Neuroprotective kynurenine metabolite indices are abnormally reduced and positively associated with hippocampal and amygdalar volume in bipolar disorder

Abstract

Inflammation-related changes in the concentrations of kynurenine-pathway metabolites occur in depression secondary to medical conditions but have not been well characterized in primary bipolar disorder (BD), with contradictory results potentially attributable to the presence or absence of psychosis and/or medication effects. In contrast, reductions in hippocampal and amygdalar volume that theoretically reflect dendritic atrophy occurring in the context of a neurotoxic process are commonly reported in unmedicated BD patients. Here we tested whether the concentrations of putatively neuroprotective (kynurenic acid, KynA) and neurotoxic (3-hydroxy-kynurenine, 3HK and quinolinic acid, QA) kynurenine-pathway metabolites were altered in primary BD and whether these metabolites were associated with hippocampal and amygdalar volume. Twenty-five moderately-to-severely depressed unmedicated subjects and 38 moderately-to-severely depressed medicated subjects who met DSM-IV-TR criteria for BD, as well as 48 healthy controls (HCs) completed a structural MRI scan and provided a blood sample for kynurenine metabolite analysis, performed using high performance liquid chromatography with tandem mass spectrometry. Gray matter volumes were measured with the automated segmentation software, FreeSurfer. A putative neuroprotective index, KynA/QA, was significantly lower in the BD subjects relative to the HCs, a finding that was unrelated to current treatment with medication or a prior history of psychosis. Further, another putative neuroprotective index, KynA/3HK was positively associated with hippocampal volume in the BD group after controlling for age, sex, body mass index (BMI), and intracranial volume (ICV). Kyn/3HK was significantly associated with total amygdalar volume in the BD group, but after controlling for age, sex, BMI, but not ICV, this association was reduced to a trend. In addition, Kyn/3HK was positively associated with amygdalar volume in the HCs although the association was no longer significant after accounting for the effects of age, sex, and BMI. The results raise the possibility that BD-associated abnormalities in kynurenine metabolism may impact the structure of the hippocampus and amygdala, highlighting a pathway through which inflammation may exert neuropathological effects in the context of depression.

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“…Higher levels of KYNA relative to QUIN may theoretically be neuroprotective. 2,3 KYNA is a glutamate receptor antagonist that can prevent excitotoxicity 44 and protect against oxidative stress.…”

“…12 Interestingly, we previously reported a reduction in the ratio of KYNA to QUIN in major depressive disorder (MDD). 2,3 Further, KYNA/QUIN was positively associated with hippocampal volume in the MDD subjects. Abnormalities in KYN pathway metabolites have also been documented in other neuroinflammatory disorders, such as Alzheimer disease.…”

“…Imbalances in kynurenine (KYN) pathway metabolism are hypothesized to be associated with dysregulated glutamatergic neurotransmission, which has been proposed as a mechanism behind neuropathological changes in various psychiatric and neurological disorders. [2][3][4] The KYN metabolic pathway is a major route for degradation of tryptophan in both the periphery and central nervous system (CNS). Various pro-inflammatory cytokines activate the enzyme indoleamine 2,3-dioxygenase (IDO), altering the metabolism of tryptophan to increase KYN release, and simultaneously enhancing the activity of the enzyme kynurenine-3-monooxygenase (KMO), shifting KYN metabolism away from kynurenic acid (KYNA) toward 3-hydroxykynurenine (3HK) and subsequently the terminal metabolite, quinolinic acid (QUIN).…”

“…8 Based in part on their contrasting effects on the NMDA receptor, KYNA has been hypothesized to exert neuroprotective effects while 3HK and QUIN have been hypothesized to be neurotoxic in the context of injury, neuroinflammatory diseases, and psychiatric diseases. [2][3][4] The proposed neuromodulatory effects of KYN metabolites receive support from the pre-clinical and clinical literature. For instance, disturbances in the KYN pathway have been documented after severe injury to the CNS.…”

“…The positive relationship between KYNA/3HK and left ventromedial PFC in HC is consistent with the hypothesis that KYNA/3HK is a neuroprotective measure given the respective actions of KYNA and 3HK in the CNS. 2,3 Further, a post-mortem analysis of MDD and bipolar patients found an increased level of QUIN-positive cells in the anterior cingulate cortex, suggesting that KYN pathway abnormalities may also affect the ventromedial PFC. 49 Why the current study only found a relationship in HC is unclear.…”