2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648403摘要：研究背景：自閉症或自閉症類群是一常見、複雜的早發性神經發展疾病。由於其高遺傳性(遺傳率大於90%)、嚴重且長期的功能障礙、以及缺乏實驗室的診斷方法和有效的預防與治療，自閉症已經被列為流行病學、分子基因學及生物標記研究最重要的課題，期待將內在表現型及基因的研究發現轉譯為未來臨床篩檢的應用，以及未來治療自閉症的發展。到目前為止，尚未證實任何常見的變異。計劃主持人先前基因體醫學國家型科技計劃(96HD008)，已經建立了450個自閉症家庭，並在339名個案中，檢驗出22名個案具基因套數變異(CNV)缺失，這是亞洲第一個基因套數變異研究。這次計劃的主要目標即為探討這些神經心理學功能(尤其是認知彈性及執行功能)，功能性(休息狀態的功能性MRI, rfMRI)及結構性聯結(擴散頻譜影像檢查ㄝDSI)，及電生理功能(相關事件電位中Mismatch Negativity [MMN] 與 p50)是否成為自閉症之認知內在表現型(生物標記)。研究目的：為了驗證在有/無CNV基因套數變異的自閉症患者及其各自未發病手足與各自兩組正常發展對照組共六組(每組22名受試者)，神經心理學功能，電生理學及腦部額葉-顳葉、額葉-紋狀體、和皮質-紋狀體-視丘等神經迴路的的腦內結構性及功能性聯結。方法：我們將會招募及評估44名有/無基因套數變異的自閉症個案，44名未發病手足，以及44名配對的年齡、性別、慣用手及智力測驗的正常對照組。所有的受試者(共132名)將透過兒童精神專科醫師與他們的家長進行ADI-R訪談及與受試者進行ADOS確認其自閉症診斷。並接受以下的評估：精神病理診斷(K-SADS-E)自閉症狀(SRS、SCQ、CAST、ABC量表)、其他的行為症狀(CBCL，SNAP-IV)及出生前後/環境的危險因子進行評估。直接的測驗包括智能(CPM/SPM, WISC-III, WAIS)，神經心理學測驗(CPT, WCST, CANTAB)，以及核磁共振檢查(T1及T2，擴散頻譜影像，休息狀態的功能性MRI檢查)，以及事件相關電位檢查(MMN及p50)。計劃的原創性與重要性：我們已經準備了ADI-R及ADOS這兩個國際認定的自閉症標準診斷工具中文版，並已由其出版社WPS認定為國際研究使用之唯一中文版本。我們有世界上第一個亞洲族群的基因套數變異資料。這個計劃將會是世界上第一個基因探討套數變異的自閉症個案的危險因子、及其相關行為表現型、神經影像學、神經生理及神經心理功能內在表現型之研究。預期結果：藉由有/無CNV缺損的自閉症患者及其未發病手足的難能可貴之樣本，進行之內在表現型研究的結果，有助於我們更了解自閉症的致病機轉以及找出其神經認知功能(包括神經心理學及腦影像學[DSI, rfMRI])以及神經生理學(包括事件相關電位檢查[MMN及p50])的生物標記。除了兒童精神科醫師臨床診斷及ADI-R與ADOS評估，這些潛在性生物標記可以協助篩檢及診斷自閉症以便早期找出及診斷自閉症進行早期療育及各個發展階段之療育參考。<br> Abstract: Background: Autism or autism spectrum disorders (ASD) is a common, complex early-onset neurodevelopmental disorder. Due to its high heritability (heritability > 90%) and severe long-term impairment without available laboratory diagnosis, effective prevention or biological treatment, this disastrous disease has been prioritized for epidemiological, molecular genetic and biomarker studies to translate the genetic and endophenotype discoveries into future clinical application for screening and diagnosis, and development of treatment for ASD. Up to now, no common variants have been identified. The PI’s previous NRPGM (96HD008) project has established 450 ASD families and identified 22 probands with ASD with copy number variations (CNV) in a sample of 339, the first CNVs findings in ASD in Asian population. The current project aims to investigate whether neuropsychological function (particularly cognitive flexibility and executive function), functional (assessed by resting functional MRI, rfMRI) and structural connectivity (assessed by diffusion spectrum imaging, DSI), and electrophysiological function (assessed by event-related potential [ERP]: Mismatch Negativity [MMN] and p50) can be effective cognitive endophenotypes (biomarkers) for ASD.Specific aims:To validate the neuropsychological functioning (particularly set-shifting and executive function), electrophysiological functioning assessed by ERP [MMN and p50], structural and functional connectivity in fronto-temporal, and cortico-striato-thalamic circuitry as effective imaging endophenotypes by demonstrating the differences between ASD probands with CNVs and their unaffected siblings, probands without CNVs and their unaffected siblings, and two matched neurotypicals (n=22 for each group).Methods:We will assess 44 probands with and without CNVs, their unaffected siblings (n= 44), and age-, sex-, handedness-, and IQ-matched neurotypicals. All the subjects (n = 132 in total) will be assessed by child psychiatrists and the ADI-R interview of their parents and the ADOS of themselves for ASD diagnosis. They will also be assessed for other psychiatric disorders (K-SADS-E); autistic symptom dimensions (SRS, SCQ, CAST, ABC), other behavioral symptoms (CBCL, SNAP-IV), and perinatal/environmental risk factors by structured interview scale designed by the PI. The direct tests include intelligence (CPM/SPM, WISC-III, WPPSI-R), neuropsychological tests (CPT, WCST, CANTAB), the MRI assessments (T1 and T2 templates, Diffusion Spectrum Imaging, resting-state fMRI), and event-related potential (MMN, p50) assessments.Originality and Significance of This ProjectWe have prepared the Chinese versions of the ADI-R and ADOS, two internationally-recognized standard diagnosis instruments for diagnosis of ASD, which were approved by the WPS as the sole Chinese version in the world. We have the first CNVs data in Asian population. This project will be the first study in the world to characterize ASD probands with CNVs using behavioral phenotypes, and neuroimaging, neurophysiological, and neuropsychological endophenotypes.Anticipated Results: Using this precious sample, the results from combining endophenotype approaches for ASD probands with and without CNVs and their unaffected siblings will contribute to our understanding of pathogenesis of autism and to identifying neurocognitive (neuropsychological and imaging [DSI, rfMRI]) and neurophysiological (ERP [MMN, p50]) biomarkers. These potential biomarkers will assist in screening and diagnosis of ASD in addition to standardized clinical assessments by child psychiatrists and the ADI-R and ADOS assessments for early identification and diagnosis of ASD for early and continuous intervention throughout developmental stage.自閉症類群基因套數變異內在表現型神經心理學電生理學神經影像學autism spectrum disorderscopy number variationendophenotypeneuropsychologyelectrophysiologyneuroimage