRI的纵向应用使我们能够确定AD相关功能连接变化的临床前时间轨迹，并证明了一种可转化的指标，用于监测疾病的出现、进展以及对突触挽救治疗的反应。
