Abstract 4975: Tumor metabolism and cognitive dysfunction in CNS lymphoma

Background: The etiologic basis for neurocognitive and neuropsychological deficits in cancer patients and cancer survivors is poorly understood. Because of ongoing improvements in therapy and advances in survival, the problem of cancer-associated cognitive dysfunction is increasingly significant. While there is agreement that T2-weighted imaging abnormalities on MRI correlate with neurocognitive deficits, there has been limited insight into the neurochemical abnormalities associated with cognitive dysfunction in brain tumor patients. We are testing the hypothesis that tumor metabolism directly impairs neurotransmitter pathways and cognitive function, independent of anatomic extent of the cancer. Methods: Our approach has been to focus on a type of brain tumor, CNS lymphoma, in which we are able to simultaneously monitor cognitive function, as assayed by repeat Mini-Mental Status Examinations (MMSE), tumor volume, as assessed by MRI, and dynamic changes in the tumor metabolic microenvironment, as characterized by quantitative measurement of tumor-associated metabolites in correlation with neurotransmitters that we hypothesize to be linked to normal cognitive function. Our initial study was to evaluate 14 subjects with CNS lymphoma that were treated on a phase I trial of the immunomodulatory agent lenalidomide. Volumetric analysis of CNS lymphomas was performed using Smartbrush Software (Brainlab) on pre-and post-therapy MRI9s conducted at baseline and at monthly restaging. Metabolomic analysis of cerebrospinal fluid (CSF), using GC/MS, was conducted at baseline and at timepoints within 1 week of corresponding MRI. MMSE tests were conducted in all subjects at baseline and at corresponding monthly restaging examinations. Results: Of 20 CSF metabolites analyzed, including 12 neurotransmitters, elevated CSF lactate correlated most strongly with impaired neurocognitive function as measured by MMSE score. (P=2.5e-6; rho= -0.66). Patients with high lactate had lower relative CSF concentration of the inhibitory neurotransmitter GABA, and higher concentrations of the excitotoxic glutamate. Notably, we determined that CSF lactate concentration more significantly correlated with lower MMSE score than size of the brain tumor, as quantified by volumetric analysis of tumor T2 hyperintensity and lesional contrast-enhancing volume. Conclusions: To our knowledge, this is the first data linking cancer metabolism, neurotransmitter dysregulation, and neurocognitive deficits in a brain tumor patient population. We anticipate that elucidation of the mechanistic basis between tumor lactate metabolism, neurotransmitter imbalance, and neurocognitive deficits will provide potential opportunities for pharmacologic intervention to preserve neurologic function and potentially minimize cognitive and neuropsychological deficits in cancer patients. Citation Format: Lakshmi Subbaraj, Huimin Geng, Jigyasa Sharma, Marisa LaFontaine, James L. Rubenstein. Tumor metabolism and cognitive dysfunction in CNS lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4975.