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Extracranial Brain Stimulation Reduces Metabolic Insufficiency Through Enhanced Cerebral Blood Flow in CVN-AD Alzheimer's Model

颅外脑刺激通过增强 CVN-AD 阿尔茨海默病模型中的脑血流量来减少代谢不足

基本信息

批准号：
10554248
负责人：
DENNIS Alan TURNER
金额：
$ 36.23万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10554248
关键词：
Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Animal Disease Models Animal Model Animals Behavioral Biological Markers Blood Vessels Blood capillaries Blood flow Brain Cells Cephalic Cerebrovascular Circulation Chronic Clinical Clinical Trials Deep Brain Stimulation Degenerative Disorder Dementia Disease Disease Progression Disease model Dose Electric Stimulation Electrodes Electroencephalography Etiology Frequencies Genotype Glucose Goals Hippocampus Human Hyperemia Impairment Lasers Link Measures Memory Metabolic Metabolic Marker Metabolic stress Metabolism Modeling Motor Motor Activity Mus Nerve Degeneration Neurons Outcome Outcome Assessment Penetration Phenotype Physiological Physiology Radial Schedule Senile Plaques Sensory Signal Transduction Skin Stroke Surrogate Markers Syndrome Testing Time Translating abnormally phosphorylated tau aged aging brain appropriate dose awake behavior test behavioral outcome cholinergic circadian conventional therapy cranium density disease phenotype dosage efficacious treatment electric field experimental study functional improvement gene therapy hemodynamics improved in vivo metabolomics mouse model neurological rehabilitation neuron loss neuropathology neuroregulation neurovascular neurovascular coupling pre-clinical predictive marker response spreading depression subcutaneous tau-1 translational approach translational model translational potential voltage

项目摘要

Alzheimer's disease is a progressive degenerative disorder of unclear etiology and disease-modifying treatments remain elusive. However, there are abnormalities in substrate delivery to the brain, altered capillary reactivity, neurovascular coupling, and hemodynamic responsiveness to metabolic stress, such as low glucose or spreading depression, in both the disease and animal models (CVN-AD). Our hypothesis is that transcranial alternating current electrical stimulation (tACS) can improve metabolic insufficiency in a dose dependent and dynamic manner in the CVN-AD animal model of Alzheimer's disease, modulating disease progression and degeneration. We will apply tACS through skull mounted electrodes first on a scheduled approach, comparing 10 and 40 Hz stimulation to enhance cerebral blood flow and improve substrate delivery to the brain, assisted by Dr.'s Peterchev and Schmidt. Further, we will test behavioral outcomes to assess the effects of chronic, scheduled tACS and sham tACS over 4 weeks, starting at the critical points of degeneration at 12 and 24 weeks of age in the CVN-AD model, assessing outcome with probe trial errors on a Barnes maze, cerebral blood flow, measures of neurodegeneration. As a second goal we will develop dynamic, metabolic need-based tACS, using closed loop approaches. Surrogate physiological markers will include electrical recordings, glucose recordings, and EEG signals of activity to augment blood flow in a dynamic manner to improve immediate metabolic substrate supply and reduce degeneration. These experiments will establish the feasibility and parameters to translate into initial human studies using either semi-permanent skull mounted or temporary skin electrodes. Since current density and intracranial penetration of tACS is limited in humans various translational strategies will be devised to include dynamic biomarkers and appropriate stimulation levels through subcutaneous electrodes.

阿尔茨海默病是一种病因不明的进行性退行性疾病，治疗仍然难以捉摸。然而，在向大脑的底物递送中存在异常，改变了毛细血管反应性、神经血管耦合和对代谢应激（如低血糖）的血流动力学反应性或扩散性抑郁症，在疾病和动物模型（CVN-AD）中。我们的假设是经颅交流电刺激（tACS）可以改善代谢功能不全，在阿尔茨海默病的CVN-AD动物模型中，以剂量依赖性和动态方式调节疾病进展和退化。我们将首先在预定的方法中通过颅骨安装电极应用tACS，比较10和40 Hz 刺激，以提高脑血流量和改善底物输送到大脑，协助博士。的彼得切夫和施密特。此外，我们将测试行为结果，以评估慢性，计划性的 tACS和假tACS超过4周，从12周龄和24周龄的变性临界点开始， CVN-AD模型，在巴恩斯迷宫上用探针试验误差评估结果，脑血流量，神经退行性变的指标作为第二个目标，我们将开发动态的、基于代谢需求的tACS，使用闭环方法。替代生理标志物将包括电记录、葡萄糖记录和活动的EEG信号，以动态的方式增加血流，以改善即时的代谢底物供应和减少变性。这些实验将建立可行性和参数，以转化为初步的人体研究使用半永久性颅骨安装或临时皮肤电极。由于电流密度和 tACS的颅内渗透在人类中是有限的，将设计各种翻译策略，包括动态生物标记和通过皮下电极的适当刺激水平。