文章：

化疗诱导的认知改变的候选机制

Candidate mechanisms for chemotherapy-induced cognitive changes

原文发布日期：2007-03-01

DOI: 10.1038/nrc2073

类型: Review Article

开放获取: 否

要点：

1. Evidence for chemotherapy-induced cognitive changes comes from studies that have used neuropsychological testing, imaging (structural and functional magnetic resonance imaging (MRI) and positron emission tomography (PET)) and electrophysiological (electroencephalogram) assessments. Emerging data from animal studies also support the effect of chemotherapy on cognitive function.
2. Most chemotherapy agents administered systemically do not cross the blood–brain barrier in significant doses; however, the amount that enters the brain can be modified by genetic variability in blood–brain barrier transporters. In addition, recent data from animal studies suggest that very small doses of common chemotherapy agents can cause cell death and reduced cell division in brain structures crucial for cognition, even at doses that do not effectively kill tumour cells.
3. Chemotherapy might cause cognitive changes through DNA damage caused directly by the cytotoxic agents or through increases in oxidative stress. Many chemotherapeutic agents also cause the shortening of telomeres, thereby accelerating cell ageing. Genetic variability in DNA-repair genes might influence the extent of, and recovery from, chemotherapy-associated DNA damage.
4. Chemotherapy-induced cognitive changes might also be related to the neurotoxic effects of cytokine deregulation. Cytokine deregulation and inflammation can also lead to increased oxidative stress, which could establish a cycle of increased DNA damage that triggers additional cytokine release.
5. Variability in genes that regulate neural repair and/or plasticity, such as apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF), and neurotransmission, such as catechol-O-methyltransferase (COMT), might increase the vulnerability of an individual to chemotherapy-induced cognitive changes.
6. Changes in levels of oestrogen and testosterone are associated with cognitive decline, and can be influenced by chemotherapy (for example, chemotherapy-induced menopause) or hormonal treatments, such as tamoxifen or aromatase inhibitors for breast cancer or androgen ablation for prostate cancer.
7. The effects of chemotherapy-associated cardiovascular toxicity and alterations in neuroendocrine function on cognitive function require investigation.

要点翻译：

1. 化疗引发认知改变的证据来自神经心理学测试、影像学（结构和功能磁共振成像及正电子发射断层扫描）及电生理学（脑电图）评估的研究。动物研究的新数据也支持化疗对认知功能的影响。
2. 大多数全身给药的化疗药物难以大量透过血脑屏障；然而，通过血脑屏障转运蛋白的遗传变异可改变进入大脑的药量。此外，动物研究的最新数据表明，极小剂量的常见化疗药物即可在与认知密切相关的脑结构中引发细胞死亡并减少细胞分裂，其剂量甚至不足以有效杀伤肿瘤细胞。
3. 化疗可能通过细胞毒性药物直接造成DNA损伤或增加氧化应激而导致认知改变。许多化疗药物还会缩短端粒，从而加速细胞衰老。DNA修复基因的遗传变异可能影响化疗相关DNA损伤的程度及恢复过程。
4. 化疗引发的认知改变也可能与细胞因子失调的神经毒性作用相关。细胞因子失调和炎症反应还会加剧氧化应激，形成DNA损伤加重与细胞因子进一步释放的恶性循环。
5. 神经修复和/或可塑性相关基因（如载脂蛋白E和脑源性神经营养因子）以及神经传递相关基因（如儿茶酚-O-甲基转移酶）的变异，可能增加个体对化疗所致认知改变的易感性。
6. 雌激素和睾酮水平变化与认知衰退相关，并可能受化疗（如化疗引发的绝经）或激素治疗影响，例如乳腺癌患者使用的他莫昔芬或芳香酶抑制剂，前列腺癌患者的雄激素剥夺治疗。
7. 化疗相关心血管毒性及神经内分泌功能改变对认知功能的影响尚需进一步研究。

英文摘要：

The mechanism(s) for chemotherapy-induced cognitive changes are largely unknown; however, several candidate mechanisms have been identified. We suggest that shared genetic risk factors for the development of cancer and cognitive problems, including low-efficiency efflux pumps, deficits in DNA-repair mechanisms and/or a deregulated immune response, coupled with the effect of chemotherapy on these systems, might contribute to cognitive decline in patients after chemotherapy. Furthermore, the genetically modulated reduction of capacity for neural repair and neurotransmitter activity, as well as reduced antioxidant capacity associated with treatment-induced reduction in oestrogen and testosterone levels, might interact with these mechanisms and/or have independent effects on cognitive function.

摘要翻译： 

化疗所致认知变化的机制在很大程度上仍不清楚；然而，已有若干候选机制被提出。我们认为，癌症与认知障碍的共同遗传危险因素——包括低效率外排泵、DNA修复机制缺陷和/或免疫反应失调——以及化疗对这些系统的影响，可能共同促成患者化疗后的认知下降。此外，经遗传调控的神经修复能力下降、神经递质活性降低，以及由治疗引起的雌激素和睾酮水平下降所伴随的抗氧化能力减弱，既可能与上述机制相互作用，也可能独立影响认知功能。

原文链接：

Candidate mechanisms for chemotherapy-induced cognitive changes