Studies in Dementia and Neurodegenerative Diseases

阿尔茨海默病（AD）的预测因子和生物标志物 在与UCSF的艾德·戈茨尔博士和其他研究人员的合作中，我们开发了一种方法，用于分离血液外泌体，并使用神经元表面标记物NCAM和L1 CAM通过免疫沉淀富集它们的神经元来源。到目前为止，我们已经进行了五项病例对照研究，测量外泌体Ab，tau，Ser和Tyr磷酸化IRS-1和其他蛋白质，在AD和对照受试者。我们发现了非常显著的差异，对于某些蛋白质，可以准确区分两组。此外，外泌体差异可能存在于临床前阶段，并可能预测AD。我发表了五篇关于这个主题的手稿（在阿尔茨海默氏症和痴呆症，FASEB J（两次），神经学和临床和转化神经学年鉴）。未来一年的一个主要目标是在来自巴尔的摩老龄化纵向研究（BLSA）、阿尔茨海默病神经影像学倡议（ADNI）、哈佛老龄化脑研究和WRAP（威斯康星州）的大型队列中验证外泌体标志物作为AD的诊断和预后生物标志物。BLSA、哈佛衰老脑研究和WRAP是评估这些标志物的纵向变化及其在临床前阶段预测AD、疾病进展和从MCI向AD转化的潜力的理想方法。 与NIA 3 T MRI设备经理大卫赖特博士合作，我在NIA 3 T MRI设备上采用了一种新的磁共振波谱（MRS）方法，该方法使我们能够获得与AD发病机制相关的脑代谢物（葡萄糖、乳酸盐）和神经递质（谷氨酸盐和GABA）的体内测量结果。首先，我对健康志愿者进行了一项研究，将MRS与静息功能磁共振成像结合起来，该研究提供了大脑功能连接的测量，并显示了神经递质水平与大脑连接之间的联系。这项研究发表在Neuroimage上。在MCI/AD患者和健康志愿者的病例对照研究中，我们发现与对照组相比，患者的葡萄糖和乳酸较高，谷氨酸和GABA较低，这表明这些MRS标记物可用作AD的诊断生物标志物。目前正在编写手稿。 我还研究了AD和CSF炎症标志物的认知表现和临床状态之间的关联，发现一种特定的促炎细胞因子IL-12水平较高，预示着更好的认知和更少的脑萎缩;这篇手稿目前正在审查中。 我们与法国里尔大学的Mohamad El Haj博士合作，在一组AD患者中与对照组相比，对过去和未来事件的自传体生成进行了三项研究。我们发现，与对照组相比，患者的未来和过去事件更相似，并且产生未来事件的能力与患者的情景记忆密切相关。此外，产生未来事件的能力与额叶功能相关。这些发现表明，记忆过去和想象未来依赖于共同的大脑结构，这两者在AD中都受到损害。我们在Neuropsychologia、Hippocampus和Journal of Alzheimer's disease杂志上发表了两项研究，描述了这些发现。此外，我们在《衰老研究评论》杂志上发表了两篇关于衰老和AD中的情景记忆以及对APOE的影响的系统综述。 AD治疗研究 我进行了一项概念验证II期、双盲、随机、安慰剂对照临床试验，以评估exendin-4（exendin）治疗轻度认知障碍（MCI）/早期AD参与者的安全性和耐受性。迄今为止，57名受试者已入组并开始接受研究药物（艾塞那肽或安慰剂）治疗。参与者接受研究药物治疗18个月，每6个月收集一次结局指标。16名参与者完成了研究，6名参与者退出了研究，6名继续参与。我的新年目标是达到40名参与者的入学目标。 我还继续在健康志愿者中进行一项双去甲环丝氨酸（一种选择性丁酰胆碱酯酶抑制剂）的I期、双盲、安慰剂对照、剂量递增、单次给药、安全性、耐受性和药代动力学研究。抑制丁酰胆碱酯酶是一种新型的对症治疗中/晚期AD的治疗方法。 最后，今年我们获得了IRB对间歇性热量限制（ICR）研究的最终批准，该研究实施5-2 CR（交替5天常规热量摄入和2天CR）。这是一项在超重中年受试者中进行的为期8周的5-2 CR研究，旨在评估对胰岛素抵抗、代谢、认知能力、fMRI活性和生物标志物的潜在有益作用。如果这项研究是积极的，ICR可能是中年AD一级预防的候选干预措施。

Predictors and biomarkers of Alzheimer's Disease (AD) In collaboration with Dr. Ed Goetzl from UCSF and other investigators, we developed a methodology for isolating blood exosomes and enriching them for neuronal origin by immunoprecipitation using neuronal surface markers NCAM and L1 CAM. To date, we have conducted five case control studies measuring exosomal Ab, tau, Ser and Tyr phosphorylated IRS-1, and other proteins, in AD and control subjects. We found highly significant differences that, for some proteins, accurately discriminate between the two groups. In addition, exosomal differences may be present at the preclinical stage and may predict AD. I published five manuscript on the topic (in the journals Alzheimer's and Dementia, FASEB J (twice), Neurology, and Annals of Clinical and Translational Neurology). One major goal for the coming year is to validate exosomal markers as diagnostic and prognostic biomarkers of AD in large cohorts from the Baltimore Longitudinal Study of Aging (BLSA), the Alzheimer's Disease Neuroimaging Initiative (ADNI), The Harvard Aging Brain Study, and the WRAP (Wisconsin). The BLSA, Harvard Aging Brain Study, and WRAP are ideal to assess longitudinal changes in these markers and their potential to predict AD at the preclinical stage, disease progression and conversion from MCI to AD. In collaboration with the NIA 3T MRI Facility manager, Dr. David Reiter, I have employed a novel Magnetic Resonance Spectroscopy (MRS) methodology at the NIA 3T MRI facility, which allows us to obtain in vivo measures on brain metabolites (glucose, lactate) and neurotransmitters (glutamate and GABA), which are relevant to AD pathogenesis. First, I conducted a study of healthy volunteers combining MRS with resting fMRI, which provides measures of brain functional connectivity, and showed a link between neurotransmitter levels and brain connectivity. The study was pubmished in Neuroimage. In a case-control study of patients with MCI/AD and healthy volunteers, we show higher glucose and lactate, and lower glutamate and GABA in patients compared to controls, suggesting that these MRS markers may be used as diagnostic biomarkers for AD. The manuscript is currently under preparation. I also studied the association between cognitive performance and clinical status in AD and CSF inflammatory markers and found that higher levels of one particular pro-inflammatory cytokine, IL-12, predicts better cognition and less brain atrophy; this manuscript is currently under review. In collaboration with Dr. Mohamad El Haj from University of Lille, France, we conducted three studies on autobiographical generation of past and future events in a cohort of AD patients compared to controls. We found that future and past events are more similar in patients compared to controls and that the ability to generate future events is closely related with the patient's episodic memory. In addition, the ability to generate future events was associated with Frontal Lobe functions. These findings suggest that remembering the past and imagining the future rely on common brain structures, which are both impaired in AD. We published two studies describing these findings in the journals Neuropsychologia, Hippocampus, and Journal of Alzheimer's disease. In addition, we published two systematic review on Episodic Memory in aging and AD, and on the effects on APOE in the journal Aging Research Reviews. Treatment studies in AD I conduct a proof of concept Phase II, double blind, randomized, placebo-controlled, clinical trial to assess the safety and tolerability of exendin-4 (exenatide) treatment in participants with Mild Cognitive Impairment (MCI)/early AD. To this date, 57 participants have been enrolled and started on treatment with study drug (exenatide or placebo). Participants receive study drug for 18 months and outcome measures are being collected every six months. Sixteen participants completed the study, six participants withdrew from the study, and six continue participation. My goal for the new year is to reach the enrollment target of forty participants. I also continue to conduct a Phase I, double-blind, placebo-controlled, ascending, single-dose, safety, tolerability and pharmacokinetic study of Bisnorcymserine, a selective butyrylcholinesterase inhibitor, in healthy volunteers. Inhibition of butyrylcholinesterase is a novel therapeutic approach for symptomatic treatment in moderate/advanced AD. Finally, this year we acquired final IRB approval for a study of Intermittent caloric restriction (ICR)implementing 5-2 CR (alternating 5 days of regular calorie intake and 2 days of CR). This is a 8-week study of 5-2 CR in overweight middle aged subjects to assess potential beneficial effects on insulin resistance, metabolism, cognitive performance, fMRI activity and biomarkers. If this study is positive, ICR may be a candidate intervention for primary prevention of AD at midlife.