Olfactory Function in Schizophrenia: A Lifespan Analysis

描述(申请人提供)：精神分裂症目前被认为是一种复杂的遗传性疾病，神经元发育改变，可能在生命的早期，对确定脆弱性很重要。神经发生和神经发育发生在成人嗅觉上皮细胞中，嗅觉系统的探测可以提供对这种疾病神经发育改变的神经生物学基础的洞察。事实上，对精神分裂症患者的研究表明，嗅觉系统存在强烈的行为、结构和功能障碍。我们和其他人的研究表明，嗅觉大脑区域受到神经退化和遗传介导的神经发育过程的影响。该项目是从寿命的角度检查这些化学感觉损伤的基础的唯一系统性努力。到目前为止，我们的努力已经确定：1)精神分裂症患者一生中普遍存在稳定的嗅觉缺陷；2)没有看到显著的药物效果；3)患者的一级亲属存在类似的心理物理、结构和功能缺陷；以及4)潜在的面部结构，如鼻腔和上颚体积异常。在胎儿早期，大脑形态发生与颅面形态发生在胚胎亲密性中进行。因此，对颅面部和脑畸形的定量分析，以及对嗅觉系统的详细心理物理评估，可能会提供有关精神分裂症发育性起源的重要信息。在这个应用中，我们建议从早期神经发育的角度对嗅觉系统的结构和功能异常进行深入的评估。我们将研究40名精神分裂症患者、40名其他方面健康的一级家庭成员、40名无关的健康对照和40名出现早期精神病症状的高危受试者。将利用新的方法来检查神经发育对患者化学感觉功能障碍的影响，包括鼻腔/腭部体积、结构MRI和面部形态的定量检查。这些损伤的预测性效用将通过检查患精神病风险增加的受试者来探索。我们的工作模型是，嗅觉障碍反映了神经发生和突触形成的发育障碍过程，这些措施可能代表精神分裂症潜在的胚胎学畸形发生的特定标记。精神分裂症目前被认为是一种复杂的遗传性疾病，大脑结构和功能的早期发育异常对确定疾病的易感性非常重要。这项研究将检查精神分裂症患者嗅觉能力的变化，并对鼻腔和口腔进行详细测量，并绘制面部和大脑结构和地形图。我们认为，在患者中看到的强烈嗅觉障碍反映了早期发育过程的障碍，对这些功能和结构的分析可能提供关于精神分裂症发育起源的重要信息。

DESCRIPTION (provided by applicant): Schizophrenia is currently thought to be a complex genetic disorder, with altered neuronal development, perhaps very early in life, important in determining vulnerability. Neurogenesis and neurodevelopment occur in the adult olfactory epithelium, and probes of the olfactory system may provide insights into the neuro-biological basis of altered neurodevelopment in this disorder. Indeed, studies of patients with schizophrenia have demonstrated robust behavioral, structural, and functional impairments of the olfactory system. Our work, along with others', has indicated that olfactory brain regions are affected by both neurodegenerative and genetically-mediated neurodevelopmental processes. This project represents the only systematic effort to examine the underpinnings of these chemosensory impairments from a life-span perspective. To date, our efforts have established that: 1)pervasive and stable olfactory deficits exist across the lifespan in schizophrenia; 2)no significant medication effects are seen; 3)similar psychophysical, structural, and functional deficits exist in first-degree relatives of patients; and 4)underlying facial structures such as nasal and palate volumes are abnormal. Over early fetal life, cerebral morphogenesis proceeds in embryological intimacy with craniofacial morphogenesis. As such, quantitative analysis of craniofacial and cerebral dysmorphology along with a detailed psychophysical assessment of the olfactory system may provide important information concerning the developmental origins of schizophrenia. In this application, we propose an in-depth assessment of the structural and functional abnormalities of the olfactory system from an early neurodevelopmental perspective. We will study 40 schizophrenia patients, 40 otherwise healthy first-degree family members, 40 unrelated healthy controls, and 40 high-risk subjects who present with early symptoms of psychosis. New methods will be utilized to examine the neurodevelopmental contributions to chemosensory dysfunction in patients including nasal/palate volume, structural MRI, and quantitative examination of facial morphology. Predictive utility of these impairments will be probed by examining subjects at increased risk for the development of psychosis. Our working model is that olfactory impairment reflects developmentally disturbed processes of neurogenesis and synapse formation and that these measures may represent specific markers of embryological dysmorphogenesis underlying schizophrenia. Schizophrenia is currently thought to be a complex genetic disorder, with early developmental abnormalities in brain structure and function, being important in determining vulnerability to illness. This study will examine changes in smell abilities in schizophrenia along with detailed measurements of the nasal and oral cavities and mapping of facial and brain structure and topography. We believe that robust olfactory impairment seen in patients reflects a disturbance of an early developmental process and that the analysis of these functions and structures may provide important information concerning the developmental origins of schizophrenia.