Studies in Dementia and Neurodegenerative Diseases

治疗阿尔茨海默病(AD)的埃克塞那肽。与NIA神经科学、临床研究和行为神经科学实验室的研究人员合作，我设计并继续进行了一项试点第二阶段(N=40)、双盲、随机、安慰剂对照的临床试验，以评估埃克塞那肽在早期AD患者中的安全性和耐受性。到目前为止，已有24名参与者入选，其中13人符合所有纳入标准(包括接受MCI/早期AD的临床诊断，表现出适当的认知能力障碍，并患有脑脊液抗体(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。1名参与者达到了18个月的终点，2名患者因协议规定的标准而退出，10名患者继续治疗。 开发新的AD生物标志物。与LNS的Mark Mattson博士一起，我们倡导这样的观点：新皮质能量代谢异常、兴奋性和抑制性神经传递失衡，以及随之而来的功能连接性改变在AD的发病机制和决定其区域扩散中起重要作用(这一观点在《柳叶刀神经学》的一篇广泛的综述文章中提出)。因此，我一直在使用：磁共振波谱(MRS)以获得体内脑能量(葡萄糖浓度)、神经递质水平(谷氨酸和GABA)的测量结果；静息功能磁共振成像(FMRI)以获得大脑网络中内在功能连接的测量结果；以及脑脊液采样以获得脑淀粉样变性和神经变性的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、谷氨酸和GABA；默认模式网络中的功能连接；以及脑脊液Abeta(1-42)之间存在关联。 帕金森病(PD)患者的奖赏加工。人们越来越认识到，帕金森病的很大一部分发病率与非运动、行为和认知表现有关，如奖赏认知加工的障碍。此外，多巴胺激动剂可能会在奖赏过程中造成额外的损害，最终导致冲动控制障碍，如病态赌博。我通过一项TMS/Behavior的联合研究为这一领域做出了贡献，该研究表明：PD患者没有与奖励期望相关的生理皮质信号，并通过TMS进行测量；使用普拉克索恢复这一信号；使用左旋多巴和普拉克索均可增加冒险行为；当患者服用普拉克索时，风险承担增加与奖励TMS信号之间的相关性。这项研究发表在《运动障碍》杂志上。 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，我们发表了我们在额颞叶痴呆队列中C9ORF72扩展的发现。此外，我们合作撰写了一篇综述文章，讨论额颞部痴呆和肌萎缩侧索硬化症之间的临床、病理和遗传联系。

Exenatide for the treatment of Alzheimer's Disease (AD). In collaboration with researchers from the NIA Laboratories of Neurosciences, Clinical Investigations and Behavioral Neurosciences, I designed and continue to conduct a pilot Phase II (N = 40), double blind, randomized, placebo-controlled, clinical trial to assess the safety and tolerability of exenatide treatment in participants with early AD. To this date, 24 participants have been enrolled, out of which 13 fulfilled all inclusion criteria (including receiving clinical diagnosis of MCI/early AD, showing appropriate impairment in cognitive performance and having cerebrospinal fluid Ab(1-42) < 192 pg/dl) and were started on treatment with the study drug (exenatide or placebo). One participant reached the 18-month end-point, 2 were withdrawn due to protocol-specified criteria, and 10 continue treatment. Developing novel AD biomarkers. Together with Dr. Mark Mattson from LNS, we advocate the view that abnormalities in neocortical energy metabolism, imbalances in excitatory and inhibitory neurotransmission, and consequent changes in functional connectivity play important roles in AD pathogenesis and determine its regional spread (this view was presented in an extensive review article in Lancet Neurology). Consequently, I have been using: Magnetic Resonance Spectroscopy (MRS) to obtain in vivo measures on brain energetics (concentration of glucose), neurotransmitter levels (glutamate and GABA); resting fMRI to obtain measures of intrinsic functional connectivity within brain networks; and 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, glutamate and GABA in the precuneus; functional connectivity within the default mode network; and CSF Abeta(1-42). Reward processing in Parkinson's disease (PD). It is increasingly recognized that a significant portion of morbidity in PD is associated with non-motor, behavioral and cognitive, manifestations, such as impairments in the cognitive processing of rewards. Moreover, dopamine agonists may cause additional impairment in reward processing, culminating in impulse control disorders, such as pathological gambling. I contributed to the field with a combined TMS/behavioral study that showed: patients with PD do not have a physiologic cortical signal associated with reward expectation and measured with TMS; restoration of this signal with pramipexole; an increase in risk taking with both levodopa and pramipexole; a correlation between increased risk taking and the reward TMS signal when patients took pramipexole. The study was published at the journal "Movement Disorders". 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 addition, we collaborated in writing a review article on the clinical, pathological and genetic links between Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.