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.

艾塞那肽治疗阿尔茨海默病（AD）。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，设计并继续进行一项II期试验（N = 40），双盲、随机、安慰剂对照的临床试验，以评估艾塞那肽治疗早期AD患者的安全性和耐受性。到目前为止，已有24名参与者入组，其中13名符合所有纳入标准（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，脑脊液Ab(1-42) < 192 pg/dl），并开始使用研究药物（艾塞那肽或安慰剂）进行治疗。1名受试者达到了18个月的终点，2名因方案规定的标准而退出，10名继续治疗。