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Clinical Chemistry 52: 2043-2048, 2006. First published September 21, 2006; 10.1373/clinchem.2006.073544
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Right arrow Lipids, Lipoproteins, and Cardiovascular Risk Factors
(Clinical Chemistry. 2006;52:2043-2048.)
© 2006 American Association for Clinical Chemistry, Inc.

Lipids, Lipoproteins, and Cardiovascular Risk Factors

Lipoprotein(a) in the Cerebrospinal Fluid of Neurological Patients with Blood–Cerebrospinal Fluid Barrier Dysfunction

Gabriella Pepe1,2,a, Guglielmina Chimienti1, Grazia Maria Liuzzi1, Biagia Leila Lamanuzzi1, Marina Nardulli1, Francesco Lolli3, Eduardo Anglés-Cano4 and Sabrina Matà3

1 Department of Biochemistry and Molecular Biology, University of Bari.
2 Institute of Biomembrane and BioEnergetics of Bari, Consiglio Nazionale delle Ricerche, Italy.
3 Department of Neurology, University of Florence, Italy.
4 INSERM, Paris, France.

aAddress correspondence to this author at: Department of Biochemistry and Molecular Biology, University of Bari, via Orabona, 4-70126 Bari, Italy. Fax 39-08-05-44-3317; e-mail g.pepe{at}biologia.uniba.it.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Lipoprotein(a) [Lp(a)] is a recognized pathogenic particle in human plasma, but its presence in the cerebrospinal fluid and its possible role in the central nervous system have not been documented. We tested the hypothesis that apolipoprotein(a) [apo(a)], free or as a component of the Lp(a) particle, can cross the blood–cerebrospinal fluid barrier and be found in the cerebrospinal fluid of patients affected by neurologic pathologies.

Methods: We studied paired cerebrospinal fluid/serum samples from 77 patients with inflammatory (n = 20) or noninflammatory (n = 34) blood–cerebrospinal fluid barrier dysfunction and without blood–cerebrospinal fluid barrier dysfunction (n = 23). We used ELISA to measure Lp(a) concentrations and Western blot and immunodetection to analyze apo(a) isoforms in native and reducing conditions.

Results: Entire Lp(a) with either small or large apo(a) isoforms was present in the cerebrospinal fluid of patients with blood–cerebrospinal fluid barrier dysfunction, regardless of its pathogenesis. Multiple linear regression analysis showed that both serum Lp(a) concentration (P = 0.003) and cerebrospinal fluid/serum albumin ratio (P <0.001) were predictors of the Lp(a) concentration in cerebrospinal fluid.

Conclusions: Our results demonstrate that Lp(a) can cross a dysfunctional blood–cerebrospinal fluid barrier. The unusual presence of Lp(a) in the cerebrospinal fluid could extend some of its known pathogenic effects to the central nervous system.


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The barrier between blood and cerebrospinal fluid (CSF)1 , known as the blood-CSF barrier (BCB), contributes to central nervous system (CNS) homeostasis and protects it from potentially harmful substances present in the blood. In several cerebrovascular, neuroinflammatory, and neurodegenerative disorders, functional and structural alterations of this barrier occur, leading to uncontrolled passage into the CSF of deleterious molecules that can interfere with CNS functions.

In humans, lipoproteins containing mainly apolipoproteins E (apoE) and AI (apoAI) (density <1.210 g/mL fraction) are present in the CSF, distinctly separated from their plasma counterparts, and these lipoproteins contribute to lipid transport and cholesterol homeostasis. ApoAI is derived from plasma, whereas apoE is produced in the brain (1)(2)(3)(4).

mRNA and apoB are not found in human CNS, indicating that apoB-containing lipoproteins such as LDL and lipoprotein(a) [Lp(a)], are not produced in this tissue (1). Investigation of lipoprotein particles in human CSF has failed to confirm the presence of LDL and Lp(a) (5)(6).

ApoB has been found in the CSF of patients with BCB damage with a significant positive correlation between the lipoprotein concentration and the CSF/serum albumin ratio, which is considered the main index of BCB dysfunction (7).

Oxidized LDL particles associated with blood-brain barrier dysfunction were found in the brain parenchyma of patients with cerebral infarction and were internalized by cultured astrocytes, thereby stimulating interleukin-6 secretion and indirectly influencing neuronal survival, suggesting a possible role of LDL in the pathophysiology of CNS disturbances (8).

Many studies have been conducted on the pathophysiologic role of plasma Lp(a). Increased plasma concentrations of Lp(a) and small dimensions of apo(a) were found to be associated with increased risk of cardiovascular and cerebrovascular diseases (9)(10)(11). Lp(a) competes with plasminogen for binding to lysine residues of cell membrane proteins or fibrin surfaces, leading to decreased plasmin formation; this mechanism may explain the atherothrombotic risk of Lp(a) and its apo(a) size-dependent effect (12)(13). No data are available, however, about the presence of Lp(a) in the CSF of patients with neurological diseases or the possible effects of Lp(a) in the CNS.

We investigated whether intact Lp(a) particles or free apo(a) can be found in CSF of patients with BCB dysfunction, the correlation of apo(a) passage through the BCB with the size of isoforms, and the extent and pathogenesis of the BCB alterations.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
patients and samples
We collected paired CSF/serum samples for diagnostic purposes from 77 patients (36 men and 41 women, mean age 51 years, range 18–75 years) admitted to the Neurological Clinic of the Careggi University Hospital, Florence, Italy. All CSF samples were obtained by lumbar puncture and were collected within the first week of patient hospitalization. CSF and serum routine assay for each sample included erythrocytes, leukocytes, and differential cell count; total protein concentration, albumin and IgG determination, and agarose isoelectric focusing for IgG oligoclonal bands. We also calculated the ratios of CSF to serum albumin (Qalb), CSF to serum Lp(a) [QLp(a)], and QLp(a) to Qalb ([Lp(a) index]. Qalb >7 x 10–3 was considered a marker of BCB dysfunction (14). We evaluated blood contamination of the CSF by an erythrocyte count: samples with <0.5 erythrocytes per µL were admitted to the study. All the samples were centrifuged and stored at –80 °C until assayed.

The diagnoses were determined based on clinical, laboratory, and magnetic resonance imaging data, and according to the ICD-10 and Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (15). The patients were grouped according to the state of BCB as follows: 20 patients with inflammatory BCB dysfunction (IBD) caused by CNS infection (10 cases of encephalitis and 10 of meningitis), 34 patients with noninflammatory BCB dysfunction (NIBD) (19 affected by the Guillain Barré syndrome, 6 by chronic inflammatory demyielinating polyradiculoneuropathy, 6 by spinal stenosis, and 3 by amyotrophic lateral sclerosis) and 23 patients with an inflammatory CNS disorder (multiple sclerosis) but without CSF signs of BCB dysfunction (WBD). The distinction between inflammatory and noninflammatory BCB dysfunction was based on the presence, in the latter group, of an isolated Qalb alteration in the absence of further pathological CSF changes, such as pleocytosis, oligoclonal bands, or increased lactate concentrations (16). The study was approved by the local ethics committee; all study participants gave informed consent.

apo(A) analyses
Phenotyping of apo(a) isoforms in relation to the number of kringle IV (KIV-kringle) domains (17) was performed by Western blot and immunodetection. Paired samples of serum and CSF were reduced with 0.5% 2-mercaptoethanol and subjected to 0.1% sodium dodecyl sulfate-1.5% agarose gel electrophoresis.

Immunoblotting was performed with sheep antiserum against human Lp(a) (IMMUNO, Technoclone, GMBH) and a peroxidase-conjugated secondary antibody (ICN Biomedicals), and the bands were revealed by enhanced chemiluminescence (ECL). CSF samples were tested at concentrations 15-fold higher than those of the serum samples. Apo(a) isoforms were characterized by reference to the human recombinant apo(a) isoforms, r-apo(a), mixture as already described (18). The relationship between log r-apo(a) kringle number and relative mobility produced a linear relationship that allowed us to calculate the number of kringles of each isoform. The relative entity of the 2 bands immunodetected in 1 sample was evaluated by densitometric analysis using Quantity One Quantification Software (Bio-Rad).

The presence of the disulfide bond between apo(a) and apoB100, indicating the Lp(a) particle integrity (9), was investigated by running parallel samples in native and reducing conditions (loading buffer without or with 2-mercaptoethanol) on agarose gel electrophoresis.

lp(A) determination
Lp(a) concentrations in serum as well as in CSF were measured in duplicate by ELISA with the Immunozym Lp(a) Kit that uses polyclonal anti-apo(a) antibodies that identify all the isoforms equally (Progen Biotechnik, GMBH). The reported detection limit of the reagent set, designed for the evaluation of Lp(a) in plasma or serum samples, was <50 mg/L. To make the reagent set suitable for the measurement of trace amounts of Lp(a) possibly present in CSF, additional calibrator dilutions (50, 10, and 1 mg/L, i.e., one half, one tenth, and one hundredth with respect to the lowest reagent set calibrator), were added to the reference curve. Furthermore, CSF samples were diluted by volume, 1/50 (40-fold less with respect to the recommended dilution of serum samples). For each sample, a total of 4 measurements were performed and the mean values were considered. The interassay variation, calculated from duplicate measurements in 3 series of determinations with the lowest calibrators, was 4.4%–13%.

statistics
The parametric 1-way ANOVA or the nonparametric Kruskall Wallis test were used to compare the 3 groups, as appropriate. In cases of statistical significance, Dunn multiple comparison posttest was used for the pair-wise comparison of groups.

Fisher test was applied to compare the relative prevalence of samples positive for apo(a) immunodetection in the CSF between IBD and NIBD patients.

The parametric t-test or the nonparametric Mann–Whitney test were used to compare 2 groups, as appropriate.

The Spearman correlation coefficient was used to assess the association between apo(a) isoform size and serum Lp(a) concentration. For each sample, the sum of the KIV-kringles repeat number as evaluated by phenotyping was considered, assuming an additive effect of each allele in determining the Lp(a) concentration (19).

Multiple linear regression analysis was run for serum Lp(a) concentration results, Qalb, Lp(a) index, and leukocyte count/mL as independent variables and Lp(a) concentrations in the CSF as the dependent variable. All mean values are reported with the associated SD. All median values are reported with the associated 25th–75th interquartile range. A value of P <0.05 was considered significant. The SigmaStat for Windows (Version 3.0. SPSS Inc) software package was used for all the analyses.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patients grouped according to their pathology and CSF characteristics are shown in Table 1 .


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  		Table 1. Study groups according to the pathology and CSF characteristics.

Phenotyping of serum samples revealed apo(a) isoforms of 14–36 KIV-kringles in all 3 study groups [mean 27 (5)]. The isoform distribution in serum was not significantly different among the 3 groups (P = 0.918). Immunoblot detection of the CSF samples revealed 20 that were positive for apo(a). The positive samples were from patients with BCB alterations, namely 6 of 20 IBD and 14 of 34 NIBD patients, with no significant differences between the 2 groups (P = 0.399). The isoforms were 18–35 KIV-kringles. Apo(a) was not found in the CSF from WBD patients. The apo(a) isoforms in paired CSF and serum samples showed the same electrophoretic mobility. Apo(a) immunodetection analysis of 1 sample having a single isoform and 1 sample having 2 different size isoforms is shown in Fig. 1 . The densitometric analysis revealed that in the latter sample, small-size apo(a) was 1.5-fold more abundant in serum than large-size apo(a), and in the CSF it was 8-fold more abundant.


Figure 1
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  		Figure 1. Apo(a) phenotyping in serum and CSF samples.

Western blot immunodetection of (A) a sample composed by 33/19 KIV-kringles isoforms and (B) a sample composed by 25/25 KIV-kringles isoforms. Samples and marker were reduced with 2-mercaptoethanol before loading. M, mixture of recombinant apo(a) as marker.

To test whether Lp(a) particles or free apo(a) were present in the CSF, we compared the electrophoretic behavior of samples run in reducing and in native conditions. For samples run in native conditions, the immunodetected band had slower migration than the band visualized in samples in reducing conditions (Fig. 2 ). In native conditions, the anti-apo(a) antiserum recognized a supramolecular complex consisting of apo(a) linked to apoB100. The same electrophoretic behavior was observed in both serum and its paired CSF samples.


Figure 2
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  		Figure 2. Immunoblot analysis of paired serum and CSF samples in native and reducing conditions.

Lane 1, serum sample runs in native conditions (loading buffer without 2-mercaptoethanol); lane 2, serum sample run after reduction with 0.5% 2-mercaptoethanol; lane 3, CSF sample run in native conditions; lane 4, CSF sample run under reducing conditions; M, a mixture of recombinant apo(a) as marker run under reducing conditions.

The influence of the apo(a) isoform size on the presence of Lp(a) in CSF was tested in samples from IBD and NIBD patients. The isoform distribution is shown in Fig. 3 . The size of isoforms found in CSF [mean 25 (5) KIV-kringles] was substantially lower than those found in serum samples only [mean 28 (5) KIV-kringles; P = 0.003].


Figure 3
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  		Figure 3. Analysis of the apo(a) isoforms found in serum and CSF samples of IBD and NIBD patients.

Scatter dot plot representation, line at mean. CSF, isoforms immunodetected in CSF: the total number of the plotted isoforms was 40 (i.e., 12 from 6 IBD ECL-positive samples and 28 from 14 NIBD ECL-positive samples). Serum, isoforms immunodetected in serum only. The total number of plotted isoforms was 68 (i.e., 28 from 14 IBD ECL-negative samples and 40 from 20 NIBD ECL-negative samples). a t-test, P = 0.003.

Lp(a) concentrations in serum and CSF samples are shown in Fig. 4 . In serum, Lp(a) concentrations were inversely correlated with apo(a) isoform size (r = –0.4190, P = 0.015). The median values were 35.3 mg/L (range 28.1–60.6) for IBD, 58.6 mg/L (range 13.0–258.8) for NIBD, and 73.0 mg/L (range 10.4–351.2) for WBD, without significant differences (P = 0.846; Fig. 4A ). When samples were grouped as positive and negative for apo(a) ECL immunodetection in the CSF, Lp(a) serum concentrations were substantially higher in positive (median 185.7 mg/dL, range 58.6–374.0) than in negative samples (median 28.1 mg/L, range 11.3–42.5; P = 0.0009). In CSF, Lp(a) concentrations had median values 0.11 mg/L (range 0.09–0.9) for IBD, 0.16 mg/L (range 0.09–0.04) for NIBD, and 0.01 mg/L (range 0.0–0.08) for WBD with significant differences (P = 0.002). However, the pair-wise comparison of the patient groups yielded significant differences in WBD compared with both IBD and NIBD patients (P <0.050 for both), but not in IBD compared with NIBD patient groups (Fig. 4B ).


Figure 4
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  		Figure 4. Lp(a) concentrations determined by ELISA.

Box and whiskers representation.

(A), Lp(a) concentrations in serum samples in the 3 study groups, Kruskall Wallis test; P = 0.846. (B), Lp(a) concentrations in CSF samples in the 3 study groups; Kruskall Wallis test: P = 0.002. Dunn’s multiple comparison posttest; a P <0.050 for WBD vs IBD; b P <0.050 for WBD vs NIBD.

QLp(a) in samples from patients with BCB alterations had a median value of 3.0 x 10–4 (range 3–3.5) in IBD patients and 3.0 x 10–4 (range 1.0–10) in NIBD patients, with no substantial differences (P = 0.626). The Lp(a) index had a mean value of 0.09 (0.09) in IBD and 0.31 (0.36) in NIBD, with no significant differences (P = 0.099).

The multiple linear regression analysis (R2 = 0.425) assessed the significance of the independent variables serum Lp(a) concentration (P = 0.003) and Qalb (P <0.001) as predictors of the Lp(a) concentration in the CSF.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Lp(a) is a known pathogenic particle in human plasma. Its presence and role in the CNS have not yet been documented. We have demonstrated the presence of Lp(a) in CSF samples from patients with neurological diseases characterized by BCB dysfunction.

To test the hypothesis that the Lp(a) particle may cross the BCB, we studied patients selected according to their neurological characteristics and grouped them on the basis of IBD, NIBD, or WBD.

Lp(a) analysis in our experiments was performed with 2 different, independent but complementary methods, i.e., immunoblotting, to identify the apo(a) phenotype and the integrity of the Lp(a) particle present in the CSF, and ELISA to detect the Lp(a) concentration.

Apo(a) phenotyping showed a similar isoform distribution in serum in the 3 study groups. The range of isoforms reflected the known interindividual variability of the healthy Caucasian population (9).

We found apo(a) by immunodetection in the CSF samples of IBD (30%) and NIBD patients (42%), but not in WBD patients. Furthermore, comparison of the samples analyzed in reduced and in native conditions clearly indicated that the apo(a) we detected in CSF samples was linked to apoB-100, as it was in the serum samples. This finding suggests that a BCB dysfunction can permit the transmigration of the entire Lp(a) from serum into the CSF.

It has been documented that the Lp(a) lipoparticle is susceptible to in vitro oxidative modifications that potentially amplify its antifibrinolytic and thrombotic effects, as well as its immunogenicity (20)(21)(22). Thus, the presence of intact Lp(a) in the CSF could imply its oxidability, with possible effects on the CNS because this tissue is particularly vulnerable to oxidative stress because of the high rate of oxygen use, the relatively low concentrations of antioxidants, and the high concentrations of polyunsaturated lipids.

One of our aims was to correlate the size of apo(a) with the presence of Lp(a) in the CSF. We found a wide size range of apo(a) isoforms in the CSF; our results indicate that, surprisingly, even Lp(a) particles with apo(a) isoform as large as 33 KIV-kringle are able to cross the BCB, although with less efficiency than the smaller apo(a) isoforms.

Our ELISA method allowed detection of very small amounts of Lp(a) in CSF samples. The qualitative ECL and the quantitative ELISA results were concordant: all CSF samples with apo(a) detected by ECL had Lp(a) concentrations in CSF >0.1 mg/L.

Apo(a) was detected in the CSF from both IBD and NIBD patients. This result suggests that the passage of Lp(a) into CSF is not influenced by the pathophysiologic mechanisms determining the BCB dysfunction, which can occur because of an increase of permeability of barrier capillaries, as seen in meningitis, or by a decreased CSF volume turnover rate, as seen in patients with Guillain-Barré syndrome or spinal stenosis (23). Instead, the amount of Lp(a) in CSF was correlated to the degree of BCB dysfunction, as assessed by Qalb values, and to Lp(a) serum concentration. This latter finding, together with the observed negative correlation between apo(a) isoform size and Lp(a) serum amount, explain the fact that the patients with detectable CSF Lp(a) values had lower apo(a) isoform size than the CSF-negative patients. Small apo(a) isoforms are frequently associated with high Lp(a) concentrations in plasma, which is an independent risk factor for cardiovascular diseases (9)(10)(11). Furthermore, in vitro data showed that fibrin and cells have higher affinity for small apo(a) isoforms than for large ones and supported a major role of small apo(a) isoforms in thrombotic risk (12). In the CNS, Lp(a) isoforms may have similar functional heterogeneity.

The presence of Lp(a) in the CSF, an unusual environment, raises new questions on the possible role of this lipoparticle in neurological disorders; in the CNS, as in plasma, Lp(a) may interfere with the plasmin(ogen) system, induce cytokine production, or have other harmful effects. Members of the LDL receptor family with an in vitro affinity for Lp(a) (24)(25) are present on nerve cell surfaces, suggesting the possibility that Lp(a) may interact with these cells in vivo, eliciting their response. Further studies are ongoing to clarify the role of Lp(a) in the CNS.


   Acknowledgments
 
We thank Dr. T. Latronico for helping with samples selection. The work was supported financially by Grant 2005 of the Bari University and by Grant L488/92 of the Ministero dell’Istruzione, Università e Ricerca, and by the grant for the mobility to Pepe/Anglés-Cano for the joint project CNR/INSERM, program 2004.


   Footnotes
 
1 Nonstandard abbreviations: CSF, cerebrospinal fluid; BCB, blood–cerebrospinal fluid barrier; CNS, central nervous system; Lp(a), lipoprotein(a); apo(a), apolipoprotein(a); ECL, enhanced chemiluminescence; Qalb, calculations of the CSF/serum albumin ratio; QLp(a), CSF/serum Lp(a); IBD, inflammatory BCB dysfunction; NIBD, noninflammatory BCB dysfunction; WBD, without CSF signs of BCB dysfunction.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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