Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites.
Whole-blood metabolomics of dementia patients reveal classes of disease-linked metabolites.
复制标题
DOI：
10.1073/pnas.2022857118
复制
发表时间：
2021-09-14
影响因子：
11.1
通讯作者：
Yanagida M
中科院分区：
文献类型：
--
作者：
Teruya T;Chen YJ;Kondoh H;Fukuji Y;Yanagida M
痴呆症是一种缓慢进展的，慢性的，通常不可逆转的认知功能下降。机械原因和明确的治疗仍然难以捉摸。使用综合代谢组学，我们确定了5组33种代谢物（A至E），其中13种以前报道过，可能用于诊断和治疗痴呆症，如阿尔茨海默病。七种A类化合物可作为神经毒素，而B至E类化合物可保护神经系统免受氧化应激，维持能量储备，提供营养和神经保护因子。麦角硫因、S-甲基-麦角硫因、三甲基组氨酸、甲硫氨酸和色氨酸这5种代谢物与报告的虚弱代谢物重叠。对涉及这些痴呆代谢组学标志物的认知疾病的干预可以通过抑制A化合物或通过在患者中补充B至E化合物来实现。痴呆症是由损害神经元的因素引起的。我们使用非靶向液相色谱-质谱法（LC-MS）对痴呆患者全血中的小分子标志物进行定量。分为五组（A至E）的33种代谢物在痴呆患者中与健康老年受试者相比存在显著差异。血浆中存在的7种A代谢物，包括喹啉酸、犬尿氨酸和硫酸吲哚酚，增加。它们可能在中枢神经系统（CNS）中充当神经毒素。其余26种化合物（B至E）减少，可能导致痴呆症患者失去对大脑的支持或保护。六种B代谢物通常富集在红细胞（RBC）中，均含有三甲基铵部分。这些代谢物包括麦角硫因和结构相关的化合物，这些化合物几乎没有被研究为痴呆标志物，从而验证了RBC代谢物的检查。麦角硫因是一种有效的抗氧化剂，在各种认知相关疾病中显着减少，如轻度认知障碍和虚弱。C化合物还包括一些氧化还原剂，通常在RBC中丰富（NADP+、谷胱甘肽、三磷酸腺苷、泛酸、S-腺苷甲硫氨酸和葡萄糖酸盐）。痴呆症患者中它们的水平降低也可能导致大脑功能低下。12种D代谢物含有血浆化合物，如氨基酸、甘油磷酸胆碱、十二酰肉毒碱和2-羟基丁酸，这些化合物通常保护大脑，但它们在痴呆症中的减少可能会降低这种保护作用。七种D化合物以前已被确定为痴呆症标志物。B至E化合物可能通过直接或间接作用对维持CNS至关重要。红细胞代谢物如何在中枢神经系统中起作用，以及为什么它们在痴呆症中显着减少仍有待确定。
Dementia is a slowly progressing, chronic, and usually irreversible decline in cognitive function. Mechanistic causes and definitive treatments remain elusive. Using comprehensive metabolomics, we identified five groups of 33 metabolites (A to E), 13 of them previously reported, possibly useful for diagnosis and therapy of forms of dementia, such as Alzheimer’s disease. Seven A compounds may act as neurotoxins, whereas B to E compounds may protect the nervous system against oxidative stress, maintain energy reserves, supply nutrients and neuroprotective factors. Five metabolites, ergothioneine, S-methyl-ergothioneine, trimethyl-histidine, methionine, and tryptophan, overlap with those reported for frailty. Interventions for cognitive diseases involving these dementia metabolomic markers may be accomplished either by inhibiting A compounds or by supplementing B to E compounds in patients. Dementia is caused by factors that damage neurons. We quantified small molecular markers in whole blood of dementia patients, using nontargeted liquid chromatography–mass spectroscopy (LC-MS). Thirty-three metabolites, classified into five groups (A to E), differed significantly in dementia patients, compared with healthy elderly subjects. Seven A metabolites present in plasma, including quinolinic acid, kynurenine, and indoxyl-sulfate, increased. Possibly they act as neurotoxins in the central nervous system (CNS). The remaining 26 compounds (B to E) decreased, possibly causing a loss of support or protection of the brain in dementia. Six B metabolites, normally enriched in red blood cells (RBCs), all contain trimethylated ammonium moieties. These metabolites include ergothioneine and structurally related compounds that have scarcely been investigated as dementia markers, validating the examination of RBC metabolites. Ergothioneine, a potent antioxidant, is significantly decreased in various cognition-related disorders, such as mild cognitive impairment and frailty. C compounds also include some oxidoreductants and are normally abundant in RBCs (NADP+, glutathione, adenosine triphosphate, pantothenate, S-adenosyl-methionine, and gluconate). Their decreased levels in dementia patients may also contribute to depressed brain function. Twelve D metabolites contains plasma compounds, such as amino acids, glycerophosphocholine, dodecanoyl-carnitine, and 2-hydroxybutyrate, which normally protect the brain, but their diminution in dementia may reduce that protection. Seven D compounds have been identified previously as dementia markers. B to E compounds may be critical to maintain the CNS by acting directly or indirectly. How RBC metabolites act in the CNS and why they diminish significantly in dementia remain to be determined.
登录
查看更多内容
影响因子：
5.6
作者：
Adesso S;Magnus T;Cuzzocrea S;Campolo M;Rissiek B;Paciello O;Autore G;Pinto A;Marzocco S
通讯作者：
Marzocco S
影响因子：
5.5
作者：
CROSSLAND, J;MITCHELL, JF;WOODRUFF, GN
通讯作者：
WOODRUFF, GN
DOI：
10.1016/j.jpba.2014.10.010
发表时间：
2015-03-25
影响因子：
3.4
作者：
Gonzalez-Dominguez, Raul;Garcia-Barrera, Tamara;Luis Gomez-Ariza, Jose
通讯作者：
Luis Gomez-Ariza, Jose
影响因子：
6.1
作者：
FERNSTROM, MH;BAZIL, CW;FERNSTROM, JD
通讯作者：
FERNSTROM, JD
影响因子：
16.8
作者：
Cohen TJ;Friedmann D;Hwang AW;Marmorstein R;Lee VM
通讯作者：
Lee VM