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防止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，但对于LI如何提供治疗益处，人们几乎没有达成一致意见。LI治疗通常通过测量血清浓度来监测。血药浓度的测量相对容易且成本低廉，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问题。脑中Li浓度的测定应更好地反映其生物化学可利用性、临床治疗和毒性，并有助于确定Li的治疗作用和神经毒性机制。体内7Li磁共振波谱(MRS)是一种无创性的直接测量脑内Li浓度的方法。但测量整个大脑的锂浓度只是第一步。对于LI在大脑中的环境，特别是它的细胞内/细胞外(i/e)比率，人们知之甚少。因为大多数生化过程发生在细胞内，所以通常认为LI在大脑神经元的细胞内空间发挥其临床相关作用。通常情况下，~7Li MRS不能区分细胞内和细胞外LI，但局部横向(T2)自旋弛豫测量可以通过观察双指数松弛曲线来区分活体细胞内和细胞外LI，其中两个组分代表细胞内外环境中具有不同T2的阳离子。我们假设，体内细胞内的Li T2显著低于细胞外的Li T2；测量体内的7Li T2衰变将由于分室而导致双指数行为，并允许确定Li I/e比率。我们的具体目标是：1)使用T2的局部7Li MRS测量，直接根据观察到的双指数行为估计大鼠脑内细胞内和细胞外LI的比率；2)通过测量注射甘露醇以破坏血脑屏障的细胞内和细胞外单独的7Li信号，以及通过测量一种基于稀土的化合物来分离这两个信号，来确认细胞内和细胞外信号的识别。这项拟议的研究结果将首次在体内测量锂在大脑中的i/e比率。长期目标是测量人脑中Li的i/e比率。这项研究的结果将为使用一种可推广的近似内插法估计人脑中LI/E比值的原理证明提供数据。了解Li在人脑中的i/e比率将有助于深入了解Li在双相情感障碍中的作用机制(S)以及神经毒性的潜在原因。与公共卫生相关：锂(Li)是治疗双相情感障碍的一种重要疗法，双相情感障碍是一种毁灭性的精神疾病，发生在大约3%的人口中。了解锂的生物化学原理可以导致更有效的治疗。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.