Comorbidities, confounders, and the white matter transcriptome in chronic alcoholism.
Comorbidities, confounders, and the white matter transcriptome in chronic alcoholism.
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DOI：
10.1111/acer.12341
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发表时间：
2014-04
期刊：
影响因子：
--
通讯作者：
Kril JJ
中科院分区：
文献类型：
--
作者：
Sutherland GT;Sheedy D;Sheahan PJ;Kaplan W;Kril JJ
酒精滥用是世界上第三大疾病和残疾原因，慢性滥用的一个潜在后遗症是酒精相关的脑损伤(ARBD)。这在临床上表现为认知功能障碍，在病理上尤其表现为白质萎缩。慢性酒精中毒与ARBD之间的联系机制在很大程度上仍不清楚，但它也因常见的并存疾病而变得复杂，如肝脏损伤和营养缺乏。尤其是肝硬变，往往会导致肝性脑病，这是一种原发的神经胶质疾病。在一项新的转录学研究中，我们只针对慢性酗酒者的白质，试图梳理ARBD的发病机制。具体地说，在有和没有肝性脑病的酗酒者中，我们研究了前额叶和初级运动皮质，这两个区域经历了不同程度的神经元丢失。我们的结果表明，肝性脑病和两个混杂因素，灰质污染和低RNA质量，是ARBD基因表达的主要驱动因素。这三个因素都超过了酒精本身的影响。特别是，低质量的RNA样本的特征是翻译机器上调，而肝性脑病与线粒体能量代谢途径下调有关。在HE酒精中毒患者中的发现与这种情况下的代谢性酸中毒是一致的。相比之下，非酒精性痴呆症患者脑白质中的基因表达发生了广泛但微妙的变化。尽管有后者的结果，但这项研究表明，在人类死后脑组织的转录研究中，显著的混杂因素可以被识别、量化和‘去除’，以揭示疾病特有的信号。
Alcohol abuse is the world's third leading cause of disease and disability and one potential sequel of chronic abuse is alcohol-related brain damage (ARBD). This clinically manifests as cognitive dysfunction and pathologically as atrophy of white matter in particular. The mechanism linking chronic alcohol intoxication with ARBD remains largely unknown but it is also complicated by common co-morbidities such as liver damage and nutritional deficiencies. Liver cirrhosis, in particular, often leads to hepatic encephalopathy, a primary glial disease. In a novel transcriptomic study we targeted the white matter only of chronic alcoholics in an attempt to tease apart the pathogenesis of ARBD. Specifically, in alcoholics with and without hepatic encephalopathy, we explored both the prefrontal and primary motor cortices, two regions that experience differential levels of neuronal loss. Our results suggest that hepatic encephalopathy, along with two confounders, gray matter contamination and low RNA quality, are major drivers of gene expression in ARBD. All three exceeded the effects of alcohol itself. In particular, low quality RNA samples were characterized by an upregulation of translation machinery while hepatic encephalopathy was associated with a downregulation of mitochondrial energy metabolism pathways. The findings in HE alcoholics are consistent with the metabolic acidosis seen in this condition. In contrast non-HE alcoholics had widespread but only subtle changes in gene expression in their white matter. Notwithstanding the latter result this study demonstrates that significant confounders in transcriptomic studies of human post mortem brain tissue can be identified, quantified and ‘removed’ to reveal disease-specific signals.
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DOI：
10.1111/j.1530-0277.2010.01197.x
发表时间：
2010-07
期刊：
Alcoholism, clinical and experimental research
影响因子：
--
作者：
Pfefferbaum A;Rosenbloom MJ;Fama R;Sassoon SA;Sullivan EV
通讯作者：
Sullivan EV
DOI：
10.1523/jneurosci.3136-11.2012
发表时间：
2012-02-01
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ponomarev I;Wang S;Zhang L;Harris RA;Mayfield RD
通讯作者：
Mayfield RD
影响因子：
12.7
作者：
KRIL, JJ;HARPER, CG
通讯作者：
HARPER, CG
影响因子：
2.9
作者：
Iwamoto, K;Bundo, M;Kato, T
通讯作者：
Kato, T
影响因子：
2.9
作者：
Mexal, S.;Berger, R.;Leonard, S.
通讯作者：
Leonard, S.