A Multimodal Imaging Study of Dopamine in Early Psychosis

早期精神病中多巴胺的多模态成像研究

• 批准号: 10679099
• 负责人: Ragy Ramsis Girgis
• 金额: $ 70.62万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679099
• 关键词: Antipsychotic Agents; Biological Markers; Brain; Brain imaging; Cell Nucleus; Chemicals; Clinical; Clinical assessments; Corpus striatum structure; Data; Development; Dopamine; Early identification; Early treatment; Feasibility Studies; Fostering; Functional disorder; Image; Individual; Magnetic Resonance Imaging; Measures; Molecular; Multimodal Imaging; Nature; Noise; Outcome; Pathology; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Positron-Emission Tomography; Psychoses; Psychotic Disorders; Public Health; Raclopride; Reporting; Ritalin; Safety; Sampling; Schizophrenia; Substantia nigra structure; Symptoms; Techniques; Therapeutic; Therapeutic Intervention; Time; Ventral Striatum; Ventral Tegmental Area; Work; biomarker development; clinical high risk for psychosis; duration of untreated psychosis; early psychosis; experience; follow-up; imaging study; indexing; multimodality; neuromelanin; pharmacologic; presynaptic; prevent; psychotic symptoms; recruit; translational study; transmission process; uptake

A large body of evidence suggests that abnormal striatal dopamine (DA) transmission is a key pathophysiological phenomenon in schizophrenia (SCZ), mainly within the associative striatum (AST). However, it remains unclear where striatal DA abnormalities in psychosis start and whether they can be turned into a biomarker for development of psychotic illness. Early studies in individuals at clinical high-risk for psychosis (CHR) demonstrated that patients had higher [18F]DOPA uptake (i.e., DA synthesis capacity) in the AST compared to healthy control subjects (HC). One study reported that CHR individuals who developed a syndromal psychotic disorder had higher [18F]DOPA uptake than CHR individuals who did not progress. However, more recent work in larger samples has not replicated either finding. We recently completed a feasibility study in which we used [11C]-(+)-PHNO w/methylphenidate (MPH) challenge to examine intrasynaptic DA transmission in 14 CHR individuals and 14 HCs. We found that intrasynaptic DA transmission was significantly elevated in the limbic/ventral striatum (VST), and not in any other ROI, in CHR individuals compared to HC. There was a strong correlation between intrasynaptic DA transmission in VST and total negative symptoms in the CHR group in which greater displacement was related to less negative symptoms. CHR subjects experienced no change in positive symptoms with MPH challenge, which demonstrates the safety of this technique. Additionally, our preliminary data with neuromelanin sensitive MRI (NM-MRI), a MR technique of measuring NM, a metabolite of DA, in different presynaptic nuclei (the substantia nigra [SN; the ventromedial portion of which projects to the AST] and ventral tegmental area [VTA; which projects to the VST]), demonstrate positive relationships between the contrast-to-noise ratio (CNR) of NM-MRI in the SN and positive symptoms in CHR and SCZ subjects. Taken together, these findings may reflect: 1) that striatal DA abnormalities in early psychosis progress in a temporo-spatial manner from VST to AST; 2) a clinical pattern in which negative symptoms are related to limbic DA transmission and positive symptoms reflect DA function in associative regions; 3) differences in biomarker (i.e., PHNO w/MPH challenge, NM-MRI, [18F]DOPA). This proposal will aim to advance our understanding of the nature, topography, and timing of striatal DA alterations in early psychosis by using multimodal PET/MR imaging (i.e., [11C]raclopride w/MPH challenge and NM-MRI) in the same CHR patients. We will recruit 115 CHR individuals. All subjects will undergo [11C]raclopride w/MPH and NM-MRI imaging along with clinical assessments. Patients will be followed every 3 months for two years or until conversion to psychosis, whichever comes first, to assess for conversion to psychosis and clinical outcomes. Clarifying the nature, timing, and topography of DA abnormalities in early psychosis will greatly inform translational studies and could provide support for alternative initial therapeutic interventions to prevent progression in early psychosis.

大量的证据表明，异常的纹状体多巴胺（DA）传输是一个关键， 精神分裂症（SCZ）的病理生理现象，主要在联合纹状体（AST）内。 然而，尚不清楚精神病患者纹状体DA异常的起始位置以及是否可以逆转 转化为精神病发展的生物标志物在临床高风险个体中的早期研究 精神病（Psychosis）证明患者具有较高的[18F]多巴摄取（即，DA合成能力） 与健康对照受试者（HC）相比的AST。一项研究报告说， 综合征型精神障碍患者的[18F]多巴摄取量高于无进展的精神障碍患者。 然而，最近在更大样本中的工作并没有重复这两个发现。我们最近完成了一个 可行性研究中，我们使用[11 C]-（+）-PHNO w/哌甲酯（MPH）挑战， 突触内DA传递在14个HCs和14个HCs中。我们发现突触内多巴胺传递 在边缘/腹侧纹状体（VST）显著升高，而在任何其他ROI中， 相比HC。VST突触内DA传递与VST总突触数之间存在强相关性。 阴性症状的患者中，更大的位移与较少的阴性症状有关。 MPH激发后，受试者的阳性症状没有变化，这表明 这项技术的安全性。此外，我们的初步数据与神经黑色素敏感的MRI（NM-MRI），一个MR 在不同的突触前核（黑质[SN; 腹内侧部分，其中项目的AST]和腹侧被盖区[VTA;其中项目的 VST]），证明SN中NM-MRI的对比噪声比（CNR）与 阳性症状的受试者中的SCZ和SCZ。总之，这些发现可能反映：1）纹状体DA 早期精神病的异常以从VST到AST的时空方式进展; 2） 其中阴性症状与边缘DA传递有关，阳性症状反映DA功能， 相关区域; 3）生物标志物的差异（即，PHNO w/MPH激发，NM-MRI，[18F]DOPA）。这 该提案旨在促进我们对纹状体DA改变的性质、地形和时间的理解 通过使用多模式PET/MR成像（即，[11 C]雷氯必利（伴MPH激发和NM-MRI） 同样的病人。我们将招募115名志愿者。所有受试者将接受[11 C]雷氯必利w/MPH 以及NM-MRI成像沿着临床评估。患者将每3个月随访一次，持续两年，或 直到转化为精神病，以先发生者为准，以评估转化为精神病和临床 结果。阐明精神病早期DA异常的性质、时间和地形将大大有助于 为转化研究提供信息，并可为替代性初始治疗干预提供支持， 早期精神病的进展。