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性质，分子基础，基本神经化学以及精神分裂症神经系统级功能障碍的临床相关性的目标迈进。今年，我们在促进我们对精神分裂症患者的独特且不断增长的同类群体的多模式神经影像学研究方面取得了重大进展。特别是，不仅要表征突触前多巴胺合成能力的新努力，而且该人群中的D1和D2/3受体的可用性在今年的参与者中已经取得了成功，并且随着进一步的应计评估，将允许评估有关该疾病中突触前和后突触后多巴胺功能的关键假设。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，以扩大该实验室的工作特征性精神分裂症相关的损害，在执行任务性能和夸张的纹状体多巴胺合成过程中。具体而言，这个正在进行的项目将使我们能够直接评估理论，即精神分裂症神经病理生理学的变化反映在通过扰乱的皮质多巴胺能张力和由于次级D1至D2/3受体关系而导致的信号噪声比率受到损害的信号噪声比率而反映出适当的网络活动。 如前所述，精神分裂症中认知控制和助记肌神经回路的严重干扰不仅是受影响个体的明显残疾的来源，而且还为测试有关在精神分裂症中涉及的基因的测试假设提供了有价值的表型。例如，通过测量N后N后连续的工作记忆任务期间区域脑血流，即使在任务上表现良好并且进一步表现出在前额叶和内侧颞叶区域的连接性相对良好的患者中，我们已经重新确认了异常的前额叶激活模式，这表现出强烈的歧视能力，这表现出强烈的歧视和不良的参与者。后者的发现在其他两个数据集中得到了前瞻性验证，这表明前额叶 - 边缘功能轴的干扰可能是疾病特征标记。然后深入研究分子机制，我们还报告了一种独特的基因诊断相互作用，该相互作用是在涉及Catechol-O-甲基转移酶的基因编码的区域脑血流上，COMT构成了基因，该基因具有较弱的常见变异，该变异与精神分裂症的风险和依次相关，并且在均匀的范围内均与正常的攻击性相关，并在范围内构成了强烈的攻击，并且在较强的范围内，并且在较大的范围内，并具有较高的范围，并且在各自的范围内均具有较高的攻击性，并且在各自的范围内都具有起作用的功能。特别是，我们已经确定，即使在精神分裂症患者中也存在静止，背侧外侧前额叶皮质和内侧颞叶血流之间也存在反比关系，这是由COMT基因型介导的。这是在健康研究参与者中看不见的作用，并提出了基线前额叶前膜神经网络网络活性在患有精神分裂症患者的基线前额叶神经网络活动中的基因性皮质多巴胺能和基本偏见之间的重要相交。采用类似的策略，我们在这一队列中扩大了工作，以确定与其他风险基因相互作用，这些风险基因在工作记忆性能和基础静止状况下都影响神经功能。今年，我们已经表明，脑源性神经营养因子（BDNF）的遗传变异是调节海马发育和功能的关键分子，这也与精神分裂症神经病生理学的方面有关，在多个认知和多种认知方面具有相同的认知性差异，在多个研究中扮演着独立的预测作用，在多种方面差异很大，因此差异如此差异，因此差异很大，因此差异很大，因此差异很大，因此差异很差。 （Eisenberg等，2013）。总之，这一系列的实验阐明了一种机械解释，这些解释是对先前在精神分裂症中鉴定的特征静止状态和与认知挑战相关的神经异常的变化。此外，我们最近通过确定助记符编码期间的活动可能表明了这种疾病的遗传责任的指标（Rasetti等，2013），我们最近扩大了对精神分裂症相关的海马功能障碍的研究。 推进这些研究路线为其他中央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性的筛查（2013）），并最终有望帮助治疗目标发现。 （Masdeu等，2013） 同时，与行为神经内分泌学部分合作，我们采用了一种敏锐的激素操纵，旨在理解过度障碍障碍的神经底物的多模式神经影像学方法（Baller等人，2013年）。 在健康和PMDD患者中，在性类固醇激素抑制性抑制性类固醇激素期间的fMRI和PET指标，以及单独的，孕激素和雌激素增加的给药，无论是健康和PMDD患者，我们都发现，PMDD患者对工作的临时性临床，对临床的临床挑战，无论是在临床上，无论是临床的，都表现出偏见揭开这种常见且昂贵的精神障碍的神经基础。 最后，与NHGRI的Sidransky博士合作，我们已经能够洞悉与GBA基因突变有关的帕金森氏病的病理生理学，GBA是GBA的基因，该基因破坏了Gauchers病。 通过我们的多阶段宠物方法，我们表征了与特发性和与GBA相关的帕金森氏症有关的多巴胺能和灌注异常（Goker-Alpan等，2012）。