基因多型性對工作記憶的影響: 以功能性磁振造影分析

Influence of gene polymorphism on working memory: an fMRI approach

陳致中(Chih-Chung Chen)

指導教授 ： 邱泓文

共同指導教授 ： 胡朝榮(Chaur-Jong Hu)

臺北醫學大學/醫學科技學院/醫學資訊研究所/博士(2016年)

摘要

研究背景及目的: 人類的整體認知能力和工作記憶功能息息相關，而工作記憶又高度由遺傳因素所影響。在各種腦部的神經傳導物質和神經營養因子中，多巴胺在工作記憶的發展和可塑性上扮演很重要的角色。因此，過去針對工作記憶的研究多著重在 COMT 基因的多型性上。目前，我們對於 APOE 和 BDNF 基因多型性對於工作記憶的影響還不是非常清楚。
研究材料及方法: 以參加體檢且無主觀及客觀認知功能障礙的中年健康志願者為研究對象, 志願者先接受 APOE 或 BDNF 的基因多型性分析。實驗一針對 APOE 基因之多型性，將受試者分為帶 APOE4 和不帶 APOE4 兩組，實驗二針對 BDNF 基因之多型性，將受試者分為帶 Met-allel 和不帶 Met-allel 兩組。所有受測者均在功能性磁振造影下執行 n-back 工作記憶測試。實驗一分析九位帶 APOE4 和九位不帶 APOE4 受試者的功能性磁振造影資料；實驗二則分析十一位帶 BDNF Met-allel 和九位不帶 Met-allel 受試者的功能性磁振造影資料。
結果: 所有組別的工作記憶表現相近，無統計上顯著差異。在功能性磁振造影分析下，四組受測者均呈現工作記憶需求增加時，腦部活化區域增加的現象。帶 APOE4 受試者在較低工作記憶需求時，呈現比不帶 APOE4 受試者更多的腦部活化，有統計上的差異。但在較高工作記憶需求時，呈現比不帶 APOE4 受試者更少的腦部活化，也具有統計上的差異。帶 BDNF Met-allel 受試者則呈現一致性地在右上額葉迴及中枕葉迴活化較低的現象，具有統計上顯著差異。
結論: 從本研究得知，APOE 和 BDNF 基因多型性對於認知功能正常之健康人，在工作記憶上仍有一些影響。推測 APOE4 可能造成工作記憶容量的下降，而 BDNF Met-allel 則可影響工作記憶網路的發育和分化。建議未來進行更大規模和更長時間的研究來支持本實驗的發現。

關鍵字

基因多型性 ； 工作記憶 ； 功能性磁振造影

並列摘要

BACKGROUND AND PURPOSE: Variations in general cognitive abilities covary with individuals’ working memory (WM) capacity. WM is influenced by a highly heritable (99%)
common factor. Among several neurotransmitters and neurotrophic factors, dopamine plays important role in WM development and plasticity. Previous gene-cognition
association studies of WM have mainly focused on Catechol-O-Methyltransferase (COMT) genes. The effects of polymorphisms in APOE and Brain-Derived Neurotrophic
Factor (BDNF) genes on WM are not completed understood yet.
MATERIALS AND METHODS: Healthy middle-aged participants without objective or subjective cognitive impairment underwent APOE or BDNF genotyping. A two-arm study was
designed. APOE4 carriers and non-carriers were recruited in study 1 and BDNF Met-allele carriers and non-carriers were recruited in study 2. In both studies, all candidates received blood oxygen level– dependent contrast (BOLD) fMRI examinations during n-back WM tasks. In study 1, fMRI data of 9 APOE4 carriers and 9 non-carriers were compared. In study 2, fMRI data of 11 BDNF Met-allele carriers and 9 non-carriers were compared.
RESULTS: The WM performance was similar in all groups. All groups displayed increased brain activation in response to increases in WM loads. During low-WM-load tasks, the APOE4 carriers recruited significantly greater additional processing resources than the non-APOE4 carriers. During moderate- and high-WM-load tasks, the APOE4 carrier group displayed fewer increases in activation than the non-APOE4 carrier group. The BDNF Met allele carrier group showed consistently lower brain activation in the right superior frontal gyrus (SFG) and the middle occipital gyrus than that of the noncarrier group (P < .001). No brain region showed increased activation during WM tasks in the Met allele group.
CONCLUSIONS: APOE and BDNF genetic polymorphisms may affect WM in healthy subjects. The patterns of brain activation during different levels of WM load suggest possible subclinical impairment of WM capacity in APOE4 carriers. BDNF Met-allele carriers have lower brain activation in the right SFG and middle occipital gyrus. Defective development of the WM network during brain maturation or differentiation is a possible mechanism. Additional studies with a larger sample and longer follow-up period are warranted.

並列關鍵字

APOE ； BDNF ； polymorphism ； working memory ； fMRI

參考文獻

Chen, C.-J., Chen, C.-C., Wu, D., Chi, N.-F., Chen, P.-C., Liao, Y.-P., … Hu, C.-J. (2013). Effects of the apolipoprotein E ε4 allele on functional MRI during n-back

Huang, C. C., Liu, M. E., Chou, K. H., Yang, A. C., Hung, C. C., Hong, C. J., … Lin, C. P. (2014). Effect of BDNF Val66Met polymorphism on regional white matter

Molendijk, M. L., Bus, B. A. A., Spinhoven, P., Kaimatzoglou, A., Oude Voshaar, R. C., Penninx, B. W. J. H., … Elzinga, B. M. (2012). A systematic review and metaanalysis on the association between BDNF val(66)met and hippocampal volume--a genuine effect or a winners curse? American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics: The Official Publication of the International Society of Psychiatric Genetics, 159B(6), 731–740.

Liu, C. K., Lin, R. T., Chen, Y. F., Tai, C. T., Yen, Y. Y., & Howng, S. L. (1996). Prevalence of dementia in an urban area in taiwan. Journal of the Formosan Medical Association = Taiwan Yi Zhi, 95(10), 762–768.

Albert, P. R. (2011). What is a functional genetic polymorphism? Defining classes of functionality. Journal of Psychiatry & Neuroscience : JPN, 36(6), 363–365.