Evaluation of Brain and Cognitive Changes in Older Adults with MCI Taking Lithium to Prevent Alzheimer Type Dementia

阿尔茨海默病(AD)是65岁及以上成年人中最常见的痴呆症原因。未选中时， 到2050年，疾病将在美国和世界范围内达到流行比例，目前还没有 干预已显示出对AD进展的明显效果。在过去的几年里，有 越来越多的人对锂在涉及神经退行性疾病的疾病中的用途进行再利用。锂治疗 与海马区的神经发生有关，上调重要的神经营养因子 作为B细胞淋巴瘤2(Bcl2)和脑源性神经营养因子(BDNF)和糖原合成酶的抑制 蛋白激酶3(GSK-3)是α和β的异构体。尤其是gsk-3α与伽马分泌酶的相互作用起着至关重要的作用。 在淀粉样前体蛋白(APP)向淀粉样β蛋白(Aβ)的转化中；锂被证明可以减少Aβ AD转基因小鼠模型的生产和记忆缺陷。葛兰素史克-3β磷酸化tau，这是 体内和体内研究表明，神经纤维缠结的形成和锂可以减少tau的磷酸化。 体外培养。锂可能改变AD轨迹的说法得到了大量观测报告的支持，这些报告表明锂可能会延迟 那些接受治疗的人会出现痴呆症。然而，进行的少数几项人体锂试验的结果是 好坏参半。还需要进一步的研究来确定锂是否具有抗痴呆剂的作用。在……里面 与以前的研究相比，我们将以更综合、更全面的方法实施RCT 在涉及最先进的超高场(7T)人体核磁共振、神经认知评估和血液- 和基于脑脊液的生物标记物测量，以研究锂作为抗痴呆剂的作用。具体的 这项试验性可行性研究的目的是检查锂在个体中潜在的疾病改善特性。 轻度认知障碍(MCI)可延缓转化为痴呆症。这项研究将随机报名 分配80名60岁及以上MCI(遗忘型、单或多个域)的人服用锂， 滴定到最大耐受血液水平(0.5meq/L)或安慰剂两年以评估锂的效果 关于保护认知和延缓转化为痴呆症。参与者将获得年度神经认知 脑结构体积的评估、基于血液和脑脊液的生物标记物测量和7T磁共振成像 (例如，海马区，总皮质灰质)。在基线时，所有受试者都将接受Aβ的正电子发射计算机断层扫描。以下是 假设将被检验：H1：A)参与者被随机服用锂两年，与安慰剂相比， 将更好地维持认知功能，主要是在记忆中，这将与 生物标志物(例如，葛兰素史克-3β、脑源性神经营养因子)。H2：a)与安慰剂相比，随机服用锂的参与者将 有更大的海马体体积和较低的总灰质变薄，这将与变化有关 生物标志物和c)更好的认知功能，主要是记忆。探索性的目标是检查锂是否 与增强大脑完整性的其他标志有关(例如，较低水平的微出血，较高的脑白质 完整性、更好的网络连通性或降低的脑脊液磷酸化tau水平)。

Alzheimer’s disease (AD) is the most common cause of dementia in adults 65 years and older. Unchecked, the disease will reach epidemic proportions in the United States and worldwide by 2050, and presently, there is no intervention that has shown a clear effect on AD progression. Over the past several years, there has been increasing interest in repurposing the use of lithium for diseases involving neurodegeneration. Lithium treatment has been associated with neurogenesis in the hippocampus, up-regulation of important neurotrophic factors such as B-cell lymphoma 2 (Bcl-2) and brain-derived neurotrophic factor (BDNF), and inhibition of glycogen synthase kinase 3 (GSK-3) isoforms α and β. In particular, GSK-3α interacts with gamma-secretase playing a critical role in the conversion of amyloid precursor protein (APP) to amyloid-beta (Aβ); lithium has been shown to reduce Aβ production and memory deficits in AD transgenic mouse models. GSK-3β phosphorylates tau, a critical step in the formation of neurofibrillary tangles, and lithium has been shown to reduce tau phosphorylation in vivo and in vitro. That lithium may alter the AD trajectory is supported by numerous observational reports showing delay of dementia onset in those treated with it. However, the results of the few human lithium trials conducted have been mixed. Additional research is needed to determine whether lithium has a role as an anti-dementia agent. In contrast to previous studies, we will implement an RCT with a more integrative, comprehensive approach than done before involving state-of-the-art ultra-high field (7T) human MRI, neurocognitive assessment, and blood- and CSF- based biomarker measurement to investigate the role of lithium as an anti-dementia agent. The specific aim of this pilot-feasibility study is to examine the potential disease modifying properties of lithium in individuals with mild cognitive impairment (MCI) in delaying conversion to dementia. The study will enroll and randomly assign 80 individuals 60 years and older with MCI (amnestic type, single or multiple domain) to take lithium, titrated to a maximally tolerated blood level (0.5 to 0.8 meq/L), or placebo for two years to assess lithium’s effects on preserving cognition and delaying conversion to dementia. Participants will receive annual neurocognitive assessment, blood- and CSF-based biomarker measurement, and 7T MR imaging of structural brain volumes (e.g., hippocampal, total cortical gray). At baseline, all subjects will undergo PET imaging for Aβ. The following hypotheses will be tested: H1: a) Participants randomized to take lithium for two years, compared to placebo, will better maintain cognitive function, primarily in memory, which b) will be associated with changes in biomarkers (e.g., GSK-3β, BDNF). H2: a) Participants randomized to take lithium, compared to placebo, will have larger hippocampal volumes and lower total gray matter thinning, which b) will be associated with changes in biomarkers and c) better cognitive function, primarily in memory. The exploratory aim examines whether lithium is related to additional markers of enhanced brain integrity (e.g., lower level of microbleeds, higher white matter integrity, better network connectivity, or decreased CSF phospho tau levels).