Time-of-day and age-related patterns in cerebrospinal fluid glucose and protein

Known circadian variations in cerebrospinal fluid (CSF) flow and composition include fluctuations in electrolytes, hormones, and neurotransmitters. However, how commonly measured CSF constituents, such as protein and glucose, vary by time-of-day is understudied. Here, we identify and compare time-of-day differences in CSF protein and glucose from patients who underwent CSF collection during clinical care.

Patients with CSF collected between June 2018 and May 2023 at thirteen hospitals within our institution's health system were identified. Clinical, demographic and laboratory results were recorded. CSF results were divided into 1- and 4-hour intervals based on time-of-day and patient age. Patients were excluded if there was evidence of CSF infection, bleeding, as well as age criteria excluding neonates. One-way ANOVA with post-hoc Tukey was used to analyze differences between means.

15,272 patients underwent 26,397 CSF collection encounters. After exclusion, 8,210 CSF glucose and 10,103 CSF protein values remained. The CSF/blood glucose ratio showed time-of-day fluctuations; the mean ratio was higher from 00:00-04:00 (0.660), 04:00-08:00 (0.651), 16:00-20:00 (0.619), and 20:00-00:00 (0.633) than from 08:00-12:00 (0.588) and 12:00-16:00 (0.599). This pattern was also observed when dividing the time-of-day into 1-hour intervals and in every age cohort except patients 80 years and older. Children also exhibited time-of-day differences in CSF/blood glucose ratios, but the phase of their time-of-day pattern is shifted earlier to peak at 00:00-04:00. No clear time-of-day patterns were observed for CSF protein; however there was a significant association of age with CSF protein (R² = 0.2182). There were no meaningful differences in CSF protein by time-of-day after separating patients by age.

Higher CSF glucose from 00:00-08:00 and 16:00-00:00 compared to 08:00-16:00 suggests diurnal fluctuations which may be driven by a circadian rhythm. A higher CSF protein concentration was strongly associated with increasing age, without clear time-of-day variations. These results have implications for clinical interpretation and future research of the role of CSF in health and disease.