2011-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648485摘要：研究背景：注意力不足過動症(Attention-Deficit/Hyperactivity Disorder, ADHD)是常見的(5-8%)、早發性、造成長期功能障礙、具有高度遺傳性、且具有臨床上及基因學異質性的神經精神疾患。由於其障礙會持續到成年期，成人ADHD已經在過去十年於西方國家的研究中受到相當多的重視，然而亞洲國家尚未有任何相關的研究探討此議題。此五年計畫的目標為追蹤計畫主持人於5年期由國衛院補助的研究發展獎助計畫(CDG, NHRI 2005-2009)所收集在兒童期已確立ADHD診斷的青少年與健康對照組，以建立亞洲地區年輕成人ADHD結合臨床、心理社會、神經認知功能、神經影像學、及基因學的第一手完整資料庫。主要目標：1.描述ADHD症狀於成人早期的持續性與表現模式，並探討於精神病理、社會、及執行功能層面的成人期預後；次要目標：1.探討兒童期或青少年期個人(臨床、行為、和神經認知變項)、家庭、學校和環境等因子，對青少年晚期和成年期各種的精神疾病與社會功能預後之預測；2.驗證額葉紋狀體神經迴路(frontostriatal circuitry)之腦部結構性與功能性聯結是否可作為ADHD的腦部照影內在表現型，以及其與ADHD症狀和多巴胺神經傳導系統相關基因變異的關係；3.找出methylphenidate作用的大腦活化區域；4.檢測過去已報告與多巴胺和正腎上腺素傳導系統有關的候選基因(DAT1, DRD4, MAO-A, ADRA2A, ADRA2C, NET, and COMT)，其與ADHD症狀嚴重度、ADHD亞型 (持續性、共病情形、功能障礙、與治療效果)、與內在表現型(執行功能與結構性和功能性腦部造影)的相關性。研究方法：研究對象包括兒童期即被診斷為ADHD的217位年輕成人(男性180位，83%)，以及173位健康對照組(男性123位，71%)。在17-24歲時(距青少年期評估約六年後)，受試者將接受精神科診斷會談(ADHD+SADS, CAADID)以確認成人期ADHD診斷與其他符合DSM-IV的精神疾患，並收集血液樣本。評估內容包括標準化自填問卷(ADHD相關症狀：ASRS、CAARS-S:S；人格特質：TPQ；DSM-IV精神病理：ASRI-4；社會功能：AAQoL、WFIRS-S、WFIRS-P；家庭互動：PBI) 以及神經心理學測驗(智力：WAIS-III ；注意力控制與執行功能：CANTAB)。我們將選取30位持續出現ADHD症狀的受試者(persistent ADHD)及無ADHD、同性別、且同慣用手的手足(n=30)，30位有DAT1基因且/或臨床上對methylphenidate 有良好反應的ADHD患者(將於用藥一週後重複照影)，以及30位無ADHD及無其他精神疾患的健康對照組，進行擴散頻譜磁振造影(DSI)及休息狀態功能性造影(resting state fMRI)，共150次腦部照影。我們將針對3'VNTR基因及其他與多巴胺及腎上腺素系統相關的候選基因 (DRD4, MAO-A, ADRA2A, ADRA2C, NET, and COMT)，進行個案對照的關聯研究之基因定型與單套體分析。預期目標：我們預期本研究：(1)將建立亞洲族群第一個兒童期診斷為ADHD追蹤至成年早期的前瞻性長期資料； (2)將成為國際上少見具有完整、多面向的臨床、家庭、心理社會、學業/職業、神經心理、神經影像以及基因的成人ADHD資料庫。由於涵蓋腦部造影基因資料，可以確立ADHD的行為及神經認知表現型，檢測腦部造影內在表現型，以及造影基因分析，有助於找出與ADHD相關的基因變異型。<br> Abstract: Background: Attention deficit/hyperactivity disorder (ADHD) has been recognized as a common (5-8%), early-onset, long-term impairing, heterogeneous neuropsychiatric disorder with high heritability. Due to its lifelong impairments up to adulthood, adult ADHD has drawn much more attention in Western studies in the past decade; however, there has been no such study in Asian countries. This 5-year project aims to investigate the outcomes of a cohort of children with attention-deficit/hyperactivity (ADHD) and healthy controls established by the PI’s 5-year CDG (NHRI 2005-2009) to provide the first-hand data on adult ADHD in non-western countries, and will be one of few world-class studies on the topics of neurocognitive and imaging genomics on adult ADHD.Primary specific aim1.To describe the manifestation and persistence of ADHD symptoms and to investigate the psychiatric, social, and executive functioning outcomes at young adulthood among children with ADHD; Secondary specific aims1.To identify early individual (clinical, behavioral, and executive functioning and other neurocognitive variables), family, school, environmental factors predicting the symptom persistence and a wide-range of outcomes at young adulthood; 2.To validate structural and functional connectivity of frontostriatal circuitry as imaging endophenotypes of ADHD by demonstrating that structural connectivity and functional connectivity of frontostriatal circuitry are altered in patients with ADHD and their unaffected siblings, are associated with ADHD symptoms, and are associated with genes related to dopamine neurotransmitter system; 3.To identify brain area that is corresponding to the effect of methylphenidate; and4.To confirm reported candidate genes related to dopamine and noradrenergic neurotransmitter systems in the association with ADHD severity and subtypes (persistence, comorbidity, functional impairment, and treatment effects) and endophenotypes (executive function and structural and functional brain connectivity) such as DAT1, DRD4, MAO-A, ADRA2A, ADRA2C, NET, and COMT.Methods: The sample consists of a cohort of 217 young adults (180 males, 83%) who were diagnosed of ADHD at childhood and 173 healthy controls (123 males, 71%). At their ages of 17-24 (around 6 years after their assessments at adolescence), they will receive psychiatric interviews (ADHD+SADS, CAADID) to make the diagnosis of ADHD and other psychiatric disorders and blood sample collection. They will complete the following questionnaires: ASRS and CAARS-S:S for adult ADHD symptoms, TPQ for personality characteristics, ASRI-4 for DSM-IV psychopathology, AAQoL and WFIRS for social functions, and PBI for parenting styles; and perform the WAIS-III for current IQ and Cambridge Neuropsychological Test Automated Batteries for attention control and executive functioning. Among the cohort subjects, 30 subjects with persistent ADHD and their same-sex and –handedness unaffected siblings (n = 30), 30 ADHD subjects who have DAT1 and/or good response to methylphenidate (repeated MRI assessment one week later) based on clinical assessment, and 30 subjects without lifetime ADHD and any psychiatric disorder will receive diffusion spectrum imaging (DSI) and resting state functional MRI assessments (total number of MRI assessments, 150). We will genotype 3'VNTR of DAT1 gene and other candidate genes involving dopaminergic and adrenergic systems (DRD4, MAO-A, ADRA2A, ADRA2C, NET, and COMT) for case-control association studies by using SNP and haplotype analysis.Anticipated Achievements: We anticipate that this study (1) will provide the first prospective, longitudinal data of children with ADHD at late adolescence and young adulthood in Asian populations; (2) will be one of the first to establish a comprehensive, multi-dimensional dataset combining clinical, family, psychosocial, academic/vocational, neuropsychological, neuroimaging, and genetic data of young adults with ADHD. With the inclusion of imaging genetics data, the behavioral and neurocognitive phenotypes of ADHD can be validated, the imaging endophenotype can be tested, and image genetics approach may help identify genetic variants for ADHD.注意力不足過動症年輕成人期內在表現型Attention deficit/hyperactivity disorderyoung adulthoodendophenotypes