Measuring in Vivo Meth-induced Neurovascular Changes Using Quantitative MRI

描述(申请人提供)：据估计，全世界有2600万人滥用甲基苯丙胺。如此普遍的滥用以及随之而来的健康和社会后果，显然需要了解慢性冰毒导致成瘾和复发的长期神经和血管适应。冰毒暴露会干扰建立互联网络连接和连接所需的神经元和血管功能。血脑屏障(BBB)是血管-神经耦合的组成部分，对炎症机制特别敏感，血脑屏障的健康状况反映了神经血管的总体健康状况。急性接触大剂量冰毒会导致神经炎症和随后的血脑屏障通透性增加。然而，慢性冰毒诱导的神经炎症对神经血管健康的长期后果是冰毒成瘾的一个研究不足的领域。值得注意的是，这些问题还没有通过临床相关的冰毒成瘾啮齿动物模型来解决。我们的中心假设是，长期自我注射冰毒会导致持久的神经炎症，从而损害血脑屏障的神经-血管耦合。为了验证这一假设，我们将使用基于核磁共振的尖端神经成像技术来确定长期服用冰毒后炎症的进展。这些炎症反应可能是冰毒对神经血管单位的损害和随后的血脑屏障破坏的早期指标。我们将通过测量白质完整性和血脑屏障转移率来测量冰毒戒断期间冰毒诱导的神经元和血管完整性变化的时间进程，以绘制进行性组织损伤图。仅仅依靠组织学结果是不可能进行这些评估的。因此，终点结果将与内皮细胞和炎症标志物的组织学结果相关。成像实验旨在获取有关神经血管单位损伤的空间和时间模式的信息，为冰毒诱导适应的进展提供有价值的信息。此外，这项研究将为冰毒成瘾的诊断和治疗计划提供新的信息。

DESCRIPTION (provided by applicant): An estimated 26 million people abuse methamphetamine (meth) worldwide. This high prevalence of abuse and the ensuing health and societal consequences necessitates a clear need to understand the long-term neural and vascular adaptations caused by chronic meth that contribute to addiction and relapse. Meth exposure interferes with the neuronal and vascular function required to establish connectivity and wiring of interconnected networks. An integral part of vascular-neural coupling, the blood brain barrier (BBB), is particularly sensitive to inflammatory mechanisms and BBB health reflects the general health of neurovascular crosstalk. Acute exposure to high doses of meth results in neuroinflammation and subsequent increases in BBB permeability. However, the long-term consequence of chronic meth-induced neuroinflammation on neurovascular health is an understudied area of meth addiction. Notably, these issues have not been addressed using a clinically relevant rodent model of meth addiction. Our central hypothesis is that chronic self-administered meth results in lasting neuroinflammation that compromises neural-vascular coupling of the BBB. To test this hypothesis, we will use cutting edge magnetic resonance based neuroimaging techniques to identify the progression of inflammation following prolonged meth self-administration. These inflammatory responses may be early indicators for meth-induced damage to neurovascular units and subsequent break down of the BBB. We will measure the time course of meth-induced changes in neuronal and vascular integrity during abstinence from meth by measuring white matter integrity and BBB transfer rate to map progressive tissue damage. These assessments are not possible by relying solely on histological outcomes. Therefore, the end point results will be correlated with histological outcomes on endothelial and inflammatory markers. The imaging experiment is designed to acquire information about spatial and temporal patterns of damage to neurovascular unit providing valuable information on the progression of meth-induced adaptations. Further, this study will provide novel information for diagnostic and treatment planning for meth addiction.