Influence of Uric Acid on Vascular and Cognitive Functions: Evidence for an Ambivalent Relationship

Abstract

The growing recognition of the public health impact of cognitive impairment and dementia has sparked a global initiative to identify risk factors and develop strategies to prevent or slow the progression of these cognitive disorders. Uric acid, the end product of the metabolism of purine nucleotides, has been reported as a key factor of many conditions potentially involved in cognitive dysfunction/dementia. In addition, some studies support the hypothesis that elevated uric acid levels could reduce the risk of Alzheimer's disease, slow down the decline of cognition, and delay the progression of Alzheimer's disease, while other evidence achieves opposite positions. These discrepancies might reflect a biological ambivalence for uric acid depending on a very complex interplay of factors that include its concentrations achieved in biological fluids, the nature, and concentration of free radicals, the presence and concentration of other antioxidant molecules, potentially responsible for bi-directional effects of uric acid on brain health/functioning. In this narrative review, we attempt to elucidate the influential role of uric acid metabolism in cognitive functioning by discussing pathophysiological mechanisms putatively involved, being well aware that none of them can be considered one-sided due to the complexity of the human organism.

Keywords: cardiovascular disease; cerebrovascular disease; cognitive function; uric acid.

Figure 1

Mechanism leading to hyperuricemia.

Figure 2

Mechanism potentially involved in the pathophysiology of cognitive dysfunction related to uric acid metabolism. Local and systemic inflammation and oxidative stress, induced by xanthine oxidase activity and monosodium urate deposition in joints and arteries, represent an important indirect mechanism linking uric acid metabolism, serum uric acid abundance, and cognitive dysfunction, both of vascular and non-vascular origin. Dash and red arrows represent a direct product of uric acid and its production process. Continuous black arrows indicate the secondary effect of uric acid and its production. ROS: Reactive Oxygen Species; MSU: Monosodium Urate; H₂O₂: Hydrogen Peroxide; O₂⁻: Superoxide Anion; XO: Xanthine Oxidase; XDH: Xanthine Dehydrogenase; FAD: Flavin Adenine Dinucleotide; NO: Nitric Oxide: NADH: Nicotinamide Adenine Dinucleotide.

Figure 3

Main reaction and interaction involving xanthine oxidoreductase complex. Nicotinamide Adenine Dinucleotide. ROS: Reactive Oxygen Species; H₂O₂: Hydrogen Peroxide; O₂₋: Superoxide Anion; XO.