Ion concentrations in CSF and serum are differentially and precisely regulated

Fluctuations of extracellular brain ion concentrations have been associated with transitions between brain states such as sleep and wakefulness, and disturbances have been implicated in a variety of neurological conditions, including dementia, epilepsy and migraine. This study aims to define the normal CSF ion profile and identify key factors influencing its regulation. In this cross-sectional study, we analysed samples from 42 individuals (16 men), including 28 healthy participants and 14 patients with medically unexplained neurological symptoms. Age spanned between 20 and 55 years. Using validated clinical assays, we measured paired CSF and serum concentrations of Ca²⁺, Cl⁻, K⁺, Mg²⁺ and Na⁺. We examined their interrelationships and assessed the impact of blood-brain barrier permeability (the albumin quotient), age, sampling time and sex. CSF ion concentrations were highly stable and maintained within distinct, narrow ranges, separate from serum ranges for all ions measured (<i>P</i> < 0.0001), with no overlapping. Cl^- (+25%), Na⁺ (+5%) and Mg²⁺ (+37%) concentrations were higher, while K⁺ (-30%) and Ca²⁺ (-50%) concentrations were lower. Consistent with an independent and active CNS homeostatic control, CSF concentrations of K⁺, Cl^- or Mg²⁺ showed no significant correlation with their serum counterparts, while Na⁺ and Ca²⁺ displayed moderate associations with serum levels. Moreover, blood-brain barrier permeability had no significant impact on CSF ion concentrations. Small, but significant, age-related declines were observed for Cl^-, Mg²⁺ and Ca²⁺ in CSF, and circadian fluctuations affected K⁺, which increased slightly in the afternoon. Minor sex differences were noted, with men exhibiting slightly higher Mg²⁺ and Ca²⁺ levels. Our findings demonstrate that CSF ion concentrations are precisely regulated at the barriers of the CNS, largely independent of serum levels and with low interindividual variation, reinforcing the concept of a highly controlled CNS environment. This distinct ion composition may help modulate neuronal excitability, supporting brain state transitions such as sleep-wake cycling. Identification of hydration status as a potential confounding factor suggests that normalization to CSF-Na⁺ may improve the detection of pathological disruptions in CSF ion homeostasis. These insights reinforce the foundation for using CSF ion profiles as biomarkers for neurological disorders.