Estimating Intracellular Lithium in Brain in vivo by 7Li MRS

描述（由申请人提供）：锂（Li）是治疗急性躁狂症和预防双相情感障碍复发的首选药物。尽管其广泛的临床应用和对其作用机制的广泛研究，但对Li如何提供治疗益处的看法却很少。Li治疗通常通过测定血清浓度来监测。血清浓度测量相对容易和便宜，但治疗范围内的治疗失败是常见的，神经毒性是一个持续的关注。脑内Li浓度的测定应能更好地反映其生化有效性、临床疗效和毒性，并有助于确定Li的治疗作用机制和神经毒性。体内7Li磁共振波谱（MRS）是一种直接测量脑内Li浓度的无创方法。但是测量整个大脑的Li浓度只是第一步。人们对脑内Li的环境知之甚少，特别是其细胞内与细胞外（i/e）的比值。由于大多数生化过程发生在细胞内，因此通常认为Li在大脑神经元的细胞内空间发挥其临床相关作用。胞内和胞外Li通常不能用7Li mrs来区分，但局部横向（T2）自旋弛豫测量可以通过观察双指数弛豫曲线来区分胞内和胞外Li，其中两个组分代表胞内和胞外环境中具有不同T2s的阳离子。我们假设体内细胞内Li T2明显低于细胞外Li T2；体内7Li T2衰变的测量将由于分隔导致双指数行为，并允许确定Li i/e比。我们的具体目标是：1)使用T2的定位7Li MRS测量，直接从观察到的双指数行为来估计大鼠脑内细胞内与细胞外Li的比例；2)通过测量输注甘露醇破坏血脑屏障后分离的细胞内和细胞外7Li信号以及一种以铥为基础的化合物分离这两种信号来确认细胞内和细胞外信号的识别。拟议研究的结果将提供大脑中Li的i/e比的首次体内测量。长期目标是测量人脑中Li的i/e比。本研究的结果将为使用近似插值方法的原理证明提供数据，该方法可以扩展到估计人脑中Li的i/e比。了解人脑中Li的i/e比值将有助于深入了解Li在双相情感障碍中的作用机制和神经毒性的潜在原因。公共卫生相关性：锂（Li）是治疗双相情感障碍的重要药物，双相情感障碍是一种毁灭性的精神疾病，约占人口的3%。了解锂的生物化学作用可以带来更有效的治疗。这个项目研究脑细胞中的锂，以更好地了解它是如何工作的。

DESCRIPTION (provided by applicant): Lithium (Li) is the treatment of choice for acute mania and for relapse prevention in bipolar disorder. Despite its widespread clinical use and extensive research into its mechanisms of action, there is little agreement about how Li provides therapeutic benefit. Li treatment is usually monitored by measuring the serum concentration. Serum concentrations are relatively easy and inexpensive to measure, but treatment failures in the therapeutic range are common and neurotoxicity is a constant concern. Measurement of brain Li concentration should better reflect its biochemical availability, clinical therapy, and toxicity and help identify Li's mechanisms of therapeutic action and neurotoxicity. In vivo 7Li magnetic resonance spectroscopy (MRS) is a noninvasive method for measuring directly the brain concentration of Li. But measurement of the overall brain Li concentration is only a first step. Little is known about the environment of Li in the brain, particularly its intracellular-to-extracellular (i/e) ratio. Because most biochemical processes occur within the cell, it is often presumed that Li exerts its clinically relevant effects in the intracellular space of neurons in the brain. Intra- and extracellular Li cannot normally be distinguished by 7Li MRS. But localized transverse (T2) spin relaxation measurements can distinguish intra- and extracellular Li in vivo by observing biexponential relaxation curves, where the two components represent cations with different T2s in the intra- and extracellular environments. We hypothesize that the intracellular Li T2 in vivo is significantly lower than the extracellular Li T2 ; measurement of the 7Li T2 decay in vivo will result in biexponential behavior due to compartmentation and permit the determination of the Li i/e ratio. Our Specific Aims are to: 1) use localized 7Li MRS measurements of T2 to estimate the ratio of intra- to extracellular Li in rat brain in vivo directly from the observed biexponential behavior; 2) confirm the identification of intracellular and extracellular signals by measuring the separate intra- and extracellular 7Li signals after infusion of mannitol to disrupt the blood-brain barrier and a thulium-based compound to separate the two signals. The results of the proposed study will provide the first in vivo measurements of the i/e ratio of Li in the brain. The long-term goal is to measure the i/e ratio of Li in human brain. The results of this study will supply data for demonstrating proof-of-principle for using an approximate interpolation method that could be extended to estimate the i/e ratio of Li in human brain. Knowledge of the i/e ratio of Li in human brain will provide insight into Li's mechanism(s) of action in bipolar disorder and potential causes of neurotoxicity. PUBLIC HEALTH RELEVANCE: Lithium (Li) is an important treatment for bipolar disorder, a devastating mental illness that occurs in about 3% of the population. Understanding how lithium works biochemically can lead to more effective treatment. This project studies lithium in brain cells to understand better how it works.