Studies in Dementia and Neurodegenerative Diseases

治疗阿尔茨海默病(AD)的埃克塞那肽。我继续进行概念验证第二阶段的双盲、随机、安慰剂对照临床试验，以评估埃塞那肽在MCI/早期AD参与者中的安全性和耐受性。到目前为止，已有30名参与者入选，其中16人符合纳入标准(MCI/早期AD的临床诊断，脑脊液抗体(1-42)和192pg/dl)，并开始接受研究药物(埃塞那肽或安慰剂)的治疗。8名参与者完成了研究，2名参与者退出了研究，6名继续接受治疗。 AD的预测因子和生物标志物。在与NIA生物统计学家拉里·布兰特的合作下，我检查了纵向跟踪的各种生理和实验室指标的表现，作为AD的预测因素。我们发现，血压、血脂和抑郁症状的纵向变化是未来AD诊断的重要预测因素，而且提前时间较长(这项研究目前正在《美国老年学会杂志》上进行综述)。此外，我对ADNI的AD和MCI患者的结构MRI图像实施了一种名为独立分量分析的数据约简技术，并研究了结构协方差模式如何预测临床诊断。这种方法使我们能够根据未来的诊断对受试者进行高度准确的分类(可以说，这是有史以来达到的最高水平)；这项研究目前正在发表在《衰老神经生物学》杂志上。此外，我在FDG-PET上研究了ADNI参与者的外周胰岛素抵抗与局部脑葡萄糖代谢的关系。我们发现，胰岛素抵抗与MCI阶段海马区代谢的不适应性增加有关，因此，促进了AD的发病(手稿目前正在准备中)。 与David Reiter博士合作，我在NIA 3T MRI设备中使用了一种新的磁共振波谱(MRS)方法，使我们能够在体内测量与AD发病相关的大脑代谢物(葡萄糖、乳酸)和神经递质(谷氨酸和GABA)。我在健康志愿者中进行了一项研究，将这些测量与静息功能磁共振相结合，后者提供了大脑功能连通性的测量，显示了这些神经递质水平和大脑连通性之间的联系。这项研究发表在《神经影像》杂志上。此外，基于MRS测量，我研究了大脑葡萄糖代谢和神经传递之间的关系；这项研究目前正在《大脑研究》杂志上发表评论。我还检查了AD患者的认知表现与脑脊液炎症标志物之间的关系，发现较高的脑脊液IL-12预示着更好的认知；这项研究目前正在《神经炎症杂志》上进行综述。最后，我将MRS和fMRI与脑脊液采样相结合，获得了脑淀粉样变性和神经退行性变的Abeta和tau测量结果。这些联合横断面fMRI/MRS/CSF研究的初步(未发表)结果表明，楔前叶中的葡萄糖、乳酸、谷氨酸和GABA之间存在关联；默认模式网络中的功能连接；以及脑脊液生物标志物之间存在关联。 额颞叶变性的遗传学和表型特征研究。我与国家神经疾病和中风研究所和德克萨斯理工大学的研究人员合作，在一个封闭的额颞叶痴呆症队列中进行了基因研究。去年，我们在《衰老神经生物学》杂志上发表了我们在额颞部痴呆队列中对C9ORF72扩展的研究结果。此外，我还参与了FTD中的一项GWAS研究，该研究目前正在《自然遗传学》杂志上进行审查。

Exenatide for the treatment of Alzheimer's Disease (AD). I continued to conduct a proof of concept Phase II, double blind, randomized, placebo-controlled, clinical trial to assess the safety and tolerability of exenatide treatment in participants with MCI/early AD. To this date, 30 participants have been enrolled, out of which 16 fulfilled inclusion criteria (clinical diagnosis of MCI/early AD, cerebrospinal fluid Ab(1-42) < 192 pg/dl) and were started on treatment with the study drug (exenatide or placebo). Eight participants completed the study, two participants were withdrawn from the study, and 6 continue treatment. Predictors and biomarkers of AD. In collaboration with NIA biostatistician, Larry Brant, I examined the performance of various physiological and laboratory measures followed longitudinally as predictors for AD. We found that longitudinal changes in blood pressure, lipids and depressive symptoms are significant predictors of future AD diagnosis with long lead times (the study is currently under review in the Journal of the American Geriatrics Society). In addition, I implemented a data reduction technique called Independent Component Analysis to structural MRI images of subjects with AD and MCI from ADNI and studied how patterns of structural covariance predict clinical diagnosis. This approach allowed us to classify subjects according to their future diagnosis with a high degree of accuracy (arguably, the highest ever achieved); the study is currently under review in the journal Neurobiology of Aging. In addition, I studied how peripheral insulin resistance is associated with regional brain glucose metabolism on FDG-PET in ADNI participants. We found that insulin resistance is associated with a maladaptive increase in metabolism at the hippocampus during the MCI stage, therefore, promoting AD pathogenesis (manuscript is currently under preparation). In collaboration with 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. I conducted a study in healthy volunteers, in which I combined these measures with resting fMRI, which provides measures of brain functional connectivity, which showed a link between these neurotransmitter levels and brain connectivity. The study was pubmished in Neuroimage. In addition, based on MRS measures, I examined the association between brain glucose metabolism and neurotransmission; the study is currently under review in the journal Brain Research. I also examined the association between cognitive performance in AD and CSF inflammatory markers and found that higher CSF IL-12 predicts better cognition; this study is currently under review in the Journal of Neuroinflammation. Finally, I combined MRS and fMRI with CSF sampling to obtain Abeta and tau measures of brain amyloidosis and neurodegeneration. Preliminary (unpublished) results from these combined cross-sectional fMRI/MRS/CSF studies suggest the presence of associations between: glucose, lactate, glutamate and GABA in the precuneus; functional connectivity within the default mode network; and CSF biomarkers. Genetic and phenotypic characterization studies in Frontotemporal Lobar Degeneration. I collaborated with researchers from the National Institute of Neurological Disorders and Stroke and Texas Tech University to perform genetic studies in a closed Frontotemporal Dementia cohort. This last year, we published our findings of C9ORF72 expansions in our Frontotemporal Dementia cohort in Neurobiology of Aging. In addition, I contributed to a GWAS study in FTD, which is currently under review in Nature Genetics.