2015-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648554摘要：研究背景:自閉症類群疾患為一種常見、嚴重，且在臨床上、基因學上異質性很高的神經發展性疾病，由於此疾患之高盛行率、長期功能障礙、且尚未有有效之預防及治療方法。為了發展自閉症類群的預防、早期發現與介入，對此疾患之長期預後、病因和生物指標(內在表現型)之研究實有其迫切性。本計畫為五年期研究，首要目標是將追蹤研究者先前所建立的NRPGM(96HD008)研究個案及其手足在青少年與成年早期之心理社會以及神經認知功能之發展與變化；其次，本研究將追蹤研究個案及其健康手足在腦部的結構性及功能性連結是否可作為此症之內表現型研究目的:一、從5-8年的追蹤中，研究自閉症類群患者在核心症狀、神經認知功能與社會心理之變化與穩定性，以期找出自閉症類群疾患預後之預測因子。二、驗證額葉-顳葉、皮質-紋狀體-丘腦、預設模式網絡 (default mode network) 及其他潛在迴路、神經心理功能(例如：認知彈性、執行功能及視覺空間記憶)和結構(體積、皮質厚度、皮質皺摺、白質纖維路徑)以及功能性聯結(靜息態功能性核磁共振造影與社交作業核磁共振造影)。藉由呈現造影資料的穩定性，檢驗未患病手足於初收案及追蹤點之影像學特性是否均介於自閉症類群疾患患者及典型發展者之間，發展有效的造影內表現型(即生物指標)。研究方法:本研究將追蹤兩組研究對象:(1)重新評估373位自閉症類疾患與150位正常發展者之臨床、心理社會和神經認知功能；(2)評估70位自閉症類疾患患者、40位未患病手足以及110位正常發展者(70位配對自閉症類群疾患，40位配對未患病手足配對)之腦部的結構性及功能性聯結。評估內容包含:自閉症症狀評估(唯自閉症類群疾患患者:自閉症診斷訪談修訂版(ADI-R)及自閉症診斷觀察量表(ADOS)；全體受試者: SRS, SCQ, CAST, AQ 問卷)、精神疾病共病症評估(K-SADS-E)、行為/精神病理學評估(CBCL, SNAP-IV, ASRS, ASRI)、教育/社福資源/介入、以及周產期/環境因子。第一組智商大於70的研究對象和第二組研究對象將接受神經心理學測驗((CPT, CANTAB, 6個社會作業)以及第二組研究對象腦部核磁共振造影檢查(T1與T2模板、擴散頻譜造影與靜息態功能性核磁共振造影)。另外, 所有研究對象將抽血作為將來免疫、發炎及環境物質暴露之研究用。預期結果:本研究為亞洲第一個研究患自閉症類群疾患兒童及青少年在神經認知與心理社會功能變化之縱貫性研究，找出可能的神經影像學內在表現型(生物指標)，並使用先進的影像技術(Tract-based automatic analysis, TBAA; multi-echo 靜息態功能性核磁共振造影以及 single-echo 靜息態功能性核磁共振造影)與多面向評估。本研究成果將能增進吾人對於臺灣漢族自閉症類群疾患的長期發展、其心理社會功能、與腦部功能和結構的了解，以期能促進未來自閉症類群轉譯醫學研究的進展。<br> Abstract: Background: Autism spectrum disorder (ASD) is a common severe, clinically and genetically heterogeneous childhood-onset neurodevelopmental disorder. Due to its high prevalence and severe lifelong impairment without effective prevention and treatment, there is a dearth to investigating its longitudinal outcome, pathogenesis, and biomarkers (endophenotypes) for the development of prevention, early detection, and intervention. The ultimate goals of this 5-year project are to prospectively investigate the outcome and changes of psychosocial and neurocognitive functions of a cohort of probands with ASD established by the PI’s NRPGM (96HD008) at adolescence and young adulthood as the primary aim; and to test whether structural and functional brain connectivity can be effective endophenotypes of ASD combining the unaffected sibling and follow-up designs as the secondary aims. Primary Specific Aims:1. To investigate the neurocognitive (neuropsychological, social cognition, structural and functional connectivity) and psychosocial outcomes at adolescence and young adulthood among children with ASD as compared to age- and sex-matched typically developing (TD) controls; Secondary Specific Aims:1 To examine the changes and stability of, and to identify predictors for ASD core symptoms, neurocognition, and psychosocial functions across a 5-8 follow-up period; 2.To validate the neuropsychological functioning (e.g., set-shifting, executive function, and visuo-spatial memory etc.) and structural (morphometric, cortical thickness, gyrification, white matter tract integrity) and functional connectivity (resting-state fMRI and social task fMRI) in fronto-temporal, cortico-striato-thalamic, default mode network, and other potential circuits as effective imaging endophenotypes (biomarkers) by demonstrating the stability of these imaging data and the intermediate position of unaffected siblings between ASD probands and TD at Time 1 and follow-up. Methods: We will prospectively follow up two cohorts: (1) 373 ASD and 150 TD for reassessments of clinical, psychosocial, and neuropsychological outcomes and (2) 70 ASD, 40 unaffected siblings of ASD, 70 TD for ASD, 40 TD for unaffected siblings) for additional reassessments of structural and functional brain connectivity. The assessments include ASD symptoms (ASD only: Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Scale; all: SRS, SCQ, CAST, AQ). They will also be assessed for other psychiatric disorders (K-SADS-E), behaviors/psychopathology (CBCL, SNAP-IV, ASRS, ASRI), resource/intervention, and perinatal/environmental risk factors. For the first cohort subjects whose IQ > 70 and all the second cohort subjects will receive the neuropsychological tests (CPT, CANTAB, 6 social tasks) and the second cohort will receive MRI assessments (T1 and T2 templates, Diffusion Spectrum Imaging, resting-state fMRI). In addition, all the study subjects will have blood withdrawal for future immunity, inflammation, and environmental exposure studies.Anticipated ResultsThe significance of this project is the first longitudinal study to investigate the changes of neurocognitive and psychosocial functions of children with ASD and to identify the potential neuroimaging endophenotype (biomarkers) for ASD in Asian with advanced imaging technique (Tract-based automatic analysis, TBAA; multi-echo resting-state fMRI in addition to single-echo resting-state fMRI) and multidimensional assessments. The success of this project will fill the gap of our understanding of longitudinal outcomes of ASD and the developmental changes of psychosocial function and structural and functional brain activity of Han Chinese in Taiwan, and is anticipated to facilitate the progress of translational research in ASD.自閉症類群疾患神經認知功能內在表現型後續追蹤社會心理結果發展變化