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岁及以上成年人痴呆症的最常见原因。未经检查， 到2050年，这种疾病将在美国和世界范围内达到流行病的程度，目前还没有 干预对AD进展有明显影响。在过去的几年里， 对锂在涉及神经变性的疾病中的再利用的兴趣增加。锂盐治疗 与海马的神经发生、重要神经营养因子的上调有关， 如B细胞淋巴瘤2（Bcl-2）和脑源性神经营养因子（BDNF），以及抑制糖原合成酶 激酶3（GSK-3）亚型α和β。特别是GSK-3α与γ-分泌酶相互作用，在细胞内起关键作用。 在淀粉样前体蛋白（APP）转化为淀粉样β蛋白（Aβ）的过程中;锂已被证明可以减少Aβ 在AD转基因小鼠模型中的生产和记忆缺陷。GSK-3β磷酸化tau蛋白，这是 神经元缠结的形成，并且锂已经显示出在体内和体内减少tau磷酸化。 体外锂可能会改变AD的轨迹，这一点得到了许多观察报告的支持，这些报告显示， 然而，少数几个人体锂试验的结果表明， 混合。需要进一步的研究来确定锂是否具有抗痴呆剂的作用。在 与以前的研究相比，我们将实施一项RCT，其方法比 在涉及最先进的超高场（7 T）人体MRI、神经认知评估和血液检查之前， 和基于CSF的生物标志物测量以研究锂作为抗痴呆剂的作用。具体 这项试点可行性研究的目的是检查锂在个体中的潜在疾病修饰特性 轻度认知障碍（MCI）延迟向痴呆症的转化。本研究将随机入组 分配80名60岁及以上MCI（遗忘型，单域或多域）患者服用锂， 滴定至最大耐受血液水平（0.5至0.8 meq/L），或安慰剂两年，以评估锂的作用 保持认知能力和延缓痴呆症的发生参与者将获得年度神经认知 评估、基于血液和CSF的生物标志物测量以及结构脑体积的7 T MR成像 (e.g.,海马，总皮质灰色）。基线时，所有受试者将接受Aβ PET成像。以下 将检验假设：H1：a）与安慰剂相比，随机接受锂治疗两年的受试者， 将更好地维持认知功能，主要是记忆，这B）将与以下变化有关： 生物标记（例如，GSK-3β、BDNF）。H2：a）与安慰剂相比，随机接受锂的受试者将 海马体积更大，总灰质变薄程度更低，这B）将与 c）更好的认知功能，主要是记忆力。探索性的目的是研究锂是否 与增强的脑完整性的附加标记物有关（例如，微出血水平较低，白色物质较高 完整性、更好的网络连接性或降低的CSF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).