Citalopram as a posterior cortical protective therapy in Parkinson disease

摘要 PD伴痴呆（PDD）的生物学基础是异质性的，涉及多个认知领域， 具有挑战性的特点。额纹状体执行/注意力障碍是核心的早期特征， 受多巴胺能神经传递的影响当一种独特的视觉空间认知综合症-- 被认为是由非多巴胺能的变化介导的-开始实质上影响后 皮质区这些损伤的病理学基础是多种多样的，并涉及有毒的 错误折叠的神经元α-突触核蛋白沿着非突触核蛋白病变如β-淀粉样蛋白 （Abeta）斑块、tau聚集体和血管性认知障碍。这些的异质性 病理及其临床表现总结为“双重打击”假说：一个广为接受的，但 在目前的PD模型中，这是一个从未被测试过的原理。我们提出了一个概念验证PD 一项旨在延缓视空间认知能力下降的试验，这是PDD的关键组成部分。在帕金森病中， Abeta斑块水平-远低于阿尔茨海默病（AD）诊断阈值-与血清素相关 终端损耗这种特异性的阿糖胞苷-Abeta特征适用于PD，但不适用于AD。我们发表的多中心 PD观察结果显示，选择性5-羟色胺再摄取抑制剂（SSRI）与较低的PDD相关 转换风险和改变的CSF Abeta-42水平。我们的初步数据，使用Abeta匹兹堡化合物B (PiB)PD患者的正电子发射断层扫描（PET）显示2年视空间皮质Abeta斑块累积较少 并减少服用胆碱能药物的受试者的视觉空间认知下降，这可能改变了一个关键因素， PDD风险的仲裁者。我们的长期愿景是进行一项PD/PDD预防试验，其中西酞普兰将被 在与A β相关的认知能力下降之前开始。我们的中心假设是，西酞普兰在PD中的使用将减少 视觉空间皮质Abeta斑块累积，导致与以下相关的视觉空间认知下降的改善 PDD.我们的目的是在西酞普兰每日20 mg，持续2年的概念验证试验中检验这一假设。 无抑郁症的PD受试者（年龄≥65岁）（n=58）。在目标1中，我们将测试2年PiB PET累积的差异 在西酞普兰组和安慰剂组之间的视觉空间皮层中。在目标2中，我们将衡量 这种视空间皮层Abeta对视空间认知功能的干预。在目标3中，我们将测试 西酞普兰相对于安慰剂提供最小的临床重要的益处差异， 多领域认知的共同衡量标准，蒙特利尔认知评估，与PDD诊断有关。在 在这项研究的结论中，我们将有充分的数据集来评估我们严格的Go/No-Go标准， 这种安全和可推广的PDD预防疗法。我们还将进行分析（目标1、2和3）， 有助于证实或无效的双重打击模型的PD-PDD发病机制，一个显着的贡献 PD领域与其他阿尔茨海默氏病和相关痴呆症（ADRD）的影响，以及。

Abstract The biological basis of PD with dementia (PDD) is heterogeneous, involves multiple cognitive domains, and is challenging to characterize. Fronto-striatal executive/attentional impairments are core early features and are influenced by dopaminergic neurotransmission. PDD arises when a distinct visuospatial cognitive syndrome-- thought to be mediated by non-dopaminergic changes—begins to substantially affect the integrity of posterior cortical regions. The pathological substrates underlying these impairments are diverse and involve the toxic effects of misfolded neuronal alpha-synuclein along with non-synuclein pathologies such as Amyloid-beta (Abeta) plaques, tau aggregates, and vascular cognitive impairment. The heterogeneous nature of these pathologies and their clinical manifestations is summarized by the “dual-hit” hypothesis: a well-accepted but never-before-tested principle in current models of PDPDD pathogenesis. We propose a proof-of-concept PD trial aimed at delaying visuospatial cognitive decline, a critical component of PDD. In PD, low-range cortical Abeta plaque levels—well below the Alzheimer’s disease (AD) diagnostic threshold—associate with serotonin terminal losses. This specific serotonin-Abeta characteristic is true of PD but not AD. Our published multicenter PD observational findings show that selective serotonin reuptake inhibitors (SSRIs) associate with lower PDD conversion risk and altered CSF Abeta-42 levels. Our preliminary data, using Abeta Pittsburgh compound B (PiB) positron emission tomography (PET) in PD, show less 2-year visuospatial cortex Abeta plaque accrual and reduced visuospatial cognitive decline in subjects on serotoninergic medications, perhaps modifying a key arbiter of PDPDD risk. Our long-term vision is a PDPDD prevention trial, in which citalopram would be initiated prior to Abeta-linked cognitive decline. Our central hypothesis is that citalopram use in PD will reduce visuospatial cortex Abeta plaque accrual, leading to an amelioration of visuospatial cognitive decline linked to PDD. Our objective is to test this hypothesis in a proof-of-concept trial of citalopram 20mg daily over 2 years in PD subjects (age ≥65) without depression (n=58). In Aim 1, we will test differences in 2-year PiB PET accrual within the visuospatial cortex between citalopram and placebo groups. In Aim 2, we will measure the impact of this visuospatial cortex Abeta intervention upon visuospatial cognitive function. In Aim 3, we will test whether citalopram relative to placebo confers a minimal clinically important difference of benefit as assessed by a common measure of multi-domain cognition, the Montreal Cognitive Assessment, linked to PDD diagnosis. At the conclusion of this study, we will have well-powered dataset to assess our rigorous Go/No-Go criteria for this safe and generalizable PDD prevention therapy. We will also conduct analyses (Aims 1, 2, & 3) that will help to either substantiate or invalidate the dual-hit model of PDPDD pathogenesis, a significant contribution to the PD field with implications for other Alzheimer’s disease and related dementia (ADRD) conditions as well.