Studies in Dementia and Neurodegenerative Diseases

痴呆症和神经退行性疾病研究

• 批准号: 8552544
• 负责人: Dimitrios Kapogiannis
• 金额: $ 77.03万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8552544
• 关键词: Acetylcholine; Acetylcholinesterase; Advocate; Agonist; Alzheimer' s Disease; Amyloid beta-Protein; Amyloid deposition; Amyloidosis; Amyotrophic Lateral Sclerosis; Animal Model; Animals; Behavioral; Biological Markers; Brain; Brain-Derived Neurotrophic Factor; Butyrylcholinesterase; Caloric Restriction; Cerebrospinal Fluid; Clinic; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Collaborations; Community Outreach; Complement; Controlled Clinical Trials; Data; Dementia; Disease; Disease Progression; Dopamine Agonists; Dose; Double-Blind Method; Drug Kinetics; Energy Metabolism; Enrollment; Event; Frontotemporal Dementia; Frontotemporal Lobar Degenerations; Functional Magnetic Resonance Imaging; Genetic; Glucose; Glutamates; Goals; Health; Human; Impairment; Impulse Control Disorders; In Vitro; Intake; Journals; Laboratories; Levodopa; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measures; Memory Disorders; Metabolic; Metabolism; Morbidity - disease rate; Movement Disorders; National Institute of Neurological Disorders and Stroke; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurology; Neurons; Neurosciences; Neurotransmitters; Outcome; Oxidative Stress; Parkinson Disease; Participant; Pathogenesis; Pathological Gambling; Patients; Performance; Pharmaceutical Preparations; Phase; Physiological; Placebo Control; Placebos; Plasma; Play; Protocols documentation; Publishing; Randomized; Research Activity; Research Personnel; Rest; Rewards; Risk-Taking; Role; Safety; Sampling; Screening procedure; Senile Plaques; Signal Transduction; Specific qualifier value; Synapses; Synaptic plasticity; Texas; Therapeutic; Toxic effect; Universities; Work; Writing; base; clinical Diagnosis; cohort; design; disease diagnosis; exenatide; expectation; gamma-Aminobutyric Acid; glucagon-like peptide; healthy volunteer; improved; in vivo; inclusion criteria; inhibitor/antagonist; lectures; mild neurocognitive impairment; neocortical; neuroimaging; neuronal survival; neurotransmission; novel; novel therapeutic intervention; pramipexol; receptor; restoration; reward processing; scyllo-inositol; tau Proteins

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.

用于治疗阿尔茨海默病（AD）的艾塞那肽。与NIA神经科学实验室、临床研究和行为神经科学的研究人员合作，我设计并继续进行一项试验性II期（N = 40）、双盲、随机、安慰剂对照临床试验，以评估艾塞那肽治疗早期AD参与者的安全性和耐受性。到目前为止，已经招募了24名参与者，其中13名符合所有入选标准（包括接受MCI/早期AD的临床诊断，显示认知能力的适当损害和具有脑脊液Ab（1-42）< 192 pg/dl），并开始用研究药物（艾塞那肽或安慰剂）治疗。1名参与者达到了18个月的终点，2名参与者因方案规定的标准而退出，10名参与者继续治疗。 开发新的AD生物标志物。与LNS的Mark Mattson博士一起，我们主张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变化在AD发病机制中起重要作用并决定其区域传播（该观点在Lancet Neurology的一篇广泛综述文章中提出）。因此，我一直在使用：磁共振波谱（MRS）来获得大脑能量（葡萄糖浓度），神经递质水平（谷氨酸和GABA）的体内测量;静息功能磁共振成像来获得大脑网络内内在功能连接的测量;和CSF采样来获得脑淀粉样变性和神经变性的Abeta和tau测量。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;默认模式网络内的功能连接;和CSF Abeta（1-42）之间存在关联。 帕金森病（PD）的奖励处理。人们越来越认识到，PD的发病率的一个显着部分与非运动，行为和认知，表现，如奖励的认知处理的障碍。此外，多巴胺激动剂可能会导致额外的损害奖励处理，最终在冲动控制障碍，如病理性赌博。 我通过一项TMS/行为联合研究对该领域做出了贡献，该研究显示：PD患者没有与奖励预期相关的生理皮层信号，并使用TMS进行测量;使用普拉克索恢复了该信号;使用左旋多巴和普拉克索时风险承担增加;当患者服用普拉克索时，风险承担增加与奖励TMS信号之间存在相关性。这项研究发表在《运动障碍》杂志上。 额颞叶变性的遗传和表型特征研究。我与美国国家神经疾病和中风研究所以及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遗传研究。去年，我们发表了我们在额颞叶痴呆队列中C9 ORF 72扩增的发现。此外，我们还合作撰写了一篇关于额颞叶痴呆和肌萎缩侧索硬化症之间的临床、病理和遗传联系的综述文章。