A Multimodal Imaging Study of Dopamine in Early Psychosis

大量证据表明，纹状体多巴胺(DA)的异常传递是 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，目前尚不清楚精神病患者纹状体DA异常是从哪里开始的，以及它们是否可以转化 成为精神病发展的生物标记物。对临床高危人群的早期研究 精神病(CHR)显示患者在脑组织中有较高的[18F]DOPA摄取(即DA合成能力)。 AST与健康对照组(HC)比较。一项研究报告说，患有慢性阻塞性肺病的人 精神障碍综合征患者的[18F]DOPA摄取率高于无进展的慢性阻塞性肺病患者。 然而，最近在更大样本中进行的工作并没有重复这两个发现。我们最近完成了一项 在可行性研究中，我们使用[11C]-(+)-PHNO与哌醋甲酯(MPH)挑战来检查 14例慢性阻塞性肺疾病患者和14例肥厚性脑病患者的DA突触内传递。我们发现突触内多巴胺传递 在慢性阻塞性肺疾病患者中，在边缘/腹侧纹状体(VST)显著升高，而在任何其他ROI中均无显著升高 与HC相比。VST区突触内多巴胺传递与总的DA传递密切相关 CHR组的阴性症状，移位越大，阴性症状越少。 慢性阻塞性肺疾病受试者在接受mph挑战时，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磁共振成像(NM-MRI)， 测定不同突触前核团(黑质)中DA代谢物NM的技术 腹内侧部投射到AST]和腹侧被盖区[VTA；投射到 VST])，证实了SN中NM-MRI的对比噪声比(CNR)与 慢性阻塞性肺疾病和精神分裂症患者的阳性症状。综上所述，这些发现可能反映了：1)纹状体DA 从VST到AST的时间-空间方式发展的早期精神病的异常；2)临床模式 哪些阴性症状与边缘DA传递有关，哪些阳性症状反映DA功能 联合区域；3)生物标志物的差异(如PHNO w/mph challengl，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 在早期精神病中使用多模式PET/MR成像(即，[11C]拉氯普利具有mph挑战和NM-MRI) 在相同的慢性阻塞性肺疾病患者中。我们将招募115名CHR人员。所有受试者都将接受[11C]拉氯普利，每小时1英里。 以及NM-MRI成像和临床评估。患者将每3个月进行一次跟踪，为期两年或 直到转化为精神病，以先发生者为准，评估转化为精神病和临床 结果。澄清早期精神病患者DA异常的性质、时间和地形图将极大地 为转化性研究提供信息，并可为替代初始治疗干预提供支持，以预防 早期精神病的进展。

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.