The Metabolome Profiling and Pathway Analysis of Attention Deficit Hyperactivity Disorder

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Project title/計畫英文名

Project Number/計畫編號

MOST105-2314-B002-060-MY3

Translated Name/計畫中文名

注意力不足過動症之代謝體研究與路徑分析

Project Principal Investigator/計畫主持人

CHI-YUNG SHANG

Funding Organization

Ministry of Science and Technology

Co-Investigator(s)/共同執行人

高淑芬

Website

link

Start date/計畫起

01-08-2016

Expected Completion/計畫迄

12-07-2017

摘要：背景：注意力不足過動症（attention-deficit/hyperactivity disorder，以下簡稱ADHD）是對個人、家庭及社會具有極大衝擊之早發型疾病，因此對於ADHD的早期發現與診斷就十分重要。目前ADHD的診斷主要是依據臨床觀察與會談工具，但這些方法不可避免會有許多的主觀差異性，因此尋找客觀的生物標記是一個重要課題。而代謝體是研究生物體內細胞所有代謝物的生物反應過程，因為代謝體是基因體、轉錄體、以及蛋白質體的終端產物，因此會更接近病患的症狀表現型，所以分析ADHD組與健康控制組在代謝物方面的區別，將有助於探索ADHD的病理機轉。但到目前為止，尚未有ADHD代謝體研究的相關報告，因此在這個三年計畫中，我們將進行血清的代謝體分析，以期能發現ADHD行為障礙和神經心理障礙相關的代謝體生物標記。目的：1. 找出ADHD診斷的代謝體標記；2. 找出這些代謝體標記與ADHD行為障礙和神經心理障礙之間的關係；3. 利用路徑分析找出這些代謝體標記所涉及的生物路徑，以發現ADHD的致病代謝機轉。個案與方法：本研究為三年的計畫，經過嚴謹的樣本數估計，我們將收集35位未曾使用過藥物治療的ADHD兒童與35位年齡、性別、和身高體重指數相配對的健康受試者，同時使用液相層析–質譜法和氣相層析–質譜法，來進行受試者血清中代謝體的分析鑑定。我們將使用ADHDRS-IV、SNAP-IV、CBCL、CGI-ADHD-S、SAICA、以及Family APGAR-C等量表評估受試者的行為症狀，並使用CPT和CANTAB評估其神經心理功能，我們將以條件邏輯迴歸和偏最小二乘判別分析法，來找出與ADHD有顯著相關的代謝體標記，最後我們將進行路徑與拓樸分析，以發現ADHD的生物調節路徑。預期結果：使用配對的研究設計，我們預期能找到能區分ADHD組與健康控制組的特定代謝體標記，此外，透過路徑分析將能使我們了解這些代謝體標記在生物調節路徑中所扮演的角色。本研究結果將有助於探索ADHD的病理生理機轉，特別是代謝體生物標記與ADHD的行為障礙/神經心理障礙之間的關係。
Abstract: Background: Because attention deficit hyperactivity disorder (ADHD) is an early onset andlong-term impairing disorder with tremendous impact on individuals, families, and societies,detection and diagnosis are very important for ADHD. Current diagnosis of ADHD relies mainly onclinical observation and interview tools that may involve a great subjective variability, and thus theinvestigation of objective biomarkers for ADHD is warranted. Metabolomics is the study of abiologic process involving all metabolites that are end products of the cellular process in a wholeorganism. Because metabolites represent the downstream expression of genome, transcriptome, andproteome, metabolomic profiles are more proximal to the behavioral phenotypes of ADHD.Analyzing metabolic differences between children with ADHD and healthy controls will provideinsight into underlying disease pathology. To date, there has been no metabolomics study on ADHD.In this 3-year project, we will perform a metabolomics analysis of serum to identify potentialbiomarkers for the behavioral and neuropsychological deficits of ADHD.Specific Aims:1. To identify the specific metabolomic profiles of ADHD;2. To identify the relationship between metabolomic profiles and behavioral/neuropsychologicaldeficits of ADHD;3. To map relevant metabolites to their corresponding metabolic pathways to profile the underlyingmechanisms of metabolic regulation of ADHD.Subjects and Methods: This is a 3-year project. After careful calculation of sample size, we willrecruit 35 drug-naïve children with ADHD, aged 7-18, and 35 healthy controls with matched age,sex and BMI. Using both liquid chromatography–mass spectrometry and gas chromatography–massspectrometry, serum-based metabolomic profiling will be performed. The behavioral measuresinclude ADHDRS-IV, SNAP-IV, CBCL, CGI-ADHD-S, SAICA, and Family APGAR-C.Neuropsychological testing, including CPT and CANTAB, will be performed. Conditional logisticregression and partial least squares discriminant analysis will be applied to identify significantmetabolites for ADHD. Pathway enrichment and topology analyses will be conducted to evaluate theregulated pathways.Anticipated Results: Using a matched study design, we anticipate to identify specific metabolitesthat show significant differences between ADHD and control groups. In addition, results of pathwayanalysis may offer more biological understanding in explaining the underlying metabolic regulationamong children with ADHD. Our findings will significantly contribute to our knowledge of thepathophysiological mechanisms of ADHD, especially the metabolomic pathway related to thebehavioral/neuropsychological deficits of ADHD.

Keyword(s)

注意力不足過動症
行為障礙
代謝體
神經心理障礙
路徑分析
Attention-deficit/hyperactivity disorder
behavioral deficits
metabolomics
neuropsychological deficits
pathway analysis

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The Metabolome Profiling and Pathway Analysis of Attention Deficit Hyperactivity Disorder

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