Evidence for sex difference in the CSF/plasma albumin ratio in ~20 000 patients and 335 healthy volunteers

Abstract

Given sex‐related differences in brain disorders, it is of interest to study if there is a sex difference in the permeability of the blood‐cerebrospinal fluid barrier (BCSFB) and the blood‐brain barrier (BBB). The CSF/serum albumin ratio (QA lb) is a standardized biomarker that evaluates the function of these barriers. In previous studies, contradictory results have been reported with respect to sex difference using this quotient, possibly because of small population sizes and heterogeneity with respect to ages. QA lb measurements in more than 20 000 patients between 1 and 90 years visiting our hospitals revealed a significant sex difference in all age groups also when excluding patients with pathologically high CSF albumin > 400 mg/L. Similar pattern was found in 335 healthy volunteers in similar age intervals. Although also other factors are likely important, our observation is consistent with lower integrity of the brain barriers in males. If the difference in QA lb is caused mainly by a difference in barrier function, this may require different drug doses and strategies for efficient central nervous system (CNS) delivery in males and females, as well as it may indicate differences in brain metabolism. Moreover, our study emphasizes that different reference values should be used both for different ages and sexes.

Increased age and male sex are independently associated with higher frequency of blood–cerebrospinal fluid barrier dysfunction using the albumin quotient

“…Our findings are in line with those from a study by Parrado-Fernández et al which was recently conducted in a population of over 20,000 patients with unspecified diseases as well as in control subjects [17]. They observed significantly higher QAlb in men than in women and irrespective of age, but the implications of such a sex discrepancy on B-CSF-B dysfunction were not discussed (e.g., in terms of percentage of patients positive for abnormal QAlb value).…”

“…The female hormone, 17β-estradiol [29], may drive a different expression of the enzymes involved in the BBB breakdown [30,31], ultimately leading to a protective role on BBB [32]. Interestingly, because QAlb sex-specific values do not change in puberty or menopause, the role of a genetic predisposition linked to sex chromosomes together with that of hormones themselves should be considered [17,33].…”

“…From another perspective, the different distribution of QAlb defined B-CSF-B dysfunction by sex indeed opens up a discussion on the relevant potential implications for clinical practice. If this difference is genetically determined [17,33], we believe that QAlb threshold values should be normalized by sex and age in order not to overestimate B-CSF-B alteration in men, or, on the contrary, underestimate it in women. In the present work, QAlb values appear to be 2.2 units higher in men than in women irrespective of age and neurological pathology.…”

“…QAlb values were recently reported to be higher in men than women regardless of age in a large population of patients with unspecified disorders and in healthy volunteers [17]. The implication of QAlb sex-related differences in clinical practice was, however, not addressed.…”

The blood–brain barrier in health and disease: Important unanswered questions

“…Are there sex differences in BBB properties? There is evidence for variation in male and female patient CSF/serum albumin ratio (Parrado-Fernández et al, 2018), and BBB sexual dimorphism has been proposed to underlie differences in response to traumatic brain injury and infection and in proclivity to autoimmune disease (Cruz-Orengo et al, 2014; Jullienne et al, 2018; Maggioli et al, 2016).…”