Blood-cerebrospinal fluid barrier permeability in Alzheimer's disease

Abstract

The role of blood-cerebrospinal fluid barrier (BCB) dysfunction in Alzheimer's disease (AD) has been addressed but not yet established. We evaluated the BCB integrity in 179 samples of cerebrospinal fluid (CSF) retrospectively collected from AD patients and control cases using both CSF/serum albumin ratio (QAlb) and CSF secretory Ca2+-dependent phospholipase A2 (sPLA2) activity. These analyses were supplemented with the measurement of total tau, amyloid-β1-42 (Aβ1-42), and ubiquitin CSF levels. We found that due to its higher sensitivity, CSF sPLA2 activity could 1) discriminate AD from healthy controls and 2) showed BCB impairment in neurological control cases while QAlb could not. Moreover, the CSF sPLA2 activity measurement showed that around half of the AD patients were characterized by a BCB impairment. The BCB dysfunction observed in AD was independent from Mini-Mental State Examination score as well as CSF levels of total tau, Aβ1-42, and ubiquitin. Finally, the BCB dysfunction was not limited to any of the CSF biomarkers-based previously identified subgroups of AD. These results suggest that the BCB damage occurs independent of and probably precedes both Aβ and tau pathologies in a restricted subgroup of AD patients.

Fig. 1

Comparison of sPLA2 activity with QAlb in AD and control groups. A) There was a significant difference in sPLA2 activity (F_(2,91) = 6.788; p = 0.002) but not in Q_Alb (F_(2,89) = 0.369; p = 0.693) between H-Control_45–75 years group and ND-Control_{45–75 years} or AD_{45–75 year} group. Data are shown as mean±SD; B) Bland-Altman analysis showing the agreement between Q_Alb and sPLA2 activity for the measurement of BCB impairment in 158 clinically diagnosed AD or non-demented cases. Q_Alb and CSF sPLA2 activity are normalized to the average of all values of the corresponding parameters and converted to percentage. The mean difference±2 SDs are represented by horizontal solid and dotted lines, respectively. C) Proportion of patients with normal and abnormally increased sPLA2 activity in H-Control_{45–75 years} (n = 21), ND-Control_{45–75 years} (n = 19), AD_{45–75 years} (n = 54) and AD_{>75 years} (n = 85) using the cutoff value of 4.82 ΔFI/min.

Fig. 2

Area under the receiver operating characteristic curve indicating the discriminating ability of CSF measurements of sPLA2 activity, Q_Alb, T-tau, Aβ_1–42, Ubiquitin and T-tau/Aβ_1–42 ratio A) in patients with AD_{45–75 years} (n = 54) versus controls (n = 40), and B) in patients with AD_{45–75 years} (n = 54) versus H-Control_{45–75 years} (n = 21). The optimal cutoff levels, sensitivity, specificity and AUC are shown in Table 2. T-tau, total tau.

Fig. 3

sPLA2 activity in AD subgroups and effects of gender, age, MMSE, ApoE4 genotype, total tau, Aβ_1–42, and ubiquitin on this activity. A) Iqbal’s Decision Tree [25] employed for identifying various AD subgroups based on CSF levels of T-tau, Aβ_1–42 and ubiquitin; B) Proportion of patients with normal and abnormally increased sPLA2 activity in HARO (n = 11), ATEO (n = 24), AELO (n = 71) and LEBALO (n = 32) AD subgroups using the cutoff value of 4.82 ΔFI/min. C) Gender and ApoE4 proportion as well as MMSE, Age, and CSF levels of T-tau, Aβ_1–42, Ubiquitin, Q_Alb, and sPLA2 activity in AD patients with normal (n = 92) and abnormally increased (n = 46) sPLA2 activity. Categorical data were assessed using Fisher’s test. Continuous variables are expressed as mean±SD. Differences were assessed using Mann-Whitney’s test (MMSE, age, T-tau, Aβ_1–42, and Ubiquitin) or Student’s t-test (Q_Alb and sPLA2 activity). Statistical differences are indicated by an asterisk. T-tau, total tau.