Citalopram as a posterior cortical protective therapy in Parkinson disease

西酞普兰作为帕金森病后皮质保护疗法

• 批准号: 10627937
• 负责人: Vikas Kotagal
• 金额: $ 60.45万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10627937
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease diagnostic; Alzheimer' s disease related dementia; Amyloid beta-42; Amyloid beta-Protein; Area; Attention; Biological; Biological Markers; Biostatistics Core; Brain; Cerebrospinal Fluid; Characteristics; Citalopram; Clinical; Clinical Research; Clinical Trials; Cognition; Cognition Disorders; Cognitive; Complex; Confidence Intervals; Data; Data Set; Dementia; Development; Diagnosis; Future; Goals; Impaired cognition; Impairment; Intervention; Judgment; Knowledge; Laboratory Research; Lewy Bodies; Link; Measures; Mediating; Mental Depression; Modeling; Nature; Nerve Degeneration; Neurologic; Neurons; Outcome; Parietal; Parkinson Disease; Parkinson' s Dementia; Pathogenesis; Pathologic; Pathology; Pharmaceutical Preparations; Pittsburgh Compound-B; Placebo Control; Placebos; Positron-Emission Tomography; Prevention approach; Prevention therapy; Prevention trial; Primary Prevention; Public Health; Publishing; Randomized; Research; Risk; Risk Factors; Selective Serotonin Reuptake Inhibitor; Senile Plaques; Serotonin; Tauopathies; Testing; Time; Toxic effect; Vascular Cognitive Impairment; Verbal Learning; Visuospatial; abeta accumulation; alpha synuclein; clinically relevant; cognitive function; cognitive impairment in Parkinson' s; cognitive testing; dementia risk; efficacy trial; executive function; human old age (65+); neurotransmission; novel strategies; placebo group; preventive intervention; tau aggregation

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.

抽象的 帕金森病伴痴呆 (PDD) 的生物学基础是异质的，涉及多个认知领域，并且 很难描述。额纹状体执行/注意力障碍是核心早期特征， 受多巴胺能神经传递的影响。当出现明显的视觉空间认知综合症时，PDD就会出现—— 被认为是由非多巴胺能变化介导的——开始显着影响后部的完整性 皮质区域。这些损伤背后的病理基础是多种多样的，并且涉及有毒物质 错误折叠的神经元 α-突触核蛋白以及非突触核蛋白病理（例如淀粉样蛋白-β）的影响 (Abeta) 斑块、tau 蛋白聚集和血管性认知障碍。这些的异质性 “双重打击”假说总结了病理学及其临床表现：一个被广泛接受但 这是当前 PDPDD 发病机制模型中从未测试过的原理。我们提出了概念验证 PD 旨在延缓视觉空间认知衰退的试验，视觉空间认知衰退是 PDD 的一个关键组成部分。在 PD 中，低范围皮质 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 终端损失。这种特定的血清素-Abeta 特征适用于 PD，但不适用于 AD。我们发表的多中心 PD 观察结果表明，选择性血清素再摄取抑制剂 (SSRI) 与较低的 PDD 相关 转换风险和脑脊液 Abeta-42 水平改变。我们的初步数据，使用 Abeta 匹兹堡化合物 B (PiB) PD 中的正电子发射断层扫描 (PET)，显示 2 年视觉空间皮层 Abeta 斑块累积较少 并减少了服用血清素药物的受试者的视觉空间认知能力下降，这可能改变了一个关键 PDPDD风险的仲裁者。我们的长期愿景是进行 PDPDD 预防试验，其中西酞普兰将 在 Abeta 相关的认知能力下降之前就开始了。我们的中心假设是西酞普兰在帕金森病中的使用会减少 视觉空间皮层 Abeta 斑块累积，导致视觉空间认知能力下降的改善 PDD。我们的目标是通过为期 2 年每天 20 毫克西酞普兰的概念验证试验来检验这一假设。 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 在西酞普兰和安慰剂组之间的视觉空间皮层内。在目标 2 中，我们将衡量以下方面的影响： 这种视觉空间皮层 Abeta 对视觉空间认知功能的干预。在目标 3 中，我们将测试是否 经评估，西酞普兰相对于安慰剂具有最小的临床重要益处差异 多领域认知的常见测量方法——蒙特利尔认知评估，与 PDD 诊断相关。在 在这项研究的结论中，我们将拥有功能强大的数据集来评估我们严格的通过/不通过标准 这种安全且通用的 PDD 预防疗法。我们还将进行分析（目标 1、2 和 3） 有助于证实或否定 PDPDD 发病机制的双重打击模型，这是一项重大贡献 PD 领域对其他阿尔茨海默病和相关痴呆 (ADRD) 疾病也有影响。

项目成果

Cognitive correlates of dual tasking costs on the timed up and go test in Parkinson disease.

• DOI: 10.1016/j.prdoa.2022.100158
• 发表时间: 2022
• 期刊: CLINICAL PARKINSONISM & RELATED DISORDERS
• 作者: Harrie, Ashley;Hampstead, Benjamin M.;Lewis, Cate;Herreshoff, Emily;Kotagal, Vikas
• 通讯作者: Kotagal, Vikas

Serotonin Transporter Imaging in Multiple System Atrophy and Parkinson's Disease.

• DOI: 10.1002/mds.29220
• 发表时间: 2022-11
• 期刊: Movement disorders : official journal of the Movement Disorder Society