科學家繪製大腦前額葉皮質基因活動圖譜

威爾・丹納姆報導By Will Dunham

華盛頓，9月23日（路透社）——科學家已繪製出大腦關鍵區域「前額葉皮質」內基因活動的詳細圖譜，藉此深入了解正常發育，以及阿茲海默症、巴金森氏症和思覺失調症等重大腦部疾病。WASHINGTON, Sept 23 (Reuters) - Scientists have created a detailed map of gene activity within a crucial part of the brain called the prefrontal cortex, gaining insight into normal development and major brain disorders such as Alzheimer's disease, Parkinson's disease and schizophrenia.

在9項獨立研究中，研究人員檢視各類腦細胞隨時間發生的變化，並朝破解若干最具破壞性腦部疾病背後分子機制的方向取得進展，向可能的新療法邁出一步。In nine separate studies, the researchers examined changes in individual types of brain cells that occur over time and made progress toward deciphering molecular processes that underlie some of the most devastating brain disorders, a step toward possible new treatments.

前額葉皮質是大腦外層的前部，位於額頭後方。它協助人類規劃、做決策、調節情緒並調整行為。它也容易受到年齡相關退化影響，其功能會在許多精神疾病與神經退化性疾病中受影響。The prefrontal cortex is the front part of the brain's outer layer, located behind the forehead. It helps a person plan, make decisions, regulate emotions and adapt behavior. It also is sensitive to age-related decline, and its functions are affected in many psychiatric and neurodegenerative disorders.

研究檢視了超過630萬個腦細胞細胞核中的基因活動，這些細胞包括神經元、免疫細胞、與血管相關的細胞，以及有助維持腦部功能的支持細胞。樣本來自1,494名已故捐贈者，年齡從嬰兒到108歲不等，且具有不同遺傳血統。Gene activity was examined in the nuclei of more than 6.3 million brain cells — neurons, immune cells, cells associated with blood vessels and support cells that help maintain brain function — from 1,494 deceased donors, ranging in age from infancy to 108 years old, and with various genetic ancestries.

這些捐贈者包括未被診斷出腦部疾病的人，也包括被診斷罹患阿茲海默症、巴金森氏症、路易氏體失智症、血管性失智症、思覺失調症和雙相情緒障礙症等疾病的人。The donors included people with no diagnosed brain disorder as well as people diagnosed with conditions such as Alzheimer's, Parkinson's, Lewy body dementia, vascular dementia, schizophrenia and bipolar disorder.

研究找出若干疾病之間共有的模式，也找出部分個別疾病特有的模式。The research identified patterns shared across some of the diseases as well as some specific to individual disorders.

紐約市西奈山伊坎醫學院疾病神經基因體學中心主任、這項研究的主持人之一帕諾斯・魯索斯醫師表示：「整體而言，這些研究有助說明疾病相關變化發生的位置，以及哪些生物過程值得更深入研究。」這項研究週三發表於《自然》等期刊。"Together, these studies help explain where disease-related changes occur and which biological processes deserve closer investigation," said Dr. Panos Roussos, director of the Center for Disease Neurogenomics at the Icahn School of Medicine at Mount Sinai in New York City and a leader of the research published on Wednesday in Nature and other journals.

魯索斯說：「有用的治療必須在正確的細胞中影響正確的生物過程。這份圖譜有助縮小搜尋範圍。它可以辨識脆弱的細胞族群，揭示與保留腦部功能相關的過程，並協助研究人員決定要測試哪些潛在治療標的。」"A useful treatment needs to influence the right biological process in the right cells. This map helps narrow that search. It can identify vulnerable cell populations, reveal processes associated with preserved brain function and help researchers decide which potential treatment targets to test," Roussos said.

這項工作是PsychAD研究聯盟的一部分，並獲美國政府國家衛生研究院所屬國家老化研究所支持。The work was conducted as part of the PsychAD research consortium, with support from the National Institute on Aging, part of the US government's National Institutes of Health.

高度相似之處STRONG SIMILARITIES

阿茲海默症、路易氏體疾病、血管性失智症和巴金森氏症，在涉及神經細胞發育、神經元溝通和血管生物學的基因活動方面，呈現特別強烈的相似性。研究人員也在小膠質細胞中找出阿茲海默症與巴金森氏症共有的路徑；小膠質細胞是大腦內常駐的免疫細胞。Alzheimer's, Lewy body disease, vascular dementia and Parkinson's showed particularly strong similarities in gene activity involved in nerve-cell development, neuronal communication and blood-vessel biology. The researchers also identified pathways shared in Alzheimer's and Parkinson's in microglia, the brain's resident immune cells.

研究人員比較不同年齡捐贈者的腦部樣本後發現，從發育期到成年期間出現廣泛分子變化，成年大部分時期則相對穩定，之後到晚年又再度出現變化，尤其是在免疫細胞和支持細胞中。Comparing brain samples from donors of different ages, the researchers found extensive molecular changes during development until adulthood, relative stability through much of adulthood and then renewed changes later in life, particularly in immune and support cells.

魯索斯說：「這為區分典型老化與疾病相關變化提供了參考。」"This provides a reference for distinguishing typical aging from disease-associated changes," Roussos said.

研究人員將約24歲辨識為一個轉換點；在此之後，這個腦區多數細胞類型的主體變得較為穩定。The researchers identified approximately age 24 as a transition point after which the bulk of most cell types in this region become more stable.

魯索斯說：「這並不代表大腦會在某人24歲生日那天突然完成發育，也不代表衰退從那個年齡開始。腦部生物學的其他面向，終其一生都會持續變化。」"It does not mean the brain suddenly finishes developing on someone's 24th birthday, or that decline begins at that age. Other aspects of brain biology continue to change throughout life," Roussos said.

研究人員發現了與認知差異相關的細胞模式，以及與伴隨阿茲海默症出現的憂鬱相關的細胞模式。舉例來說，有些人雖然出現顯著的阿茲海默症病理變化，卻仍保有認知功能；這些人在腦細胞中與能量相關的過程上呈現差異。The researchers found cellular patterns associated with differences in cognition and with depression accompanying Alzheimer's. For instance, people who retained cognitive function despite experiencing substantial Alzheimer's pathology showed differences in energy-related processes in brain cells.

魯索斯說：「這些結果提供了可能保護機制的線索，而這些機制還需要進一步測試。」"These provide clues to possible protective mechanisms that need further testing," Roussos said.

遺傳性基因風險INHERITED GENETIC RISK

研究人員將疾病的遺傳性基因風險連結到特定基因和細胞類型，並繪製出遺傳因素對超過1萬4,000個基因活動的影響。The researchers connected inherited genetic risk of disorders to particular genes and cell types, and mapped genetic influences on the activity of more than 14,000 genes.

他們也利用一天中不同時間死亡者的腦部樣本，重建基因活動的每日模式。在年輕與中年成人中，每日生理時鐘基因在神經元中呈現協調一致的模式。在年長成人中，這些模式較弱，也較不同步。They also reconstructed daily patterns of gene activity using brain samples from people who died at different times of day. In younger and middle-aged adults, daily clock genes showed coordinated patterns in neurons. In older adults, those patterns were weaker and less synchronized.

魯索斯說：「這顯示老化會改變大腦內每日生物節律的組織方式。恢復這些節律是否能改善腦部健康，是未來研究的一個重要問題。」"This suggests that aging changes how daily biological rhythms are organized within the brain. Whether restoring those rhythms could improve brain health is an important question for future research," Roussos said.

研究人員也為個別阿茲海默症捐贈者建立分子輪廓，並辨識出不同個體在基因調控以及細胞類型之間預測互動上的差異。The researchers also built molecular profiles for individual donors who had Alzheimer's, and identified differences in gene regulation and predicted interactions between cell types among individuals.

魯索斯說：「這有助解釋具有相同診斷者之間的生物差異，也為研究更個人化的治療策略奠定基礎。」"This helps explain biological variation among people with the same diagnosis, and provides a foundation for investigating more individualized treatment strategies," Roussos said.

（威爾・丹納姆報導；丹尼爾・沃利斯編輯）(Reporting by Will Dunham; Editing by Daniel Wallis)