VALPROATE TRIAL

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心机构，不一定为研究者机构。这项研究代表了一种新的临床试验策略，旨在评估AD精神病理学的前瞻性“预防性”治疗，并评估可能改变AD病理生理学几个方面的方法，从而可能产生神经保护作用，这将通过监测疾病的临床进展以及相关生物标志物和成像数据进行评估。 本研究的主要目的是在一项随机化、安慰剂对照临床试验中证明丙戊酸盐长期治疗是否延迟可能患有阿尔茨海默病（AD）且在病程中尚未发生激越或精神病的门诊患者出现激越和/或精神病。 主要次要目的是确定长达2年的丙戊酸盐慢性治疗是否延迟了认知、功能、其他行为和整体疾病指标的进展。我们推测，积极治疗将导致这些措施的下降减缓。 其他次要目标：本研究将通过评估不良事件、共病事件、生命体征和实验室指标，探讨丙戊酸盐低剂量长期治疗相较于安慰剂的耐受性和安全性。我们假设积极治疗的耐受性良好。我们将测量生活质量中可能的药物-安慰剂差异。我们假设积极治疗将与更高的生活质量评分相关。我们将研究选择的生物标志物与阿尔茨海默病病理生理学的可能相关性，以及丙戊酸盐的假定作用机制。我们将对入组的一部分患者进行重复MRI扫描，以评估在脑体积测量中是否可能存在药物-安慰剂差异。(Note我们的UCI研究中心将不参与该MRI子研究）。我们假设特异性丙戊酸盐介导的生化改变与临床和结构成像反应相关。最后，我们将检查治疗两年后停用活性药物治疗与安慰剂治疗的效果。我们假设，从第24个月到第26个月，停用活性药物与安慰剂治疗在行为、认知、功能或疾病总体指标方面的变化不会产生差异。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This study represents a novel clinical trial strategy designed to assess both prospective "prophylactic" therapy for psychopathology in AD and also to assess an approach that may alter several aspects of the pathophysiology of AD, thereby perhaps resulting in neuroprotective effects, which would be assessed by monitoring clinical progression of illness as well as relevant biomarkers and imaging data. The primary objective of this study is to demonstrate in a randomized, placebo-controlled clinical trial whether chronic valproate therapy delays the emergence of agitation and/or psychosis in outpatients with probable Alzheimer's disease (AD) who have not yet experienced agitation or psychosis during the course of their illness. The chief secondary aim is to determine whether chronic valproate therapy for up to two years delays the progression of cognitive, functional, other behavioral, and global measures of illness. We hypothesize that active therapy will result in slowing of decline in these measures. Other secondary aims: The study will address the tolerability and safety of low-dose, long-term valproate therapy versus placebo by the assessment of adverse experiences, comorbid events, vital signs, and laboratory measures. We hypothesize that active treatment will be well tolerated. We will measure possible drug-placebo differences in quality of life. We hypothesize that active treatment will be associated with higher quality of life ratings. We will study biological markers selected for their possible relevance to the pathophysiology of Alzheimer's disease, as well as the postulated mechanism of action of valproate. We will conduct repeated MRI scans in a subset of patients enrolled to assess whether there may be possible drug-placebo differences in brain volumetric measurements. (Note that our UCI site will not participate in this MRI substudy). We hypothesize that specific valproate-mediated biochemical alterations will correlate with clinical and structural imaging responses. Finally, we will examine the effects of withdrawal of active treatment vs placebo treatment after two years of treatment. We hypothesize that withdrawal of active vs placebo treatment will not yield differences in change in behavioral, cognitive, functional, or global measures of disease from month 24 to month 26.