Phosphate Dysregulation and Neurocognitive Sequelae

The endocrine regulator proteins, fibroblast growth factor 23 (FGF23) and Klotho have been well studied as mediators of phosphate metabolism. FGF23 has been implicated in the renal excretion of phosphate by limiting the docking of sodium-dependent phosphate transporters, Npt2a and Npt2c, into the luminal side of renal proximal tubular epithelial cells. By limiting Npt2a/c activity in the renal tubular epithelial cells, phosphate is reabsorbed at lower rates and is excreted at higher rates. The action of Klotho is relatively less understood but has been implicated as an FGF23 cofactor in receptor binding. Klotho is mostly synthesized in the distal tubules of the nephron relative to FGF23's activity in proximal renal tubules. The neurological sequelae due to alterations in the FGF23-Klotho axis may be explained by the direct effects of these phosphate-regulating proteins on neuronal tissues or by the roles of these proteins in phosphate metabolism. Hyperphosphatemia has been associated with vascular wall stiffness that may alter blood flow and weakenvessels in the brain. In contrast, hypophosphatemia may alter ATP usage and metabolism in the central nervous system (CNS), leading to neurological compromise. Altered levels of FGF23 and Klotho have both been associated with neurocognitive decline, clinical dementia, memory loss, and poor executive function in humans. Furthermore, FGF23 and Klotho dysregulation has been linked to structural and functional changes of the cardiovascular system with an increased risk of stroke. Subsequent research should focus on characterizing the neuropathology associated with alterations in the FGF23-Klotho system and dysregulated phosphate metabolism.