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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 高淑芬 | |
dc.contributor.author | Yi-Ling Chien | en |
dc.contributor.author | 簡意玲 | zh_TW |
dc.date.accessioned | 2021-06-16T02:33:11Z | - |
dc.date.available | 2018-09-25 | |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-07-28 | |
dc.identifier.citation | Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9:341-55.
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53911 | - |
dc.description.abstract | 自閉症類群疾患是常見的神經發展疾患,表現為相互性社會溝通障礙、與刻板重複行為,幼年初發後大多持續終生,目前並無有效的生物治療能改善臨床症狀。其臨床表現具有高度的複雜性,在病因研究上面臨極大的挑戰。本研究旨在探討,在自閉症類群疾患核心症狀以外,此症之神經認知功能與電生理反應,並探討可能的環境、與基因遺傳危險因子。
相較於健康對照組,自閉症類群患者有顯著的注意力缺損、過動衝動症狀、與反抗對立症狀,而自閉症與亞斯柏格症兩亞型在注意力缺損、與過動衝動症狀並無顯著差異,但後者有較嚴重的反抗對立行為。自閉症患者當中有65.6%同時符合注意力不足過動症的診斷,而亞斯柏格症組則有79.3%符合診斷。從診斷亞型來看,注意力缺乏亞型分別佔41.6%與33.0%,過動衝動亞型則有7.9%與14.6%,合併注意力缺乏與過動衝動者為50.5%與50.0%,最為常見。在柯能式持續注意力測驗中,自閉症與亞斯柏格症均顯示有集中注意力與持續注意力的缺損,其中自閉症患者的集中注意力較亞斯柏格症患者差,而亞斯柏格症患者的持續注意力缺損反而較自閉症嚴重。 在視覺記憶方面,自閉症類群患者有顯著的缺損,其表現會受到年齡、智商、測驗牽涉空間記憶與否、與記憶難度等影響,自閉症與亞斯伯格症兩亞型間無太大差異。患者的視覺記憶表現隨年齡而進步,但進度幅度不如常人,在牽涉空間記憶的測驗,成長更受限制。 自閉症類群患者即使到了成年仍然有顯著的知覺症狀,在日常生活中表現為低登錄量、感覺敏感、感覺迴避,且較少感覺尋求的行為。以聽覺事件相關電位探討生理基礎,患者對於長短變化的新奇刺激所引發的P3a波峰較早出現,顯示對新奇刺激較快產生自動再定向,且此現象與其臨床上社會覺察力缺損有顯著相關。此外,對於音頻變化的新奇刺激所引發的P3a,在對照組,波峰高低與感覺迴避、對形式的執著有關;而在病患組,波峰出現的早或晚可能反映患者的感覺迴避、與過度注意細節等特質。結合P3a波峰出現的latency、與自陳感覺特徵,可以有效區別患者與對照組。 在溫痛覺方面,患者受接觸性熱刺激後所產生的P2波較小,但主觀疼痛程度與對照組無異。對照組P2波與低登錄量、專注力特徵有關,但在病患則無此相關。患者整體自閉症嚴重度、與對日常刺激的低登錄量可預測其主觀疼痛程度。主觀疼痛愈強烈,則愈早出現N2波。N2波峰 latency可以預測患者疼痛程度,也可預測患者的感覺敏感、與社會性情緒問題。 探討懷孕生產併發發症的頻率,發現自閉症類群患童有較高風險經歷懷孕與生產併發症,未罹病患者的手足同樣有較高風險經歷懷孕生產併發症;病患與手足除了保溫箱的使用以外,其他併發症的發生比例也無顯著差異。但病患所經歷的併發症總數愈高,臨床自閉症狀愈嚴重,顯示懷孕生產併發症並非造成自閉症類群疾患的必要條件。有六個因子和症狀嚴重度有顯著相關,包括:子癲前症、前置胎盤、妊娠糖尿病、羊水過多、羊水過少、臍帶打結。這些因子牽涉胎盤功能、著床機轉、以及羊水的代謝。 在候選基因關聯研究中,調節腦部發育的基因WNT2與EN2和與突觸構造有關的SHANK3、以及語言功能相關的FOXP2基因的單點分析均與自閉症無顯著相關,多點分析中,唯獨WNT2與 FOXP2基因座有顯著相關。進一步分析與自閉症核心症狀的相關性,WNT2基因座A–G–A–G–G–C與刻板重複行為有相關性,而在家族研究中有顯著傳遞的rs2896218–rs6950765基因座G–G,也與刻板重複行為有顯著相關,帶有G–G基因座的病患有較為嚴重的刻板重複行為。顯示WNT2遺傳變異不只和罹患自閉症的風險有關,也和此症之臨床表現有顯著相關。在HLA-DRB1基因型研究中,自閉症患者的基因型分布與對照組有顯著差異,DR4較少,DR11與DR14較多,且此差異可能與患者神經認知功能有相關性。 綜上所述,自閉症類群患者有顯著的注意力缺損、視覺記憶缺損,到成年仍有知覺症狀、對聽覺與溫痛覺的生理反應異常。懷孕生產併發症可能與臨床症狀嚴重度有關,WNT2基因變異可能調節其刻板重複行為,HLA-DRB1也與此症風險有關。 | zh_TW |
dc.description.abstract | Autism spectrum disorders (ASD) are a group of severe, multi-factorial, life-long impairing childhood-onset neurodevelopmental disorders that begin in the first 2 years and throught the entire life. Although the high prevalence and high psychosocial impact of the illness, the research of its etiology faces critical stagnation and the effect of treatment nowadays seems far from satisfaction. Clinical and etiological heterogeneity composes of the most important challenges. This study aims to investigate (1) the neurocognitive and sensory phenotypes beyond the core symptoms of ASD; (2) electrophysological response in response to auditory and thermsl stimuli; (3) prenatal/perinatal risk factors and genetic risks.
Compared to typically developing controls (TD), youths with ASD showed more severe attention deficits, hyperactive/impulsive symptoms, and oppositinal defiant behaviors, with more severe oppositional defiant behaviors in Asperger’s disorder than autistic disorder. Around 65.6% patients with autistic disorder and 79.3% patients with Asperger’s disorder fulfilled the diagnosis of attention deficit hyperacitivty disorder. Combined type was higher than inattentive type and hyperactive/impulsive type. In Connors’ Continuous Performance Test, both autistic disorder and Asperger’s disorder revealed focused attention and sustained attention deficits, while youths with autistic disorder had more impairment in focused attention and youths with Asperger’s disorder had poorer sustained attention. In visual memory tasks, youths with ASD had a wide range of visual memory impairments that were moderated by age and IQ, in support with temporal and frontal lobe dysfunction in ASD. Memory loading of the tasks, and involvement of spatial working memory may also influence the visual memory performance. Young adults with ASD demonstrated more sensory symptoms in daily life, including lower registration, more sensory sensitivity and sensory avoiding, while fewer sensation seeking behviors. In response to duration deviant auditory stimuli, individuals with ASD showed a shorter P3a peak latency; this parameter was associated with social awareness deficits in ASD. Besides, P3a peak amplitude to frequency deviant stimuli was correlated with sensory avoiding and patterns preoccupation in TD, while P3a peak latency may reflect sensory avoiding and attention to details in ASD. Combined duration and frequency P3a latency, as well as sensory sensitivity and sensation seeking, ASD could be differentiated from TD. In contact heat evoked potentails (CHEP), individuals with ASD had attenuated CHEP response to thermal stimuli, which were correlated with self-reported sensory and autistic symptoms, indicated that CHEP parameters are potential trait markers for perceptual disturbance in individuals with ASD. Reported pain in ASD was similar to that in TD, and was predicted by N2 peak latency, overall autistic symptom severity, and low registration. N2 latency can also predict sensory sensitivity and social emotion problems. Pre-/perinatal complications occurred more frequently in both ASD probands and their unaffected siblings compared to TD controls. Probands with ASD had a higher number of complications than siblings, which may be associated with more severe autistic symptoms. The presence of some factors was associated with more severe overall autistic symptoms and/or stereotyped behaviors, suggesting a role of pre-/perinatal factor in moderating phenotype expression of ASD. The WNT2 haplotype and DRB1 genotype were not only associated with autism diagnosis but also associated with autistic symptoms and neuropsychological function respectively. The mechanisms of the pathogenesis of ASD warrant further research. | en |
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dc.description.tableofcontents | 第一章、緒論………………………………………………………………………………...1
第一節、前言…………………………………………………………………………...1 第二節、自閉症類群之盛行率………………………………………………………...3 第三節、自閉症診斷變革……………………………………………………………...3 1.3.1. 自閉症核心症狀……………………………………………………….…...3 1.3.2. 自閉症光譜………………….……………………………………………...5 1.3.3. 新版診斷流變………………………………………………………………5 第四節、神經認知功能…………………………………………………...……………6 1.4.1. 注意力缺損…………………………………………………………………6 1.4.2. 視覺記憶缺損………………………………………………………………8 第五節、知覺異常與電生理反應…………………………………………...……..…10 1.5.1. 事件相關電位………………………………………..……………………13 1.5.2. 接觸性熱誘發電位………………………………………..………………15 第六節、遺傳與非遺傳危險因子…………………………………………….………16 1.6.1. 懷孕與生產併發症…………………………………………………..……16 1.6.2. 候選基因關聯分析………………………………………………………..17 1.6.2.1. 影響腦部發育的候選基因……………………………………...…17 1.6.2.2. HLA-DRB1…………………………………………………………22 第七節、研究目的與假設 ………………………………………………………...…23 第二章、研究方法與材料……………………………………………………………..…...25 第一節、研究設計………………………………………………………….………....25 第二節、研究樣本………………………………………………………….…………25 第三節、臨床症狀評估工具……………………………………………….…………25 2.3.1. 自閉症診斷會談……………………………………………….………….25 2.3.2. 社會反應性量表…………………………………………………….…….26 2.3.3. 社會溝通量表………………………………………………………….….26 2.3.4. 自閉症狀量表……………………………………………………….…….27 2.3.5. The Chinese version of the Swanson, Nolan, and Pelham, version IV scale………………………………………………………………….….27 2.3.6. 青少年/成人感覺處理能力剖析量表…………………….………………28 第四節、神經認知功能評估…………………………………………………….……28 2.4.1. 魏氏智力測驗………………………………………………………….….28 2.4.2. 柯能式持續注意力測驗………………………………………….…….…29 2.4.3. 劍橋神經認知功能測驗……………………………………………….….29 2.4.3.1. 空間辨識記憶測驗……..……..………………………….………..29 2.4.3.2. 延遲取樣匹配測驗…………………………………………….…..30 2.4.3.3. 配對學習測驗……………………………………………………...30 2.4.3.4. 快速視覺訊息處理測驗…………………………………………...30 2.4.4. 威斯康辛卡片測驗………………………………………………………..31 2.4.5. 瑞文氏智力測驗…………………………………………………………..31 第五節、神經電生理反應評估……………………………………………………….32 2.5.1. 事件相關電位測量……………………………….……………………….32 2.5.2. 接觸性熱誘發電位測量…………………….…………………………….33 第六節、懷孕與生產史評估………………………………………………………….35 第七節、候選基因之基因型鑑定…………………………………………………….35 2.7.1. 影響腦部發育的基因………………………….………………………….35 2.7.2. HLA-DRB1基因………………………………….……………………….37 第三章、結果…………………………………………………………..…….……………..39 第一節、自閉症類群疾患之神經認知功能異常…………………………………….39 3.1.1. 注意力缺損………………………………………….…………………….39 3.1.2. 視覺記憶缺損………………………………………….………………….40 第二節、自閉症類群疾患之知覺異常與神經電生理反應特徵…………………….41 3.2.1. 日常生活知覺行為特徵…………………………………………………..41 3.2.2. 以事件相關電位測量聽覺反應…………………………………………..42 3.2.3. 以接觸性熱誘發電位測量溫痛覺反應…………………………………..43 第三節、自閉症類群疾患之候選基因與環境因子探討…………………………….44 3.3.1. 懷孕與生產併發症………………………………………………………..44 3.3.2. 調節腦部發育之候選基因………………………………………………..46 3.3.2.1. 探討遺傳關聯……………………………………………………...46 3.3.2.2. 探討基因變異與臨床表現之相關性….……………….………….47 3.3.3. HLA-DRB1基因型之相關性……………………………………………..49 第四章、討論…………………………………………………………..…………………...51 第一節、自閉症類群疾患之神經認知功能異常…………………………………….51 4.1.1. 注意力缺損……………………………………….……………………….51 4.1.2. 視覺記憶缺損…………………………………………..…………………55 第二節、自閉症類群疾患之知覺異常與神經電生理反應特徵…………………….58 4.2.1. 以量表評估知覺異常……………………………………………………..58 4.2.2. 以事件相關電位測量聽覺反應…………………………………………..58 4.2.3. 以接觸性熱誘發電位測量溫痛覺反應…………………………………..61 第三節、自閉症類群疾患之候選基因與環境因子探討…………………………….63 4.3.1. 懷孕與生產併發症………………………………………………………..63 4.3.2. 調節腦部發育之候選基因………………………………………………..66 4.3.2.1. 探討遺傳關聯…………………………………………...…………66 4.3.2.2. 探討基因變異與臨床表現之相關性……………………………...69 4.3.3. HLA-DRB1基因型之相關性分析………………………………..............72 第四節、綜合討論…………………………………………………………………….73 第五章、展望……………………………………………………………………………….75 第一節、自閉症類群疾患之神經認知功能………………………………………….75 第二節、自閉症類群疾患之知覺反應特徵………………………………………….79 第三節、自閉症類群疾患之環境與遺傳因子初探….……………………………..82 5.3.1. 懷孕與生產併發症……………………….……………...……………..82 5.3.2. 影響腦部發育的候選基因……………….……………………………..84 5.3.3. HLA-DRB1基因型………………………………………………...............86 5.3.4. 結論………………………………………………………………………...88 第六章、論文英文簡述……………………………………………………………………..89 6.1. Introduction………………………………………………………………...............89 6.2. Hypothesis………………………………………………………………………….90 6.3. Aims………………………………………………………………………………..90 6.4. Impaired sustained attention, focused attention, and vigilance……………..….......90 6.5. Visual memory and sustained attention impairment……………………………….92 6.6. Sensory symptoms and abnormal P3a response……………………………………93 6.7. Attenuated thermal response associated with sensory and social emotion symptoms…. …………………………………………….…………………………95 6.8. Higher prenatal and perinatal risk factors in patients with ASD and unaffected siblings……………………………………………………….……………………..96 6.9. Association study of the CNS patterning genes…………………………………...98 6.10. WNT2 variants associated with autistic symptoms……………………..………101 6.11. Association of HLA-DRB1 genotyping and neuropsychological function….….104 6.12. Summary and implications……………………………………………….……...106 7. 參考文獻………………………………………………………………………………..109 8. 表1~表36………………………………………………………………………………137 9. 圖1~圖11………………………………………………………………………………181 10. 附錄:碩博士班修業期間所發表之相關論文清冊…………………………………193 | |
dc.language.iso | zh-TW | |
dc.title | 自閉症類群疾患之神經認知、電生理表現型與遺傳研究 | zh_TW |
dc.title | Neurocognitive & Electrophysiological Phenotypes and Genetic Risk of Autism Spectrum Disorders | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 博士 | |
dc.contributor.coadvisor | 謝豐舟 | |
dc.contributor.oralexamcommittee | 胡海國,謝松蒼,張美惠,曾文毅,阮啟弘 | |
dc.subject.keyword | 自閉症類群疾患,注意力缺損,視覺記憶,知覺處理,事件相關電位,懷孕生產併發症,遺傳關聯, | zh_TW |
dc.subject.keyword | autism spectrum disorders,attention deficits,visual memory,sensory symptoms,event-related potentials,prenatal/perinatal risk factors,genetic association, | en |
dc.relation.page | 195 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-07-29 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 臨床醫學研究所 | zh_TW |
顯示於系所單位: | 臨床醫學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
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ntu-104-1.pdf 目前未授權公開取用 | 1.88 MB | Adobe PDF |
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