Williamson Nathan H, Ravin Rea, Cai Teddy X, Falgairolle Melanie, O'Donovan Michael J, Basser Peter J
National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
National Institute of General Medical Sciences, National Institutes of Health, Bethesda, MD 20892, USA.
PNAS Nexus. 2023 Feb 27;2(3):pgad056. doi: 10.1093/pnasnexus/pgad056. eCollection 2023 Mar.
For its size, the brain is the most metabolically active organ in the body. Most of its energy demand is used to maintain stable homeostatic physiological conditions. Altered homeostasis and active states are hallmarks of many diseases and disorders. Yet there is currently no direct and reliable method to assess homeostasis and absolute basal activity of cells in the tissue noninvasively without exogenous tracers or contrast agents. We propose a novel low-field, high-gradient diffusion exchange nuclear magnetic resonance (NMR) method capable of directly measuring cellular metabolic activity via the rate constant for water exchange across cell membranes. Exchange rates are s under normal conditions in viable ex vivo neonatal mouse spinal cords. High repeatability across samples suggest that values are absolute and intrinsic to the tissue. Using temperature and drug (ouabain) perturbations, we find that the majority of water exchange is metabolically active and coupled to active transport by the sodium-potassium pump. We show that this water exchange rate is sensitive primarily to tissue homeostasis and provides distinct functional information. In contrast, the apparent diffusion coefficient (ADC) measured with submillisecond diffusion times is sensitive primarily to tissue microstructure but not activity. Water exchange appears independently regulated from microstructural and oxygenation changes reported by ADC and relaxation measurements in an oxygen-glucose deprivation model of stroke; exchange rates remain stable for 30-40 min before dropping to levels similar to the effect of ouabain and never completely recovering when oxygen and glucose are restored.
就其体积而言，大脑是人体新陈代谢最活跃的器官。其大部分能量需求用于维持稳定的体内平衡生理状态。体内平衡改变和活跃状态是许多疾病和病症的标志。然而，目前尚无直接可靠的方法在不使用外源性示踪剂或造影剂的情况下，非侵入性地评估组织中细胞的体内平衡和绝对基础活性。我们提出了一种新型的低场、高梯度扩散交换核磁共振（NMR）方法，该方法能够通过跨细胞膜的水交换速率常数直接测量细胞代谢活性。在体外存活的新生小鼠脊髓正常条件下，交换速率为 s 。样本间的高重复性表明这些值是组织的绝对固有值。通过温度和药物（哇巴因）扰动，我们发现大部分水交换是代谢活跃的，并且与钠钾泵的主动转运相关。我们表明，这种水交换速率主要对组织体内平衡敏感，并提供独特的功能信息。相比之下，用亚毫秒级扩散时间测量的表观扩散系数（ADC）主要对组织微观结构敏感，而对活性不敏感。在中风的氧糖剥夺模型中，水交换似乎独立于 ADC 和弛豫测量所报告的微观结构及氧合变化进行调节；在氧和葡萄糖恢复之前，交换速率在 30 - 40 分钟内保持稳定，然后降至与哇巴因作用相似的水平，且在氧和葡萄糖恢复后从未完全恢复。
