Centre d'Imagerie Biomédicale, EPFL, Station 6, Lausanne 1015, Switzerland; Faculdade de Ciências da Universidade de Lisboa, Lisbon, Portugal.
Centre d'Imagerie Biomédicale, EPFL, Station 6, Lausanne 1015, Switzerland; Laboratoire d'Imagerie Fonctionnelle et Métabolique, EPFL, Lausanne, Switzerland.
Neuroimage. 2021 Jan 15;225:117498. doi: 10.1016/j.neuroimage.2020.117498. Epub 2020 Oct 24.
Brain glucose hypometabolism has been singled out as an important contributor and possibly main trigger to Alzheimer's disease (AD). Intracerebroventricular injections of streptozotocin (icv-STZ) cause brain glucose hypometabolism without systemic diabetes. Here, a first-time longitudinal study of brain glucose metabolism, functional connectivity and white matter microstructure was performed in icv-STZ rats using PET and MRI. Histological markers of pathology were tested at an advanced stage of disease. STZ rats exhibited altered functional connectivity and intra-axonal damage and demyelination in brain regions typical of AD, in a temporal pattern of acute injury, transient recovery/compensation and chronic degeneration. In the context of sustained glucose hypometabolism, these nonmonotonic trends - also reported in behavioral studies of this animal model as well as in human AD - suggest a compensatory mechanism, possibly recruiting ketone bodies, that allows a partial and temporary repair of brain structure and function. The early acute phase could thus become a valuable therapeutic window to strengthen the recovery phase and prevent or delay chronic degeneration, to be considered both in preclinical and clinical studies of AD. In conclusion, this work reveals the consequences of brain insulin resistance on structure and function, highlights signature nonmonotonic trajectories in their evolution and proposes potent MRI-derived biomarkers translatable to human AD and diabetic populations.
脑葡萄糖代谢低下被单独挑出来作为阿尔茨海默病 (AD) 的一个重要贡献者，可能也是主要诱因。侧脑室注射链脲佐菌素 (icv-STZ) 会导致脑葡萄糖代谢低下，而不会导致全身糖尿病。在这里，首次对 icv-STZ 大鼠进行了脑葡萄糖代谢、功能连接和白质微观结构的纵向研究，使用 PET 和 MRI 进行了研究。在疾病的晚期阶段测试了病理学的组织学标志物。STZ 大鼠表现出功能连接改变和脑内轴突损伤以及脱髓鞘，这些区域是 AD 的典型区域，呈现出急性损伤、短暂恢复/代偿和慢性退行性变的时间模式。在持续葡萄糖代谢低下的情况下，这些非单调趋势——在该动物模型的行为研究以及人类 AD 中也有报道——表明存在一种代偿机制，可能会招募酮体，从而允许对脑结构和功能进行部分和暂时修复。因此，早期的急性阶段可能成为一个有价值的治疗窗口，以加强恢复阶段并预防或延迟慢性退行性变，这在 AD 的临床前和临床研究中都需要考虑。总之，这项工作揭示了脑胰岛素抵抗对结构和功能的影响，强调了它们演变过程中的特征性非单调轨迹，并提出了潜在的 MRI 衍生的生物标志物，可转化为人类 AD 和糖尿病患者。
