Sex-Related Differences in Cerebrospinal Fluid Plasma-Derived Proteins of Neurological Patients

Abstract

Background and aims: Cerebrospinal fluid (CSF) protein content presents a sexual dimorphism in humans. We investigated sex-related differences in CSF IgG levels and in the quantification of intrathecal IgG synthesis (IIS). Methods: CSF, serum albumin and IgG were measured in 1519 neurological patients and both linear and hyperbolic formulas were used for the quantification of IIS. CSF-restricted oligoclonal IgG bands (OCBs) were used as “gold standard”. Results: The linear IgG Index showed a weak agreement with OCBs in males and females (k = 0.559, k = 0.587, respectively), while the hyperbolic Reiber’s formulas had a moderate agreement with OCBs in females (k = 0.635) and a weak agreement in males (k = 0.565). Higher CSF albumin and IgG levels were found in men than in women in the whole population and in subjects without IIS after adjusting for age and for serum concentrations of albumin and IgG, respectively (Quade statistics, p < 0.000001). CSF and serum albumin and IgG levels positively correlated to age in both sexes. CSF total protein content did not correlate with CSF leukocyte numbers but was higher in patients with marked pleocytosis. Conclusions: In neurological patients, men have higher levels of CSF serum-derived proteins, such as albumin and IgG.

Sex Differences under Vitamin D Supplementation in an Animal Model of Progressive Multiple Sclerosis

“…Besides the fact that males have a different composition of CSF serum-derived proteins than females, CSF flow dynamics are also sex-dependent [ 18 , 19 ]. Presumably, this is the case in our model too, where the proinflammatory cytokines were given at a speed comparable to that of the physiological CSF flow.…”

The Sexual Dimorphism in Cerebrospinal Fluid Protein Content Does Not Affect Intrathecal IgG Synthesis in Multiple Sclerosis

“…This way of carrying out biomedical research has made it possible to highlight differences that were previously existent but which had not yet been taken into consideration. In the case of CSF analysis for the classification of the neurological patient, a sex-specific approach to laboratory data has, in recent years, shown a greater permeability of BCSFB in males compared to females with a consequent increase in protein transferred from the blood to CSF [ 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…However, this remains a key point to understand because, in both cases, we may either be overestimating the altered BCSFB permeability in the male or, on the contrary, underestimating it in the female. We have recently demonstrated that not only albumin but also serum IgG are more concentrated in males than in females CSF [ 17 ]. In the present study, we tried to understand if this increased BCSFB permeability to serum IgG can somehow impact the quantitative and qualitative determination of the intrathecal IgG synthesis.…”

“…In recent years, the existence of sexual dimorphism at the level of CSF protein content has become increasingly evident, and in particular, these sex-related differences seem to concern all the concentrations of plasma-derived proteins [ 14 , 15 , 16 , 17 ]. It has emerged that QAlb is higher in males than females regardless of age as a consequence of a reduced CSF-flow rate (e.g., an increased transfer of protein from blood to CSF, reduced CSF elimination from CSF space into lymphatic organs or venous compartment) in the male sex.…”

“…This increase in QAlb levels means that male patients are more likely to receive a laboratory report suggesting altered CSF protein content and functional impairment of BCSFB with respect to females [ 14 , 16 , 19 ]. Moreover, the difference in CSF protein content found in the two sexes did not only concern albumin, the most concentrated protein in CSF, but also IgG, the second most abundant protein, as demonstrated in a population of neurological patients negative for intrathecal IgG synthesis (IIS) [ 16 , 17 ]. Furthermore, it has been shown that in addition to sex, aging can also affect CSF protein content and the BCSFB function [ 12 ].…”