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

Abstract

Background: The cerebrospinal fluid (CSF)/serum quotient of albumin (QAlb) is the most used biomarker for the evaluation of blood-cerebrospinal fluid barrier (B-CSF-B) permeability. For years QAlb was considered only as an age-related parameter but recently it has also been associated to sex. The aim of the present study was to explore the impact of sex in the determination of B-CSF-B dysfunction. Methods: The analysis was retrospectively conducted on subjects consecutively admitted to the neurological ward. CSF and serum albumin levels were measured by immunonephelometry and pathological QAlb thresholds were considered: 6.5 under 40 years, 8.0 in the age 40-60 and 9.0 over 60 years. Results: 1209 subjects were included in the study. 718 females and 491 males (age: 15-88 years): 24.6% of patients had a diagnosis of multiple sclerosis, 23.2% suffered from other inflammatory neurological diseases, 24.6% were affected by non-inflammatory neurological diseases, and for 27.6% of patients the final neurological diagnosis could not be traced. Dysfunctional B-CSF-B was detected more frequently (44 vs. 20.1%, p < 0.0001) and median QAlb value were higher (7.18 vs. 4.87, p < 0.0001) in males than in females in the overall study population and in all disease subgroups. QAlb and age were positively correlated both in female (p < 0.0001) and male (p < 0.0001) patients, however the slopes of the two regression lines were not significantly different (p = 0.7149), while the difference between the elevations was extremely significant (p < 0.0001) with a gap of 2.2 units between the two sexes. Finally, in a multivariable linear regression analysis increased age and male sex were independently associated with higher QAlb in the overall study population (both p < 0.001) and after stratification by age and disease group. Conclusions: Accordingly, identification and validation of sex-targeted QAlb thresholds should be considered as a novel tool in an effort to achieve more precision in the medical approach.

Sex difference in cerebrospinal fluid/blood albumin quotients in patients with schizophreniform and affective psychosis

“…This finding is consistent with the results of two samples of patients with neurological disorders, including some healthy controls [ 18 , 19 ]. In a first large study including 27,263 patients with neurological diseases, elevated Q Alb values were observed more frequently in male patients [ 19 ].…”

“…The study also included data from 335 healthy controls (although the definition of “healthy” was not specified), who displayed the same sex differences as well [ 19 ]. A similar study including 1209 patients with different neurological disorders also reported similar sex differences [ 18 ]. In the present study, these findings could be confirmed in a more homogeneous, well-characterized psychiatric cohort including diagnostic findings and information about potential confounding factors, such as comorbidity or psychopharmacological medication.…”

“…Examinations of large, healthy control groups are lacking so far, so the present findings cannot be generalized to neurologically and/or mentally healthy populations because LPs of a large group of healthy volunteers is difficult to justify on ethical grounds. In contrast to previous studies [ 18 , 19 ], the authors examined a more homogenous, well-characterized group of psychiatric patients. Another limitation is that the Q Alb levels were not corrected for blood admixture and this could have influenced the results; however, this effect would apply equally to female and male patients.…”

“…Moreover, Q Alb could be influenced by other factors such as body weight, body mass index, a reduction in CSF production from reasons other than age, alcohol and nicotine consumption [ 1 , 14 ]. Interestingly, an influence of sex on Q Alb was recently also noticed and discussed in two papers that investigated patient cohorts with a spectrum of neurological disorders [ 18 , 19 ].…”

Aging, Cellular Senescence, and Progressive Multiple Sclerosis

“…Age-related accumulation of senescent endothelial cells is linked to impaired tight junction structure and compromised blood-brain barrier (BBB) function (Farrall and Wardlaw, 2009 ; Yamazaki et al, 2016 ; Castellazzi et al, 2020 ). Several lines of evidence from human studies and experimental animal models support a key role for fibrinogen in neuroinflammation (Davalos and Akassoglou, 2012 ).…”