Tumor metabolism and neurocognition in CNS lymphoma

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.

Fig. 1

Example of the application of proton magnetic resonance spectroscopy in the diagnostic evaluation of primary CNS lymphoma at presentation. MRI (T1 axial post-gadolinium) demonstrates a lobular, diffusely enhancing, cortical, and subcortical mass in the left superior frontal gyrus in an 81-year-old patient. Spectroscopy of the tumor demonstrates significantly elevated lactate and choline with suppression of NAA metabolites, a characteristic pattern of metabolites in primary and metastatic brain cancers. Abbreviations: CNS, central nervous system; MRI, magnetic resonance imaging; NAA, N-acetyl aspartate.

Fig. 2

Correlation of CSF citrate concentrations with increasing age in relapsed CNS lymphoma patients. (A) Of 18 metabolites, measured at the baseline, pre-treatment time point, only CSF citrate correlated with increasing age. (B) Citrate concentrations increased with patient age (range, 47-79 years). Spearman correlation P value <.0053, ρ = 0.70, and Pearson correlation P value <.015, r = 0.63. (C) There was no correlation between CSF, GABA, or other metabolites with age. Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; GABA, gamma-aminobutyric acid.

Fig. 3

Correlation of metabolites with mini-mental state examination (MMSE) scores. Mean (±SEM) concentration of metabolites and neurotransmitters in ventricular CSF in patients with relapsed CNS lymphoma. (A) The concentrations of 18 CSF metabolites from 51 collections of ventricular CSF were correlated with paired MMSE scores determined at pre-treatment visits and up to the first 3 months of study. P values from Spearman correlation. (B) CSF lactate concentrations strongly correlated with lower MMSE score (P < 8E-8, ρ = −0.67). GABA concentrations in CSF positively correlated with MMSE score (P < .007, ρ = 0.37). Generalized estimating equation (GEE) models were established with biomarker as an independent variable and MMSE score as a dependent variable, adjusting for within-subject repeated measures. Significant GEE P values were indicated by p* for lactate and ratio of glutamate/GABA, while GEE P values were not significant for GABA and succinate. (C) CSF lactate concentrations and ratio of glutamate/GABA at baseline, pre-treatment time point, were strongly correlated with MMSE score. (D) CSF lactate and ratio of glutamate/GABA concentrations were strongly associated with the extremes of cognitive dysfunction in this study (MMSE score ≤23) compared to higher scores of ≥27. P values were calculated from 2-sided Wilcoxon test. p* indicates significant P values from GEE models, with group as an independent variable and biomarker as a dependent variable, adjusting for within-subject repeated measures. Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; GABA, gamma-aminobutyric acid.

Fig. 4

(A) Correlation of CSF lactate with concentrations of neurotransmitters and succinate. High CSF lactate correlates with lower CSF GABA concentration (P < .0008, ρ = −0.46) and with higher glutamate/GABA ratios in CNS lymphoma (P < .022; ρ = 0.32). Lactate also positively correlated with increased dopamine concentration in CSF (P < 8.4E-6, ρ = 0.58). Significant P values from GEE model were indicated by p*. (B) Time-dependent inverse correlations between CSF lactate and CSF GABA. Patient 1 demonstrated stable disease at restaging at Cycles 1 and 2 with lenalidomide. Decreases in lactate were associated with increases in GABA. Patients 13 and 14 responded to lenalidomide. Decreases in lactate were associated with increases in GABA. Patient 5 exhibited initial response to lenalidomide, with a decrease in lactate and increase in GABA at 1 month. After 2 months, lymphoma progression was associated with reciprocal increase in lactate and decrease in GABA. Patient 7 exhibited disease progression at month 2 of lenalidomide. Reciprocal increases in lactate and decreases in GABA were detected. Patient 9 exhibited early disease progression shortly after screening and was removed from the study. Reciprocal increase in lactate and decrease in GABA were detected. Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; GABA, gamma-aminobutyric acid.