Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID).
Homocysteine, hyperhomocysteinemia and vascular contributions to cognitive impairment and dementia (VCID).
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DOI：
10.1016/j.bbadis.2015.11.015
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发表时间：
2016-05
期刊：
影响因子：
--
通讯作者：
Wilcock DM
中科院分区：
文献类型：
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作者：
Hainsworth AH;Yeo NE;Weekman EM;Wilcock DM
同型半胱氨酸在所有细胞中生理性地产生，并存在于健康人的血浆中(血浆[HCy]：3-10微米)。虽然罕见的基因突变(CBS，MTHFR)会导致严重的高同型半胱氨酸血症([HCy]：100-200微米)，但轻度-中度高同型半胱氨酸血症([HCy]：10-100微米)在老年人中很常见，是中风和认知障碍的独立危险因素。由于补充维生素B(B6、B12和叶酸)具有良好的降低同型半胱氨酸的功效，这可能是导致认知障碍和痴呆(VCID)的血管因素中一个容易改变的危险因素。在这里，我们回顾了与VCID相关的HCY的生化和细胞作用。HCy的神经活动浓度高于临床相关范围。HCy<；100µM的作用主要是血管方面的，包括心肌细胞增殖、血管壁纤维化、一氧化氮信号转导受损、超氧化物生成和促凝作用。讨论了与VCID相关的降低HCy的临床试验。广泛的临床和临床前数据支持同型半胱氨酸作为VCID的介体。在我们看来，需要进行更多的联合补充维生素B的试验，结合以前试验和最近的实验工作的经验教训。为了最大限度地提高治疗效果的可能性，未来的试验应该：提供高剂量的组合补充剂(B6、B12和叶酸)；针对高危年龄范围；针对基线维生素B水平较低的队列。
Homocysteine is produced physiologically in all cells, and is present in plasma of healthy individuals (plasma [HCy]: 3–10µM). While rare genetic mutations (CBS, MTHFR) cause severe hyperhomocysteinemia ([HCy]: 100–200µM), mild-moderate hyperhomocysteinemia ([HCy]: 10–100µM) is common in older people, and is an independent risk factor for stroke and cognitive impairment. As B-vitamin supplementation (B6, B12 and folate) has well-validated homocysteine-lowering efficacy, this may be a readily-modifiable risk factor in vascular contributions to cognitive impairment and dementia (VCID). Here we review the biochemical and cellular actions of HCy related to VCID. Neuronal actions of HCy were at concentrations above the clinically-relevant range. Effects of HCy <100 µM were primarily vascular, including myocyte proliferation, vessel wall fibrosis, impaired nitric oxide signalling, superoxide generation and pro-coagulant actions. HCy-lowering clinical trials relevant to VCID are discussed. Extensive clinical and preclinical data support Hcy as a mediator for VCID. In our view further trails of combined B-vitamin supplementation are called for, incorporating lessons from previous trails and from recent experimental work. To maximise likelihood of treatment effect, a future trial should: supply a high-dose, combination supplement (B6, B12 and folate); target the at-risk age range; target cohorts with low baseline B-vitamin status.