中枢神经系统淋巴瘤中的肿瘤代谢与神经认知。
Tumor metabolism and neurocognition in CNS lymphoma.
机构信息
Department of Laboratory Medicine, University of California, San Francisco (UCSF), San Francisco, California, USA.
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, California, USA.
出版信息
Neuro Oncol. 2021 Oct 1;23(10):1668-1679. doi: 10.1093/neuonc/noab045.
BACKGROUND
The mechanistic basis for neurocognitive deficits in central nervous system (CNS) lymphoma and other brain tumors is incompletely understood. We tested the hypothesis that tumor metabolism impairs neurotransmitter pathways and neurocognitive function.
METHODS
We performed serial cerebrospinal fluid (CSF) metabolomic analyses using liquid chromatography-electrospray tandem mass spectrometry to evaluate changes in the tumor microenvironment in 14 patients with recurrent CNS lymphoma, focusing on 18 metabolites involved in neurotransmission and bioenergetics. These were paired with serial mini-mental state examination (MMSE) and MRI studies for tumor volumetric analyses. Patients were analyzed in the setting of the phase I trial of lenalidomide/rituximab. Associations were assessed by Pearson and Spearman correlation coefficient. Generalized estimating equation (GEE) models were also established, adjusting for within-subject repeated measures.
RESULTS
Of 18 metabolites, elevated CSF lactate correlated most strongly with lower MMSE score (P < 8E-8, ρ = -0.67). High lactate was associated with lower gamma-aminobutyric acid (GABA), higher glutamate/GABA ratio, and dopamine. Conversely, high succinate correlated with higher MMSE scores. Serial analysis demonstrated a reproducible, time-dependent, reciprocal correlation between changes in lactate and GABA concentrations. While high lactate and low GABA correlated with tumor contrast-enhancing volume, they correlated more significantly with lower MMSE scores than tumor volumes.
CONCLUSIONS
We provide evidence that lactate production and Warburg metabolism may impact neurotransmitter dysregulation and neurocognition in CNS lymphomas. We identify novel metabolomic biomarkers that may be applied in future studies of neurocognition in CNS lymphomas. Elucidation of mechanistic interactions between lymphoma metabolism, neurotransmitter imbalance, and neurocognition may promote interventions that preserve cognitive function.
背景
中枢神经系统（CNS）淋巴瘤和其他脑肿瘤导致神经认知功能缺陷的机制基础尚未完全阐明。我们检验了这样一个假说，即肿瘤代谢会损害神经递质通路和神经认知功能。
方法
我们使用液相色谱-电喷雾串联质谱法进行了一系列脑脊液（CSF）代谢组学分析，以评估 14 例复发性 CNS 淋巴瘤患者肿瘤微环境的变化，重点关注涉及神经传递和生物能量学的 18 种代谢物。这些代谢物与连续的简易精神状态检查（MMSE）和 MRI 肿瘤体积分析配对。患者在来那度胺/利妥昔单抗的 I 期试验中进行分析。通过 Pearson 和 Spearman 相关系数评估相关性。还建立了广义估计方程（GEE）模型，对个体内重复测量进行了调整。
结果
在 18 种代谢物中，CSF 中升高的乳酸与 MMSE 评分降低的相关性最强（P < 8E-8，ρ = -0.67）。高乳酸与低γ-氨基丁酸（GABA）、高谷氨酸/GABA 比值和多巴胺有关。相反，高琥珀酸与 MMSE 评分较高相关。系列分析表明，乳酸和 GABA 浓度的变化之间存在可重复的、时间依赖的、相互关联的关系。虽然高乳酸和低 GABA 与肿瘤增强体积相关，但与 MMSE 评分的相关性比肿瘤体积更显著。
结论
我们提供了证据表明，乳酸生成和瓦博格代谢可能会影响 CNS 淋巴瘤中的神经递质失调和神经认知功能。我们确定了新的代谢组学生物标志物，这些标志物可应用于未来 CNS 淋巴瘤神经认知的研究中。阐明淋巴瘤代谢、神经递质失衡和神经认知之间的机制相互作用，可能会促进保持认知功能的干预措施。
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