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，但关于Li如何提供治疗益处的共识很少。Li治疗通常通过测量血清浓度来监测。血清浓度测量相对容易且便宜，但在治疗范围内的治疗失败是常见的，神经毒性是一个持续的问题。脑锂浓度的测量应更好地反映其生物化学可用性，临床治疗和毒性，并有助于确定锂的治疗作用和神经毒性的机制。在体7 Li磁共振波谱（7 Li magnetic resonance spectroscopy，MRS）是一种无创的直接测量脑内Li浓度的方法。但是，测量整个大脑中锂的浓度只是第一步。关于Li在大脑中的环境知之甚少，特别是其细胞内与细胞外（i/e）的比例。由于大多数生化过程发生在细胞内，因此通常推测Li在大脑神经元的细胞内空间发挥其临床相关作用。内和细胞外锂通常不能区分7 Li MRS。但局部横向（T2）自旋弛豫测量可以区分内和细胞外锂在体内通过观察双指数弛豫曲线，其中两个组件代表阳离子与不同的T2内和细胞外环境。我们假设，在体内的细胞内的Li T2是显着低于细胞外的Li T2 ;在体内的7 Li T2衰减的测量将导致双指数行为，由于区室化，并允许的Li i/e比的测定。我们的具体目标是：1）使用T2的局部7 Li MRS测量直接从观察到的双指数行为估计体内大鼠脑中的细胞内与细胞外Li的比率; 2）通过在输注甘露醇以破坏血脑屏障和基于铥的化合物以分离两种信号之后测量分离的细胞内和细胞外7 Li信号来确认细胞内和细胞外信号的识别。拟议的研究结果将提供大脑中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。本研究的结果将提供数据证明的原理，使用近似插值方法，可以扩展到估计的i/e比在人脑中的锂。了解Li在人脑中的i/e比将有助于深入了解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）是双相情感障碍的重要治疗方法，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方式可以带来更有效的治疗。该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.