First-in-human positron emission tomography study of intranasal insulin in aging and MCI

IF 6.8 Q1 CLINICAL NEUROLOGY
Kiran K. Solingapuram Sai, Jennifer M. Erichsen, Krishna K. Gollapelli, Ivan Krizan, Mack Miller, Naresh Damuka, Thomas C. Register, Courtney Sutphen, Suzanne Craft
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引用次数: 0

Abstract

Introduction

Intranasal insulin (INI) is being explored to treat Alzheimer's disease and other conditions. The method of intranasal delivery has been shown to affect outcomes, requiring validation prior to clinical investigation. We conducted a first-in-human positron emission tomography (PET) study using a novel radiotracer, [68Ga]Ga-NOTA-insulin, administered intranasally with a specialized device (Aptar Cartridge Pump System) to evaluate the kinetics of insulin uptake and distribution in the brain.

Methods

[68Ga]Ga-NOTA-insulin was intranasally administered (≈ 0.037 ± 0.001 GBq) to adults who were cognitively normal (CN, n = 7) or had mild cognitive impairment (MCI, n = 9). A dynamic 40 minute brain PET scan, followed by a 15 minute whole-body PET/computed tomography scan was acquired. Physiologic parameters were measured at baseline, during, and post-scan. Brain uptake and time-activity curves were determined for fused PET/magnetic resonance imaging images.

Results

Radiochemistry was optimized for producing [68Ga]Ga-NOTA-insulin with high radiochemical purity (> 99%) and molar activity (95 GBq/µmol). No safety issues were identified. PMOD analyses showed whole-brain average standard uptake value (SUV;g/mL) ≈ 0.68 ± 0.01; radioactivity in the brain and whole body were undetectable by 40 and 60 minutes post radiotracer administration respectively. Elevated (p < 0.01) SUVs averaged over the 40 minute period after INI administration were observed for 11 regions: olfactory cortex, hippocampus, parahippocampus, amygdala, superior and middle temporal pole, insula, caudate, putamen, thalamus, and anterior cingulum. Time-activity curves showed different uptake patterns for MCI and CN groups. Baseline pulse pressure, plasma insulin, and phosphorylated tau217 correlated with uptake for subgroups based on cognitive status and sex.

Discussion

[68Ga]Ga-NOTA-insulin is a safe and effective PET radiotracer for validating intranasal delivery of insulin to the brain in humans and revealed significant insulin uptake in multiple brain regions. Future studies should incorporate such validation before initiating clinical trials of intranasally administered agents. Further investigation of mechanisms underlying differences in INI uptake among clinical subgroups is also needed.

Highlights

  • Intranasal [68Ga]Ga-NOTA-insulin is a safe and effective positron emission tomography radiotracer in humans.
  • Intranasal insulin increased brain uptake in multiple regions for all participants.
  • Uptake varied by cognitive status, sex, vascular factors, and amyloid burden.
  • Our protocol provides a method to validate intranasal delivery devices for future trials.

Abstract Image

鼻内胰岛素在衰老和轻度认知损伤中的首次人体正电子发射断层扫描研究
鼻内胰岛素(INI)正在被探索用于治疗阿尔茨海默病和其他疾病。鼻内给药的方法已被证明会影响结果,需要在临床研究之前进行验证。我们进行了一项首次人体正电子发射断层扫描(PET)研究,使用一种新型放射性示踪剂[68Ga] ga - nota -胰岛素,用专门的装置(Aptar Cartridge Pump System)鼻内给药,以评估胰岛素在大脑中的摄取和分布动力学。方法对认知正常(CN, n = 7)或轻度认知障碍(MCI, n = 9)的成人鼻内给予[68Ga] ga - nota -胰岛素(≈0.037±0.001 GBq)。进行了40分钟的动态脑PET扫描,随后进行了15分钟的全身PET/计算机断层扫描。在基线、扫描期间和扫描后测量生理参数。脑摄取和时间-活动曲线被确定融合PET/磁共振成像图像。结果经放射化学优化,可生产高放射化学纯度的[68Ga] ga - nota -胰岛素(>;99%)和摩尔活性(95 GBq/µmol)。没有发现安全问题。PMOD分析显示全脑平均标准摄取值(SUV, g/mL)≈0.68±0.01;放射性示踪剂给药后40分钟和60分钟,脑和全身的放射性均未检测到。升高(p <;在给药后40分钟内观察到11个区域的平均suv:嗅觉皮质、海马、副海马、杏仁核、颞上极和中极、岛、尾状核、壳核、丘脑和前扣带。时间-活性曲线显示MCI组和CN组摄取模式不同。基线脉压、血浆胰岛素和磷酸化的tau217与基于认知状态和性别的亚组摄取相关。[68Ga]Ga-NOTA-insulin是一种安全有效的PET放射性示踪剂,用于验证人类经鼻给药胰岛素到大脑,并揭示了多脑区显著的胰岛素摄取。未来的研究应该在开始鼻内给药的临床试验之前纳入这样的验证。还需要进一步研究临床亚组间INI摄取差异的机制。鼻内[68Ga]Ga-NOTA-insulin是一种安全有效的人体正电子发射断层扫描示踪剂。鼻内胰岛素增加了所有参与者大脑多个区域的摄取。摄取因认知状态、性别、血管因素和淀粉样蛋白负荷而异。我们的方案为未来的试验提供了一种验证鼻内给药装置的方法。
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来源期刊
CiteScore
10.10
自引率
2.10%
发文量
134
审稿时长
10 weeks
期刊介绍: Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.
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