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

• 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
• 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

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).

综合神经影像学部分继续朝着理解精神分裂症神经系统水平功能障碍的性质、分子基础、潜在神经化学和临床相关性的目标前进。今年，我们在进一步开展多模式神经影像学研究方面取得了实质性进展，这些研究涉及一个独特且不断增长的无药物治疗精神分裂症患者队列。特别是，新的努力，不仅表征突触前多巴胺合成能力，但也D1和D2/3受体的可用性在这一人群中已经成功，在今年的参与者，并与进一步的收益，将允许评估关键假设的综合前和突触后多巴胺功能在这种疾病。结合在相同患者中收集的皮层认知激活数据，这些数据还将提供一个平台，以扩展本实验室的工作，即在执行任务的过程中，与精神分裂症相关的前额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理论，精神分裂症的神经病理生理变化反映在失败的维持任务适当的网络活动，通过干扰皮质多巴胺能的色调和受损的信噪比，由于次优的D1到D2/3受体的关系。 正如我们先前所述，精神分裂症中认知控制和记忆神经回路的关键障碍不仅是受影响个体明显残疾的来源，而且还为检验有关精神分裂症相关基因如何可能导致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，我们再次证实了异常的前额叶激活模式，即使在任务表现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区域的严重异常连接，这表明了区分健康和生病参与者的强大能力。后一项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。然后深入研究贡献的分子机制，我们还报道了一个独特的基因诊断相互作用的局部脑血流涉及的基因编码的儿茶酚-O-甲基转移酶，COMT，其中含有共同的变化，这是微弱的，但始终与精神分裂症的风险和强烈的牵连，在执行和情感的挑战，分别在健康个体的前额叶和边缘功能。特别是，我们已经确定，即使在休息有精神分裂症患者的背外侧前额叶皮层和内侧颞叶血流，这是介导的COMT基因型之间的反比关系。这是在健康的研究参与者中没有看到的效果，并且表明精神分裂症患者中遗传决定的皮质多巴胺能张力和基线前额叶边缘神经网络活动的基本偏差之间存在重要的交叉点。采用类似的策略，我们扩大了我们在这一队列中的工作，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都会影响神经功能。今年，我们已经表明，脑源性神经营养因子（BDNF）的遗传变异，一种调节海马发育和功能的关键分子，也涉及精神分裂症神经病理生理学的各个方面，在多种认知条件下在海马生理学中起着重要的独立预测作用，并且在精神分裂症停药患者中表现得非常不同（Eisenberg et al.，2013年）。总之，这一系列的实验阐明了一个机械的解释变化的特征性休息状态和认知挑战相关的神经异常先前确定的精神分裂症。此外，我们最近扩展了我们对精神分裂症相关海马功能障碍的研究，确定记忆编码期间的活动可能是这种疾病遗传易感性的指标（Rasetti et al，2013）。 推进这些研究路线为其他中心生物标志物的研究提供了重要补充（例如，Masdeu等人报告了精神分裂症中自身免疫的筛查（2013）），并最终有望帮助治疗靶点发现。（Masdeu等人，2013年度） 与此同时，我们与行为神经内分泌科合作，采用了一种敏锐的激素操纵、多模式神经成像方法，旨在了解经前焦虑症的神经基质（Baller et al.，2013年）。 在健康和PMDD患者中，测量性类固醇激素抑制期间使用GnRH激动剂和单独使用孕酮和雌激素回加给药的fMRI和PET工作记忆指数，我们发现，无论方式或激素条件如何，PMDD患者对工作记忆挑战表现出夸大的前额叶神经反应，这与临床症状测量有关，为解开这种常见且昂贵的精神疾病的神经基础提供了急需的立足点。 最后，与NHGRI的Sidransky博士合作，我们已经能够深入了解与GBA基因突变相关的帕金森病的病理生理学，GBA基因在戈谢病中被破坏。 利用我们的多示踪剂PET方法，我们已经表征了与特发性和GBA相关的帕金森综合征相关的多巴胺能和灌注异常（Goker-Alpan et al.，2012年）。