The Basis of Psychotic Symptoms in Parkinson's Disease

帕金森病精神病症状的基础

• 批准号: 7194865
• 负责人: SPYRIDON PAPAPETROPOULOS
• 金额: $ 7.64万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-19 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7194865
• 关键词: Address; Affect; Age; Amygdaloid structure; Area; Autonomic Dysfunction; Autopsy; Autoradiography; Binding; Body Burden; Bradykinesia; Brain; Brain region; Clinical; Complex; Corpus striatum structure; Data; Denervation; Development; Disease Progression; Future; Gene Transfer; Gene Transfer Techniques; Goals; Grant; Growth Factor Gene; Histocytochemistry; Immunoblotting; Impaired cognition; In Situ Hybridization; Knowledge; Lead; Lesion by Stage; Levodopa; Lewy Bodies; Malignant - descriptor; Maps; Messenger RNA; Motor; Motor Manifestations; Muscle Rigidity; Nerve Degeneration; Nerve Growth Factors; Nucleus Accumbens; Parkinson Disease; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Process; Proteins; Publications; Publishing; Quality of life; Range; Regulation; Research Personnel; Specimen; Staging; Stem cell transplant; Structure; Substantia nigra structure; Symptoms; System; Techniques; Testing; Therapeutic; Thinking; Treatment Efficacy; Tremor; Ventral Striatum; Ventral Tegmental Area; Visual; Visual Hallucination; Work; alpha synuclein; area striata; base; brain tissue; cohort; dopamine transporter; drug development; embryonic stem cell; immunocytochemistry; improved; innovation; mortality; multidisciplinary; neurochemistry; neurogenetics; neuron loss; novel strategies; receptor

DESCRIPTION (provided by applicant): Although PD is predominated by motor symptoms (tremor, rigidity and bradykinesia) during its initial stages, with disease progression the majority of patients develop additional non-motor manifestations like cognitive impairment, psychiatric complications and autonomic dysfunction. Among the most common are visual hallucinations seen in about 1/3 of PD patients. Visual hallucinations are usually related to L-dopa therapy, significantly influence quality of life and lead to increased mortality in PD. Although their clinical variables have been somewhat defined, their neurochemical basis remains unknown. Lack of such knowledge limits therapeutic efficacy in PD and may compromise the development and use of future therapies like stem cell transplantation and nerve growth factor gene transfer. This project focuses on the characterization of the neurochemical changes leading to visual hallucinations in PD. We propose that these symptoms result from a complex process that involves accumulation of the protein alpha-synuclein and dysregulation of DAergic pathways affecting the ventral tegmental area (VTA), to later extend to the ventral striatal (nucleus accumbens) and mesocorticolimbic regions (amygdala). To this end, we will evaluate the neurodegenerative process as well as key components of the DAergic system in these regions. We propose three specific objectives to address these issues: 1) To characterize the expression of alpha-synuclein in the substantia nigra, vental tegmental area and striatum using immunocytochemistry, immunoblotting, and in situ hybridization techniques in postmortem brain specimens of PD patients with and without visual halluinations as well as age-matched controls. 2) To map and visualize the loss of DAergic projections to the limbic target areas by determining the expression of dopamine transporter (DAT) binding and 3) To examine the regulation of D1, D2 and D3 DAergic receptors using autoradiographic binding techniques in limbic brain regions in PD. Our long term objective is to identify neurochemical mechanisms related to the development of drug-induced psychotic symptoms in PD. This Small Grant (R03) application from a new investigator is concentrated in obtaining key pilot data on the etiopathogenesis of visual hallucinations (VH) in Parkinson's disease. Recent publications from our group, our preliminary results, the brain tissue availability and the multidisciplinary team assembled provide strong support for the feasibility of this project.

描述（由申请方提供）：尽管PD在其初始阶段以运动症状（震颤、强直和运动迟缓）为主，但随着疾病进展，大多数患者会出现其他非运动表现，如认知障碍、精神并发症和自主神经功能障碍。其中最常见的是在约1/3的PD患者中看到的幻视。视幻觉通常与左旋多巴治疗有关，显著影响PD患者的生活质量并导致死亡率增加。虽然他们的临床变量已经有所定义，其神经化学基础仍然未知。缺乏这些知识限制了PD的治疗效果，并可能影响未来治疗方法的开发和使用，如干细胞移植和神经生长因子基因转移。该项目的重点是表征导致PD幻视的神经化学变化。我们认为这些症状是由一个复杂的过程引起的，该过程涉及蛋白质α-突触核蛋白的积累和影响腹侧被盖区（VTA）的DA能通路的失调，后来扩展到腹侧纹状体（核腹侧）和中皮质边缘区（杏仁核）。为此，我们将评估这些区域的神经退行性过程以及DA能系统的关键组成部分。我们提出了三个具体的目标来解决这些问题：1）使用免疫细胞化学，免疫印迹和原位杂交技术在PD患者和无视觉幻觉以及年龄匹配的对照组的死后脑标本中表征黑质，腹侧被盖区和纹状体中α-突触核蛋白的表达。2)通过测定多巴胺转运蛋白（DAT）结合的表达，绘制并可视化DA能投射到边缘靶区的损失; 3）使用放射自显影结合技术检查PD边缘脑区D1，D2和D3 DA能受体的调节。我们的长期目标是确定与PD中药物诱导的精神病性症状发展相关的神经化学机制。来自一位新研究者的这项小额资助（R 03）申请集中在获得帕金森病幻视（VH）发病机制的关键试点数据。我们小组最近的出版物，我们的初步结果，脑组织的可用性和多学科团队的组装为该项目的可行性提供了强有力的支持。