Disrupted Blood-CSF Barrier to Urea and Creatinine in Mild Cognitive Impairment and Alzheimer's Disease

Objective: In this pilot study hypothesizing that blood-CSF barrier (BCSFB) function is altered in mild cognitive impairment (MCI), we evaluated small-sized biomarker distribution between serum (SER) and cerebrospinal fluid (CSF). For both MCI and Alzheimer (AD) patients we quantified CSF neurochemistry; and compared CSF/SER ratios for urea and creatinine, as well as albumin, to those of healthy controls. Methods: A compromised BCSFB in neurodegenerative states alters CSF-to-serum (CSF/SER) concentrations. We analyzed urea, creatinine and albumin, for transbarrier (across choroid plexus) distribution between CSF and serum, from patients with MCI (n=8) or AD (n=13). Lumbar CSF and arterial blood were frozen/analyzed by multiplex technology. Results: In healthy controls, the CSF creatinine was significantly concentrated ~50% above the serum level. In both MCI and AD, the CSF creatinine concentration decreased while the urea level increased; CSF albumin was also elevated in AD. CSF/SER ratios for controls, MCI and AD were: urea 0.80, 0.98, 0.86; creatinine 1.52, 1.13, 1.14; and albumin 0.0045, 0.0051, 0.0065. Thus, CSF/SER ratios for creatinine and urea in MCI were similar to those in AD patients. Conclusion: Blood-CSF barrier compromise in MCI resembled that in AD. In cognitively-impaired patients, the dissipating ratios toward equilibrium suggest disease-altered BCSFB permeability (urea and albumin) and transporter activity (creatinine/creatine). We propose that redistribution of urea and creatinine, between serum and CSF, are useful biomarkers for evaluating disease-induced alterations in CSF biochemistry and BCSFB functional status.