Imaging of Neuropsychiatric Disorders with Developmental and Genetic Mechanisms

具有发育和遗传机制的神经精神疾病的影像学

基本信息

批准号：
8745689
负责人：
Karen FAITH Berman
金额：
$ 128.91万
依托单位：
NATIONAL INSTITUTE OF MENTAL HEALTH
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8745689
关键词：
Adopted Affect Affective Agonist Antipsychotic Agents Autoimmunity Back Behavioral Biological Markers Biological Neural Networks Blood flow Brain Diseases Brain-Derived Neurotrophic Factor Catechol O-Methyltransferase Cerebrovascular Circulation Characteristics Clinical Clinical Research Code Cognition Cognitive Collaborations Complement Corpus striatum structure Data Data Set Databases Development Diagnosis Disease Dopamine Estrogens Evaluation Failure Functional Magnetic Resonance Imaging Functional disorder Gaucher Disease Gene Mutation Genes Genetic Genetic Variation Genotype Goals Gonadal Steroid Hormones Hippocampus (Brain)Hormones Image Impairment Individual Inpatients Intramural Research Program Link Measurement Measures Medial Mediating Mental disorders Methods Modality Molecular National Human Genome Research Institute National Institute of Mental Health Nature Neurobiology Neuroendocrinology Neurophysiology - biologic function Neurotransmitters Noise Oxygen Parkinson Disease Parkinsonian Disorders Participant Patients Pattern Performance Perfusion Pharmaceutical Preparations Phenotype Physiology Play Population Positron-Emission Tomography Prefrontal Cortex Procedures Progesterone Protocols documentation Regulation Reporting Research Research Personnel Rest Rewards Risk Role Schizophrenia Series Short-Term Memory Signal Transduction Source Susceptibility Gene Symptoms Synapses System Task Performances Temporal Lobe Testing Variant Water Work base cognitive control cognitive function cohort developmental genetics disability dopaminergic neuron drug withdrawal gene discovery imaging modality indexing insight neural circuit neurochemistry neuroimaging neuropsychiatry premenstrual dysphoric disorder presynaptic programs radioligand receptor relating to nervous system research facility research study response screening theories trait ward

项目摘要

The Section on Integrative Neuroimaging continues to make advances toward its goals of understanding the nature, molecular underpinnings, underlying neurochemistry, and clinical correlates of neural systems-level dysfunction in schizophrenia. This year, we have made substantial progress in furthering our multimodal neuroimaging studies of a unique and growing cohort of medication-free patients with schizophrenia. In particular, new efforts to characterize not only presynaptic dopamine synthetic capacity, but also D1 and D2/3 receptor availability in this population have been successful in this years participants, and with further accrual, will allow evaluation of key hypotheses about integrated pre- and post-synaptic dopamine functioning in this disorder. In conjunction with cortical cognitive activation data collected in the same patients, these data will also provide a platform to expand work from this lab yolking characteristic schizophrenia-associated impairments in prefrontal activation during executive task performance and exaggerated striatal dopamine synthesis. Specifically, this ongoing project will allow us to directly evaluate theories that schizophrenic neuropathophysiological changes are reflected in failures of maintaining task appropriate network activity via disturbed cortical dopaminergic tone and impaired signal-to-noise ratios due to suboptimal D1 to D2/3 receptor relationships. As we have previously described, critical disturbances in cognitive control and mnemonic neural circuitry in schizophrenia not only serve as sources of marked disability in affected individuals, but also provide a valuable phenotype for testing hypotheses regarding how genes implicated in schizophrenia might contribute risk. For example, by measuring regional cerebral blood flow during the N-back continuous working memory task, we have re-confirmed an aberrant prefrontal activation pattern even in patients who perform relatively well on the task and further demonstrated profoundly aberrant connectivity in prefrontal and medial temporal lobe regions, which showed strong ability to discriminate between healthy and ill participants. This latter finding was prospectively validated in two additional data sets, suggesting that disturbances in the prefrontal-limbic functional axis may be an illness trait marker. Delving then into contributing molecular mechanisms, we have also reported on a unique gene-diagnosis interaction operating on regional cerebral blood flow involving the gene coding for catechol-O-methyltransferase, COMT, which harbors common variation that is weakly but consistently associated with schizophrenia risk and strongly implicated in both prefrontal and limbic functioning during executive and affective challenge, respectively, in healthy individuals. In particular, we have identified that even at rest there exists in patients with schizophrenia an inverse relationship between dorsolateral prefrontal cortical and medial temporal lobe blood flow, which is mediated by COMT genotype. This is an effect not seen in healthy study participants and suggests an important intersection between genetically determined cortical dopaminergic tone and fundamental biases in baseline prefrontal-limbic neural network activity in patients suffering with schizophrenia. Adopting a similar strategy, we have broadened our work in this cohort to identify gene-diagnosis interactions with other risk genes that impact neural functioning during both working-memory performance and basal resting conditions. This year, we have shown that genetic variation in brain-derived neurotrophic factor (BDNF), a key molecule regulating hippocampal development and function, which has also been implicated in aspects of schizophrenic neuropathophysiology, plays an important, independent predictive role in hippocampal physiology under multiple cognitive conditions and does so much differently in medication-withdrawn patients with schizophrenia (Eisenberg et al., 2013). Together, this series of experiments elucidates a mechanistic explanation for variation in characteristic resting-state and cognitive challenge-related neural abnormalities previously identified in schizophrenia. In addition, we have very recently extended our study of schizophrenia-associated hippocampal dysfunction by establishing that activity during mnemonic encoding is a likely indicator of genetic liability for this illness (Rasetti et al, 2013). Advancing these lines of research provides an important complement to studies of other central biomarkers (e.g., Masdeu et als report screening for autoimmunity in schizophrenia (2013)) and ultimately promises to aid treatment target discovery. (Masdeu et al., 2013) In parallel, in collaboration with the Behavioral Neuroendocrinology Section we have employed an incisive hormone manipulation, multimodal neuroimaging approach aimed at understanding the neural substrate of premenstrual dysphoric disorder (Baller et al., 2013). Measuring both fMRI and PET indices of working-memory during sex steroid hormone suppression with a GnRH agonist and individually, progesterone and estrogen add-back administration, in both healthy and PMDD patients, we found that regardless of the modality or hormone condition, PMDD patients showed exaggerated prefrontal neural response to working memory challenge, which was related to clinical symptom measurements, providing a much-needed foothold towards unraveling the neural underpinnings of this common and costly mental disorder. Finally, in collaboration with Dr. Sidransky in NHGRI, we have been able to advance insight into the pathophysiology of parkinsonism associated with genetic mutations in GBA, a gene disrupted in Gauchers disease. With our multitracer PET approach, we have characterized both dopaminergic and perfusion abnormalities related to idiopathic and GBA-linked parkinsonism (Goker-Alpan et al., 2012).

综合神经影像科继续朝着理解精神分裂症神经系统水平功能障碍的本质、分子基础、潜在神经化学和临床相关性的目标取得进展。今年，我们在进一步对不断增长的独特且不断增长的无药物精神分裂症患者群体进行多模式神经影像学研究方面取得了实质性进展。特别是，今年参与者中不仅表征了突触前多巴胺合成能力，而且表征了该人群中 D1 和 D2/3 受体可用性的新努力已取得成功，并且随着进一步的积累，将允许评估有关综合前和多巴胺合成能力的关键假设。突触后多巴胺在这种疾病中发挥作用。结合在同一患者中收集的皮质认知激活数据，这些数据还将提供一个平台来扩展该实验室的工作，以解决执行任务执行过程中与精神分裂症相关的前额叶激活障碍和夸大的纹状体多巴胺合成。具体来说，这个正在进行的项目将使我们能够直接评估这样的理论：精神分裂症的神经病理生理学变化反映在由于 D1 与 D2/3 受体关系不理想而导致皮质多巴胺能张力紊乱和信噪比受损，从而无法维持任务适当的网络活动。正如我们之前所描述的，精神分裂症中认知控制和记忆神经回路的严重紊乱不仅是受影响个体明显残疾的根源，而且还为检验与精神分裂症有关的基因如何造成风险的假设提供了有价值的表型。例如，通过测量 N-back 连续工作记忆任务期间的局部脑血流量，我们重新确认了异常的前额叶激活模式，即使在任务执行相对较好的患者中也是如此，并进一步证明了前额叶和内侧颞叶的严重异常连接叶区域，显示出区分健康和患病参与者的强大能力。后一个发现在另外两个数据集中得到了前瞻性验证，表明前额叶边缘功能轴的紊乱可能是一种疾病特征标记。然后深入研究分子机制，我们还报道了一种作用于局部脑血流的独特基因诊断相互作用，涉及儿茶酚-O-甲基转移酶（COMT）的基因编码，该基因具有与精神分裂症风险弱但一致相关的常见变异并分别与健康个体在执行和情感挑战期间的前额叶和边缘功能密切相关。特别是，我们已经发现，即使在精神分裂症患者休息时，背外侧前额皮质和内侧颞叶血流之间也存在负相关关系，这是由 COMT 基因型介导的。这是在健康研究参与者中未发现的效应，表明基因决定的皮质多巴胺能张力与精神分裂症患者基线前额叶边缘神经网络活动的基本偏差之间存在重要交叉。采用类似的策略，我们扩大了在该队列中的工作范围，以确定基因诊断与其他风险基因的相互作用，这些风险基因在工作记忆表现和基础静息条件下影响神经功能。今年，我们发现脑源性神经营养因子（BDNF）的遗传变异是调节海马发育和功能的关键分子，也与精神分裂症神经病理生理学的各个方面有关，在海马生理学中发挥着重要的、独立的预测作用。多种认知状况，并且在停药的精神分裂症患者中表现有很大不同（Eisenberg et al., 2013）。这一系列实验共同阐明了先前在精神分裂症中发现的特征性静息状态变化和认知挑战相关神经异常的机制解释。此外，我们最近扩展了对精神分裂症相关海马功能障碍的研究，确定助记符编码过程中的活动可能是这种疾病遗传倾向的指标（Rasetti et al, 2013）。推进这些研究方向为其他核心生物标志物的研究提供了重要的补充（例如，Masdeu 等人报告了精神分裂症自身免疫筛查（2013）），并最终有望帮助发现治疗靶点。（Masdeu 等人，2013）与此同时，我们与行为神经内分泌科合作，采用了深入的激素操作、多模式神经影像学方法，旨在了解经前烦躁障碍的神经基础（Baller 等，2013）。在使用 GnRH 激动剂抑制性类固醇激素以及单独添加黄体酮和雌激素回加给药期间，测量健康人和经前抑郁症 (PMDD) 患者的 fMRI 和 PET 工作记忆指数，我们发现，无论采用何种方式或激素状况，经前抑郁症 (PMDD) 患者显示出对工作记忆挑战的夸张的前额神经反应，这与临床症状测量有关，为揭示这种常见且代价高昂的精神障碍的神经基础提供了急需的立足点。最后，通过与 NHGRI 的 Sidransky 博士合作，我们能够深入了解与 GBA 基因突变相关的帕金森病病理生理学，GBA 是一种在戈谢病中被破坏的基因。通过我们的多示踪剂 PET 方法，我们描述了与特发性和 GBA 相关帕金森病相关的多巴胺能和灌注异常（Goker-Alpan 等，2012）。