Hippocampus/Pituitary Ratio: an AD Brain Injury Marker?

描述（由申请人提供）： 下丘脑-垂体-肾上腺（HPA）内分泌轴的可能紊乱与长期大量饮酒引起的临床和行为病理学有关。(AD)研究报告了AD患者在酒精戒断期间皮质醇分泌水平异常高，以及地塞米松治疗后皮质醇昼夜分泌不受抑制。其他人发现这种神经内分泌异常在Wernicke-Korsakoff综合征病例中更常见，这表明可能与脑损伤有关。对灵长类动物的研究支持这一点，观察到长期高水平的血清皮质醇与海马组织的退化有关。注意到以前的研究，我们假设垂体体积的增加和海马体积的减少将确定一个长期的，活跃的，大量饮酒者的样本。从MRI扫描获得的体积测量，我们发现，一组最近，大量饮酒者与非饮酒对照组相比，垂体体积（H：P比）的比值降低。虽然有趣，但这项研究是在一个方便的样本中完成的。我们现在建议以前瞻性的方式进行并扩大这项调查，以确定降低的H：P体积比是否有效 作为AD受试者的状态标志。如果是这样，我们问：a）这是否表明饮酒或永久性结构变化的可逆生理后果，以及B）与高皮质醇血症相关的H：P比值降低，表明海马反馈的丧失是一种可能的生理机制？ 为了回答这些问题，我们将1）测量30名主动饮酒的AD测试受试者和30名匹配的非重度饮酒的非AD对照受试者的基线H：P体积比，2）在六个月的乙醇戒断后连续测量AD受试者的H：P体积比，和3）测量两组的基线和AD受试者的连续的昼夜唾液皮质醇分泌。从本研究中，我们期望开发有效的、前瞻性收集的数据，这些数据可以开始建立H：P体积比降低的临床和病理生理意义。我们相信，这一系列的调查将最终揭示一个重要方面的改变，由于持续的乙醇暴露，以及神经内分泌功能的恢复后，停止大量饮酒。

DESCRIPTION (provided by applicant): Possible disorders of the hypothalamic-pituitary-adrenal (HPA) endocrine axis have been implicated in both clinical and behavioral pathology resulting from the prolonged, heavy drinking of Alcohol Dependence. (AD) Studies report abnormally high levels of cortisol secretion during ethanol withdrawal as well as non-suppression of diurnal cortisol after dexamethasone in AD sufferers. Others found such neuro-endocrine abnormalities more frequently among Wernicke-Korsakoff Syndrome cases, suggesting a possible relation to brain injury. Studies from primates support this, observing chronically high levels of serum cortisol associated with degeneration of the hippocampal tissue. Noting previous research, we hypothesized that an increase in pituitary volume and a reduction in hippocampal volume would identify a sample of chronic, active, heavy drinkers. From volume measurements acquired by MRI scanning, we found that a decreased ratio of the hippocampus-to-pituitary volume (H:P ratio) characterized a group of recent, heavy drinkers as compared to a non-drinking control group. Although intriguing, this study was done in a convenience sample. We now propose to perform and extend this inquiry in a prospective fashion in order to establish whether a reduced H:P volume ratio serves as a state marker among AD subjects. If so, we ask a) does this indicate a reversible physiologic consequence of drinking or permanent structural change, and b) is reduced H:P ratio associated with hypercortisolemia, indicating loss of hippocampal feedback as a possible physiologic mechanism? To answer these questions, we will 1) measure baseline H:P volume ratios in 30, actively drinking, AD test subjects and in 30 matched, non-heavy drinking, non-AD control subjects, 2) measure H:P volume ratios serially in AD subjects after six months of ethanol abstinence, and 3) measure diurnal salivary cortisol secretion at baseline for both groups and serially for AD subjects. From this study we expect to develop valid, prospectively gathered, data that can begin to establish the clinical and patho-physiologic meaning of the decrease in the H:P volume ratio. We believe this line of investigation will ultimately shed new light on an important aspect of altered brain function due to sustained ethanol exposure as well as recovery of neuroendocrine functioning after cessation of heavy alcohol use.