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. 2023 Feb;98(2):239-251.
doi: 10.1016/j.mayocp.2022.10.012.

Population-Based Evaluation of Total Protein in Cerebrospinal Fluid

Kalli J Fautsch  1 , Darci R Block  2 , Jonathan Graff-Radford  3 , Feng Wang  4 , Emily C Craver  5 , David O Hodge  5 , Jeremy K Cutsforth-Gregory  3 , Khin P Kilgore  4 , Ronald C Petersen  3 , David S Knopman  3 , Eoin Flanagan  3 , Michel Toledano  3 , Michelle M Mielke  6 , M Tariq Bhatti  7 , John J Chen  8
Affiliations

Population-Based Evaluation of Total Protein in Cerebrospinal Fluid

Kalli J Fautsch et al. Mayo Clin Proc. 2023 Feb.

Abstract

Objectives: To present a normal range of cerebrospinal fluid (CSF) protein levels in a community-based population and to evaluate factors that contribute to CSF protein level variability.

Patients and methods: Samples of CSF protein were obtained from participants aged 32 to 95 years who underwent lumbar puncture (LP) between November 1, 2007, and October 1, 2017, as part of the Mayo Clinic Study of Aging, a longitudinal, population-based study of residents of Olmsted County, Minnesota.

Results: A total of 633 participants (58.1% male; 99.1% White; mean ± SD age, 70.9±11.6 years) underwent LP with recorded CSF protein level. Mean ± SD CSF protein level was 52.2±18.4 mg/dL (to convert to mg/L, multiply by 10), with a 95% reference interval of 24.0 to 93.4 mg/dL (range, 14.0-148.0 mg/dL). Spinal stenosis and arterial hypertension were associated with higher CSF protein levels on univariable analysis (P<.001). Increasing age, male sex, and diabetes were all independently associated with higher CSF protein levels on multivariable analysis (P<.001). In the 66 participants with repeated LPs within 2.5 years, the coefficient of repeatability was 26.1 mg/dL. Eleven participants (16.7%) had a CSF protein level difference of 20 mg/dL or more between serial LPs, and 4 (6.1%) had a difference of 25 mg/dL or more. There was a trend toward greater CSF protein level variability in patients with spinal stenosis (P=.054).

Conclusion: This large population-based study showed that CSF protein level can vary significantly among individuals. Elevated CSF protein level was independently associated with older age, male sex, and diabetes and is higher than listed in many laboratories. These findings emphasize the necessity of evidence-based reevaluation and standardization of CSF protein metrics.

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Conflict of interest statement

Dr. Knopman serves on a Data Safety Monitoring Board for the DIAN study. He serves on a Data Safety Monitoring Board for a tau therapeutic for Biogen but receives no personal compensation. He is an investigator in clinical trials sponsored by Biogen, Lilly Pharmaceuticals, and the University of Southern California. He has served as a consultant for Roche, Samus Therapeutics, Magellan Health and Alzeca Biosciences but receives no personal compensation. He receives funding from the NIH.

Dr. Mielke has consulted for Biogen, Brain Protection Company, and Labcorp and receives funding from NIH and DOD.

Dr. Petersen has consulted for Roche, Merck, Biogen, Eisai, and Nestle, and serves on the Data Safety Monitoring Board for Genentech.

Figures

Figure 1.
Figure 1.
Scatterplot for CSF Protein VS Age with a Pearson Correlation of 0.25. 83.9% (N=531) of our sample had CSF protein >35 mg/dL, the Mayo Clinic upper limit of normal.
Figure 2.
Figure 2.
Box plots for CSF protein amongst age categories. A) Participants ≥60 years had an elevated mean CSF protein compared to participants <60 years (p<.001). B) When grouped by age (30–50, 51–60, 61–70, 71–80, 81+ years), elevated CSF protein was associated with older age (p<0.001). Females are denoted by red crosses, males by blue circles.
Figure 3.
Figure 3.
Box plot for CSF protein VS Sex. A) Males were shown to have a 10.8 mg/dL elevation in CSF protein compared to females on multivariable analysis. (p<.001).
Figure 4.
Figure 4.
Box plot for CSF protein VS Diabetes. Participants diagnosed with diabetes were shown to have a 9.0 mg/dL increase in CSF protein compared to those without diabetes on multivariable analysis (p<.001).
Figure 5.
Figure 5.
Bland Altman plot of the 66 participants with 2 LPs within 2.5 years of each other.
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