Effects of kynurenine pathway metabolites on choroid plexus volume, hemodynamic response, and spontaneous neural activity: A new mechanism for disrupted neurovascular communication and impaired cognition in mood disorders

Abstract

Major Depressive Disorder (MDD) and Bipolar Disorder (BD) involve alterations of immune-inflammatory setpoints that activate the kynurenine pathway (KP), affecting serotoninergic and glutamatergic neurotransmission through indoleamine-2,3-dioxygenase (IDO) activity. This process produces metabolites like Kynurenine (Kyn), 3-Hydroxykynurenine (3-HK), Quinolinic acid (QuinA), and Kynurenic acid (KynA), these last two acting as agonist and antagonist at glutamatergic N-methyl-D-aspartate receptors (NMDARs), respectively. NMDARs, expressed in the choroid plexus (ChP) and arteriolar smooth muscle cells, regulate blood–brain-barrier permeability and cerebral artery dilation, suggesting that KP may influence neurovascular coupling, aligning blood flow with neural energy demand. KP’s role in modulating vascular tone supports this hypothesis. Altered fractional amplitude of low-frequency fluctuations (fALFF) and disrupted default mode network (DMN) activity in mood disorders are linked to cognitive deficits possibly through neurovascular uncoupling like in neurological diseases. This makes fALFF and hemodynamic response function (HRF) potential indicators of these changes. We investigated KP associations with ChP volumes, functional-MRI at rest measures like spontaneous neural activity (fALFF) and hemodynamic response function (HRF) parameters within the default mode network (DMN), and cognitive performance in 42 MDD and 36 BD inpatients experiencing a depressive episode.

Results revealed that lower QuinA/KynA ratios and higher KynA levels predict larger ChP volumes. Higher KYN and 3-HK levels, along with lower KynA levels, were associated with increased DMN fALFF and shorter time-to-peak (TTP) in HRF, suggesting altered neurovascular coupling. Mediation analyses indicated that KP metabolites influenced cognitive performance through their effects on resting state measures, affecting global cognitive functioning score, verbal fluency, and psychomotor coordination. These findings suggest that KP metabolites modulate brain function and structure via NMDAR-mediated pathways and vascular-based mechanisms, offering insights into the cognitive impairments observed in mood disorders and identifying potential therapeutic targets.