Tumor metabolism and neurocognition in CNS lymphoma

Huimin Geng; Mazie Tsang; Lakshmipriya Subbaraj; Joseph Cleveland; Lingjing Chen; Ming Lu; Jigyasa Sharma; Daniel B Vigneron; John Kurhanewicz; Marisa LaFontaine; Tracy Luks; Bruce A Barshop; Jon Gangoiti; Javier E Villanueva-Meyer; James L Rubenstein

doi:10.1093/neuonc/noab045

Tumor metabolism and neurocognition in CNS lymphoma

Neuro Oncol. 2021 Oct 1;23(10):1668-1679. doi: 10.1093/neuonc/noab045.

Authors

Huimin Geng^{1

2}, Mazie Tsang³, Lakshmipriya Subbaraj⁴, Joseph Cleveland⁴, Lingjing Chen⁴, Ming Lu^{3

4}, Jigyasa Sharma⁵, Daniel B Vigneron⁵, John Kurhanewicz⁵, Marisa LaFontaine⁵, Tracy Luks⁵, Bruce A Barshop⁶, Jon Gangoiti⁶, Javier E Villanueva-Meyer^{2

5}, James L Rubenstein^{2

3}

Affiliations

¹ Department of Laboratory Medicine, University of California, San Francisco (UCSF), San Francisco, California, USA.
² Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco (UCSF), San Francisco, California, USA.
³ Division of Hematology/Oncology, University of California, San Francisco (UCSF), San Francisco, California, USA.
⁴ Department of Medicine, University of California, San Francisco (UCSF), San Francisco, California, USA.
⁵ Department of Radiology and Biomedical Imaging, University of California, San Diego, San Diego, California, USA.
⁶ Department of Genetics and Pediatrics, University of California, San Diego, San Diego, California, USA.

Abstract

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.

Keywords: lymphoma metabolism; neurocognition; neurotransmitter pathways.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Brain Neoplasms*
Central Nervous System Neoplasms* / drug therapy
Humans
Lymphoma* / drug therapy
Lymphoma, Non-Hodgkin*
Rituximab
Tumor Microenvironment

Substances

Rituximab

Abstract

Publication types

MeSH terms

Substances

Grants and funding