Citalopram as a posterior cortical protective therapy in Parkinson disease

摘要 帕金森病合并痴呆(PDD)的生物学基础是异质性的，涉及多个认知领域，并且是 具有挑战性的刻画。额纹状体执行/注意障碍是早期的核心特征， 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征-- 被认为是由非多巴胺能变化介导的-开始实质上影响后部的完整性 皮质区域。这些损伤背后的病理基础是多样的，涉及到有毒的 错误折叠的神经元α-突触核蛋白与非突触核蛋白病理如淀粉样蛋白-β的作用 (Abeta)斑块、tau聚集体和血管认知障碍。它们的异构性 病理及其临床表现可用“双重命中”假说来概括：一种广为接受的但 在目前的帕金森病发病机制模型中，从未被测试过的原理。我们提出了一种概念验证PD 旨在延缓视觉空间认知衰退的试验，这是PDD的关键组成部分。在帕金森病中，低程皮质 Aβ斑块水平--远低于阿尔茨海默病(AD)诊断门槛--与5-羟色胺有关 终端损失。这种特殊的5-羟色胺-Aβ特征适用于帕金森病，但不适用于阿尔茨海默病。我们发布的多中心 帕金森病的观察结果表明，选择性5-羟色胺再摄取抑制剂(SSRI)与较低的PDD有关 转换风险和改变的脑脊液Abeta-42水平。我们的初步数据，使用Abeta匹兹堡化合物B (PIB)正电子发射断层扫描(PET)显示帕金森病患者2年内视空间皮质Abeta斑块增加较少 并减少了服用5-羟色胺能药物的受试者的视觉空间认知能力下降，也许改变了一个关键 帕金森病(PD)的风险仲裁者。我们的长期愿景是进行一项PDPDD预防试验，在该试验中，西酞普兰将 在Aβ相关的认知衰退之前就开始了。我们的中心假设是西酞普兰在帕金森病中的使用将减少 视空间皮质Abeta斑块增加，导致视空间认知功能下降的改善，与 PDD。我们的目标是在一项概念验证试验中验证这一假设，该试验在两年内每天服用西酞普兰20 mg。 帕金森病患者(年龄≥，65岁)，无抑郁(n=58)。在目标1中，我们将测试2年期PIB PET应计项目的差异 在西酞普兰组和安慰剂组之间的视觉空间皮质内。在目标2中，我们将衡量 这种视空间皮质对视空间认知功能的干预作用。在目标3中，我们将测试 西酞普兰与安慰剂相比提供了最小的临床上重要的益处差异，通过 多领域认知的通用测量，蒙特利尔认知评估，与PDD诊断有关。在… 这项研究的结论是，我们将拥有强大的数据集来评估我们严格的通过/不通过标准 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)，以 有助于证实或无效PDPDD发病机制的双重打击模型，这是一个重大贡献 与帕金森病领域有关的其他阿尔茨海默病和相关痴呆症(ADRD)情况的影响。

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.