注意力不足過動症之神經生物學與基因學研究

Neurobiological and Genetic Studies on Attention Deficit Hyperactivity Disorder

商志雍(Chi-Yung Shang)

指導教授 ： 高淑芬

共同指導教授 ： 楊偉勛

國立臺灣大學/醫學院/臨床醫學研究所/博士(2013年)

https://doi.org/10.6342/NTU.2013.01302

摘要

注意力不足過動症常合併執行功能障礙，但其他認知功能障礙則較少被研究，另外也沒有研究證實atomoxetine藥物治療可以改善這些認知功能障礙，而這些認知功能障礙潛在的神經構造與基因病因仍未有定論。本博士論文將分成以下四個層面來回答上述問題。
（一）神經心理學方面：(a) 探索53位在兒童期被診斷為ADHD的青少年及53位配對的健康對照組的執行功能，以劍橋神經心理測驗 (Cambridge Neuropsychological Test Automated Battery，CANTAB) 測量其執行功能，結果發現ADHD患者在這四個執行功能測驗表現均較對照組差，證實ADHD青少年患者有顯著的執行功能障礙，並在面對複雜作業時需要額外協助。
(b) 以279位ADHD患者、其未發病手足 (n=108)、及173位健康對照組，探索其執行功能與視覺記憶是否可以成為神經心理學的內表現型。我們使用CANTAB來測量執行功能以及視覺記憶，結果發現ADHD患者和其未發病手足在四個執行功能與四個視覺記憶測驗表現較健康對照組差，未發病手足在兩個視覺記憶測驗的表現介於ADHD和對照組之間，證實執行功能和視覺記憶確實可作為ADHD的神經心理學內表現型。
（二）藥物學方面：以30位8到16歲未曾服用過藥物的ADHD患者，進行一項持續12週開放標籤的atomoxetine藥物試驗，以瞭解其執行功能及視覺記憶在用藥後4週和12週的改善，結果發現患者在服藥後除了臨床表現及社會功能有顯著進步，在所測試的四項執行功能和兩項視覺記憶表現均有明顯進步，顯示atomoxetine可有效改善ADHD患者的執行功能與視覺記憶障礙。
（三）神經影像學方面：以25位ADHD患童及25位在年齡、性別、慣用手、以及智商配對的健康對照組，瞭解額葉紋狀體神經束的完整性以及其和執行功能的相關性。結果發現患者以擴散頻譜造影 (diffusion spectrum imaging，DSI) 重建的兩側各四條額葉紋狀體神經路徑 (背外側、內側、眼窩前額葉、及腹外側) 的一般性之部分異向性 (generalized fractional anisotropy) 值均較對照組低，且和ADHD的症狀嚴重度和執行功能障礙有顯著相關，特別是左側的眼窩前額葉和腹外側等神經纖維束。
（四）基因關聯性方面： (a) 以273位ADHD家族 (n=906) 的DNA在DAT1基因上找出14個單核苷酸多型性 (SNP) 與3´variable number of tandem repeat (VNTR)，結果這15個基因標記的LD結構，包含3個單套體區間，第一個區間大小為19kb，位於第二、四、六個內顯子，第二個區間大小為3kb，位於第八、十一個內顯子，第三個區間大小為953bp，位於3´UTR。單套體分析發現rs27048 (C) /rs429699 (T) 與注意力不足亞型有顯著相關，在量性分析上也發現rs27048 (C) /rs429699 (T) 與注意力不足症狀的嚴重度有顯著相關，顯示 DAT1基因在ADHD的注意力不足亞型的病理生理機轉上扮演重要角色。
(b) DAT1基因與執行功能的關聯性：以 382位ADHD家族 (n=1298) 的DNA樣本及其執行功能進行分析。單套體分析發現，第一個單套體區間rs403636 (G) /rs463379 (C) /rs393795 (C) /rs37020 (G) 和空間工作記憶的錯誤量有顯著相關性。顯示DAT1基因在ADHD的空間工作記憶障礙扮演重要角色。
綜合以上研究，本博士研究發現ADHD除了有執行功能的障礙之外，同時是世界上第一個研究證實視覺記憶是內表現型，並且atomoxetine治療可以改善執行功能與視覺記憶障礙，而ADHD的執行功能障礙與額葉紋狀體神經聯結及DAT1基因變異有明顯相關性，未來需要藉由藥物基因學以及影像基因學的研究以建立ADHD的病理生理機轉。

關鍵字

注意力不足過動症 ； 劍橋神經心理測驗 ； 執行功能 ； 視覺記憶 ； 額葉紋狀體神經路徑 ； 擴散頻譜造影 ； 多巴胺轉運基因 ； 單套體 ； 連鎖不平衡

並列摘要

Although ADHD is often associated with executive deficits, little research has report other cognitive dysfunction in ADHD. No study has investigated the effect of atomoxetine on the cognitive dysfunction in children with ADHD. In addition, the neural correlates and genetic variants of cognitive dysfunction is still inconclusive. The doctoral thesis will answer these questions from four approaches.
(1) Neuropsychological approach: (a) Using 53 adolescents with childhood diagnosis of ADHD, and 53 matched controls, we examined their EF assessed by using the tasks involving the EF of the CANTAB. The ADHD group performed worse in all the EF tasks, and needed extra assistance while complex tasks were assigned.
(b) Using 279 adolescents with ADHD, 108 unaffected siblings and 173 controls, we examined their EF and VM to test whether EF and VM can be potential endophenotypes for ADHD. The ADHD probands and the unaffected siblings significantly performed worse in all the EF tasks. The unaffected siblings occupied an intermediate position between ADHD probands and controls in the performance on two VM tasks, suggesting that EF and VM can be useful endophenotypes for ADHD.
(2) Pharmacological approach: we examined the effect of atomoxetine on EF and VM in 30 drug-naïve boys with ADHD, aged 8-16, in an open-label trial after 12-week treatment. In addition to improvement in clinical and social functions, results showed significant improvement in EF and VM after treatment with atomoxetine for 4 weeks or 12 weeks. Our findings suggest that atomoxetine is effective in improving EF and VM among boys with ADHD.
(3) Neuroimaging approach: using 25 children with ADHD and 25 matched controls, we examined the association between the integrity of FS tracts and EF. The FS reconstructed by DSI tractography were subdivided into four segments, including dorsolateral, medial prefrontal, orbitofrontal, and ventrolateral tracts. Children with ADHD had lower generalized fractional anisotropy of all the bilateral frontostriatal fiber tracts. ADHD symptom severity and EF performance significantly correlated with integrity of the FS, particularly the left orbitofrontal and ventrolateral tracts.
(4) Genetic association approach: (a) we recruited a Chinese family-based sample (n = 906), and screened 15 polymorphisms across the DAT1 gene, including 14 SNPs and the variable number of tandem repeat (VNTR) polymorphism in 3´-untranslated region (3´UTR). Calculations of pairwise LD revealed three main haplotype blocks (HBs). Haplotype analysis showed that a haplotype rs27048 (C) /rs429699 (T) was significantly associated with the inattentive subtype. Our findings indicate that the DAT1 gene may primarily affect the inattentive subtype of ADHD.
(b) We extended the family-based sample (n = 1298) and examined the association between DAT1 and EF. Haplotype-based association tests showed that a haplotype rs403636 (G) /rs463379 (C) /rs393795 (C) /rs37020 (G) in HB1 was significantly associated with SWM errors. Our findings indicate that DAT1 plays a role in the SWM errors of ADHD.
In summary, in addition to EF, we identified VM as potential endophenotype for ADHD and found significant effects of atomoxetine on EF and VM. We demonstrated that EF was linked to disturbed integrity of frontostriatal tracts and variations of the DAT1 gene. Further pharmacogenetic and imaging genetic studies are needed to establish the pathophysiological pathways underlying ADHD.

並列關鍵字

Attention-deficit/hyperactivity disorder (ADHD) ； frontostriatal tracts (FS) ； diffusion spectrum imaging (DSI) ； executive function (EF) ； visual memory (VM) ； Cambridge Neuropsychological Test Automated Battery (CANTAB) ； DAT1 ； haplotype ； linkage disequilibrium (LD)

參考文獻

Abrahams, S., Morris, R. G., Polkey, C. E., Jarosz, J. M., Cox, T. C., Graves, M., et al. (1999). Hippocampal involvement in spatial and working memory: a structural MRI analysis of patients with unilateral mesial temporal lobe sclerosis. Brain Cogn, 41(1), 39-65.

Alarcon, M., Plomin, R., Fulker, D. W., Corley, R., & DeFries, J. C. (1998). Multivariate path analysis of specific cognitive abilities data at 12 years of age in the Colorado Adoption Project. Behavior Genetics, 28(4), 255-264.

Alberts-Corush, J., Firestone, P., & Goodman, J. T. (1986). Attention and impulsivity characteristics of the biological and adoptive parents of hyperactive and normal control children. Am J Orthopsychiatry, 56(3), 413-423.

Allen, A. J., Kurlan, R. M., Gilbert, D. L., Coffey, B. J., Linder, S. L., Lewis, D. W., et al. (2005). Atomoxetine treatment in children and adolescents with ADHD and comorbid tic disorders. Neurology, 65(12), 1941-1949.

Arnsten, A. F. (2009). Toward a new understanding of attention-deficit hyperactivity disorder pathophysiology: an important role for prefrontal cortex dysfunction. CNS Drugs, 23 Suppl 1, 33-41.