Studies in Dementia and Neurodegenerative Diseases

痴呆症和神经退行性疾病研究

基本信息

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
项目类别：
财政年份：
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&apos 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

项目摘要

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.

阿尔茨海默氏病（AD）治疗的艾鉴定。我与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，我设计并继续进行试点II期（n = 40），双盲，随机，安慰剂对照，临床试验，以评估早期参与者的Exenatide治疗的安全性和耐受性。到目前为止，已有24名参与者被录取，其中13个符合所有纳入标准（包括接受MCI/早期AD的临床诊断，显示出适当的认知表现损害，并具有脑脊液AB（1-42）<192 PG/DL），并开始使用研究药物（Exenatide或Glosbo）进行治疗。一名参与者达到了18个月的终点，由于协议指定的标准而撤回了2个，而10个继续治疗。开发新颖的广告生物标志物。与LNS的马克·马特森（Mark Mattson）博士一起，我们主张了一种观点，即新皮质能量代谢异常，兴奋性和抑制性神经传递的失衡，以及随之而来的功能连通性在AD发病机理中起重要作用的变化在AD发病机理中起重要作用并确定其区域扩散（在Lancet神经学位的广泛评论文章中都提出了这一观点）。因此，我一直在使用：磁共振光谱（MRS）来获得有关脑能量（葡萄糖浓度），神经递质水平（谷氨酸和GABA）的体内测量；休息fMRI以获得大脑网络内固有功能连通性的度量；和CSF采样以获得脑淀粉样变性和神经变性的ABETA和TAU度量。这些联合横截面fMRI/MRS/CSF研究的初步（未发表）结果表明，葡萄糖，谷氨酸和GABA之间存在关联；默认模式网络中的功能连接；和CSF Abeta（1-42）。帕金森氏病（PD）中的奖励加工。越来越多地认识到，PD中很大一部分发病率与非运动，行为和认知，表现形式有关，例如奖励认知处理中的损害。此外，多巴胺激动剂可能在奖励处理中造成额外的损害，最终导致脉冲控制障碍（例如病理赌博）。我通过一项TMS/行为研究为该领域做出了贡献，该研究表明：PD患者没有与奖励期望的生理性皮质信号，并用TMS测量；用普拉克索恢复该信号； Levodopa和Pramipexole的风险增加；当患者服用pramipexole时，增加冒险和奖励TMS信号之间的相关性。该研究发表在《运动障碍》杂志上。额颞叶变性的遗传和表型表征研究。我与国家神经疾病与中风研究所和德克萨斯理工大学的研究人员合作，在封闭的额颞痴呆群中进行遗传研究。去年，我们在额颞痴呆群中发表了C9orf72扩展的发现。此外，我们在撰写了一篇有关额颞痴呆和肌萎缩性侧面硬化症之间的临床，病理和遗传联系的评论文章。