Therapeutic Effects of Intranasal Insulin in AD

鼻内胰岛素治疗AD的疗效

• 批准号: 7477639
• 负责人: SUZANNE CRAFT
• 金额: $ 37.47万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477639
• 关键词: Acute; Afferent Neurons; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Apolipoprotein E; Axon; Biological Markers; Brain; Bypass; Cerebrospinal Fluid; Cerebrum; Chronic; Clinical Trials; Cognition; Cognitive; Daily; Data; Dose; Drug Delivery Systems; Energy Metabolism; Environment; Functional disorder; Future; Genotype; Glucose; Glucose Transporter; Hippocampus (Brain); Hour; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Receptor; Insulin Resistance; Insulin-Like Growth Factor I; Intranasal Administration; Intravenous; Localized; Medial; Memory; Metabolic; Metabolism; Methodology; Nasal cavity; Neuraxis; Neurons; Neurosecretory Systems; Numbers; Participant; Pathogenesis; Pathology; Pathway interactions; Patients; Peptides; Performance; Peripheral; Persons; Pilot Projects; Placebos; Plasma; Play; Randomized; Rate; Research Personnel; Risk; Role; Safety; Signal Transduction; Spinal Puncture; Spinal Tap; Structure; Testing; Therapeutic Effect; Travel; Trigeminal System; cribriform plate; daily functioning; day; double-blind placebo controlled trial; extracellular; fluorodeoxyglucose positron emission tomography; frontal lobe; glucose metabolism; improved; novel therapeutics; olfactory bulb; programs; response; slow axonal transport; theories; treatment effect; young adult

DESCRIPTION (provided by applicant): The proposed randomized, double-blind, placebo-controlled trial will examine the effects of intranasal insulin administration on cognition, cerebral glucose metabolism, and p-amyloid (AP) for persons with Alzheimer's disease (AD). Growing evidence suggest that insulin's role in central nervous system energy metabolism is dysregulated in AD. Patients with AD have an increased risk of peripheral hyperinsulinemia and insulin resistance (reduced insulin efficiency) which down-regulate transport of insulin to the brain, and increase neuropathological features of AD. AD is associated with reduced CSF insulin levels, and intravenous insulin administration (while maintaining euglycemia) improves memory, possibly by augmenting low brain levels or by overcoming insulin resistance. Peripherally administered insulin is not a viable treatment, however, due to the risk of hypoglycemia. Intranasal administration of insulin may effectively raise CNS insulin levels without the risk of hypoglycemia. Following intranasal administration, rapid bulk flow transport of insulin occurs through extracellular pathways to brain structures supporting memory. Consistent with these findings, our preliminary data show that acute intranasal insulin administration improves verbal memory in persons with AD without inducing hypoglycemia. The proposed study will build on these findings to test the hypotheses that four months of treatment with intranasal insulin will: (1) improve cognition and daily function in patients with AD, compared to placebo; (2) increase glucose metabolism in regions that typically show reduced metabolic rates in patients with AD; and (3) modulate plasma and CSF Abeta and neuroendocrine markers. Participants will receive four months of treatment with placebo or one of two doses of insulin. A subset of participants will undergo fluorodeoxyglucose positron emission tomography (FDG PET) prior to, and at the end of treatment to determine whether intranasal insulin increases cerebral glucose metabolism. A subset of participants will also receive two baseline lumbar punctures (LPs) on separate days, 30-minutes after intranasal insulin or placebo administration to determine acute effects of insulin on CSF Abeta levels. After four months, CSF will be collected again to examine the effects of treatment on Abeta. The proposed study will provide valuable data regarding the safety, feasibility, and potential efficacy of this novel therapeutic approach and drug delivery methodology that can guide future large-scale clinical trials with insulin or other promising compounds. We will also obtain critical information about the overarching theory that lowered CNS insulin and peripheral insulin resistance contribute to AD pathophysiology.

描述（由申请人提供）：拟议的随机、双盲、安慰剂对照试验将检查鼻内胰岛素给药对阿尔茨海默病（AD）患者认知、脑葡萄糖代谢和β-淀粉样蛋白（AP）的影响。越来越多的证据表明，AD 患者中胰岛素在中枢神经系统能量代谢中的作用失调。 AD 患者外周高胰岛素血症和胰岛素抵抗（胰岛素效率降低）的风险增加，这会下调胰岛素向大脑的转运，并增加 AD 的神经病理学特征。 AD 与脑脊液胰岛素水平降低有关，静脉注射胰岛素（同时维持血糖正常）可以改善记忆力，这可能是通过增加低脑水平或克服胰岛素抵抗来实现的。然而，由于存在低血糖的风险，外周注射胰岛素并不是一种可行的治疗方法。鼻内注射胰岛素可有效提高中枢神经系统胰岛素水平，且无低血糖风险。鼻内给药后，胰岛素通过细胞外途径快速大量输送至支持记忆的大脑结构。与这些发现一致的是，我们的初步数据表明，急性鼻内胰岛素给药可改善 AD 患者的言语记忆，而不会引起低血糖。拟议的研究将建立在这些发现的基础上，检验以下假设：四个月的鼻内胰岛素治疗将：（1）与安慰剂相比，改善 AD 患者的认知和日常功能； (2) 增加 AD 患者代谢率通常降低的区域的葡萄糖代谢； (3) 调节血浆和脑脊液 Abeta 和神经内分泌标志物。 参与者将接受为期四个月的安慰剂或两剂胰岛素之一的治疗。一部分参与者将在治疗前和治疗结束时接受氟脱氧葡萄糖正电子发射断层扫描（FDG PET），以确定鼻内胰岛素是否会增加脑葡萄糖代谢。一部分参与者还将在不同的日子、鼻内胰岛素或安慰剂给药后 30 分钟接受两次基线腰椎穿刺 (LP)，以确定胰岛素对 CSF Abeta 水平的急性影响。四个月后，将再次收集脑脊液，以检查治疗对 Abeta 的效果。拟议的研究将提供有关这种新型治疗方法和药物输送方法的安全性、可行性和潜在功效的有价值的数据，可以指导未来胰岛素或其他有前途的化合物的大规模临床试验。我们还将获得有关降低中枢神经系统胰岛素和外周胰岛素抵抗导致 AD 病理生理学的总体理论的重要信息。