Kynurenine pathway dysregulation as a mechanistic link between cognitive impairment and brain damage: Implications for multiple sclerosis

• Quinolinic and kynurenic acid modulate cognition via altered neurotransmission. • Peripheral manipulation of CNS kynurenine pathway activity alters cognition. • Systemic kynurenines are associated with MS-relevant biomarkers, such as NfL. • Systemic kynurenines are associated with MS-relevant cognitive domains. Cognitive impairment is a core symptom of multiple sclerosis (MS), resulting from inflammation-related brain damage and brain network dysfunction. Inflammation also causes dysregulation of the kynurenine pathway, which is the primary route of tryptophan metabolism. Kynurenine pathway dysregulation is characterised by a shift in concentrations of tryptophan catabolites, also referred to as kynurenines. Some kynurenines have neurotoxic effects that partly resemble the molecular mechanisms of MS pathophysiology underpinning brain damage and brain network dysfunction. The kynurenine pathway may therefore qualify as a mechanistic link between systemic inflammation, brain damage, and cognitive impairment in MS. This perspective article (1) provides an overview of inflammation-related kynurenine pathway dysregulation and MS-relevant neuroimmune properties of kynurenines and (2) summarises the current evidence on associations between systemic kynurenines, imaging metrics of brain structure or related markers, and cognitive performance in populations that present with kynurenine pathway dysregulation and are prone to cognitive impairment. These findings are used to (3) set a research agenda for future studies aimed at clarifying the role of the kynurenine pathway in brain damage and cognitive impairment in MS.