Cerebrospinal Fluid Albumin Levels Research Articles

Cerebrospinal Fluid Features in Patients With Coronavirus Disease 2019 and Neurological Manifestations: Correlation with Brain Magnetic Resonance Imaging Findings in 58 Patients.

BackgroundNeurological manifestations are common in patients with COVID-19, but little is known about pathophysiological mechanisms. In this single-center study, we describe neurological manifestations of 58 patients, regarding cerebrospinal fluid (CSF) analysis and neuroimaging findings.Methods58 COVID-19 patients with neurologic manifestations and SARS-CoV-2 RT-PCR screening on CSF analysis were included. Clinical, laboratory, and brain MRI data were retrospectively collected and analyzed.ResultsPatients were mostly men (66%) with a median age of 62 years. Encephalopathy was frequent (81%), followed by a pyramidal dysfunction (16%), seizures (10%), and headaches (5%). Protein and albumin levels in CSF were increased in 38% and 23%, respectively. A total of 40% of patients displayed an elevated albumin quotient suggesting impaired blood‐brain barrier integrity. CSF-specific IgG oligoclonal band was found in five (11%) cases, suggesting an intrathecal synthesis of IgG, and 26 (55%) patients presented identical oligoclonal bands in serum and CSF. Four (7%) patients harbored a positive SARS-CoV-2 RT-PCR in CSF. Regarding brain MRI, 20 (38%) patients presented leptomeningeal enhancement.ConclusionsBrain MRI abnormalities, especially leptomeningeal enhancement, and increased inflammatory markers in CSF are frequent in patients with neurological manifestations related to COVID-19, whereas SARS-CoV 2 detection in CSF remained scanty.

Levels of islet amyloid polypeptide in cerebrospinal fluid and plasma from patients with Alzheimer's disease.

The biologically active pancreatic hormone peptide islet amyloid polypeptide (IAPP) regulates brain functions such as appetite and cognition. It also plays a role in clearance of amyloid beta (Aβ), a peptide implicated in the dementia disorder Alzheimer’s disease (AD). If IAPP becomes modified, it loses its biological activity and starts to aggregate. Such aggregations have been found in the AD brain and decreased plasma levels of the unmodified IAPP (uIAPP) have been shown in the same patients. In the current study, we analyze levels of uIAPP and total IAPP (unmodified and modified) in cerebrospinal fluid (CSF) to investigate its potential as a biomarker for AD. We found no differences in neither CSF nor plasma levels of uIAPP or total IAPP in AD patients compared to cognitive healthy individuals (NC). The levels of uIAPP in CSF of NC were positively correlated with uIAPP in plasma, Q-albumin and albumin levels in CSF, but negatively correlated with CSF levels of t-tau and p-tau. These findings were not seen in AD patients. Levels of total CSF IAPP correlated positively with total Q-albumin and albumin levels in CSF in both AD and NC. In addition, total plasma IAPP correlated positively with CSF t-tau and p-tau in NC and negatively with CSF Aβ42 in AD patients. To conclude, our studies did not find evidence supporting the use of CSF IAPP as an AD biomarker. However, our findings, indicating a compromised translocation of uIAPP in and out of the brain in AD patients as well as the correlations between total plasma IAPP and AD biomarkers, encourage further research on the role for IAPP in AD.

Differential neuro-immune patterns in two clinically relevant murine models of multiple sclerosis

BackgroundThe mechanisms driving multiple sclerosis (MS), the most common cause of non-traumatic disability in young adults, remain unknown despite extensive research. Especially puzzling are the underlying molecular processes behind the two major disease patterns of MS: relapsing-remitting and progressive. The relapsing-remitting course is exemplified by acute inflammatory attacks, whereas progressive MS is characterized by neurodegeneration on a background of mild-moderate inflammation. The molecular and cellular features differentiating the two patterns are still unclear, and the role of inflammation during progressive disease is a subject of active debate.MethodsWe performed a comprehensive analysis of the intrathecal inflammation in two clinically distinct mouse models of MS: the PLP139-151-induced relapsing experimental autoimmune encephalomyelitis (R-EAE) and the chronic progressive, Theiler’s murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD). Microarray technology was first used to examine global gene expression changes in the spinal cord.Inflammation in the spinal cord was further assessed by immunohistochemical image analysis and flow cytometry. Levels of serum and cerebrospinal fluid (CSF) immunoglobulin (Ig) isotypes and chemokines were quantitated using Luminex Multiplex technology, whereas a capture ELISA was used to measure serum and CSF albumin levels. Finally, an intrathecal Ig synthesis index was established with the ratio of CSF and serum test results corrected as a ratio of their albumin concentrations.ResultsMicroarray analysis identified an enrichment of B cell- and Ig-related genes upregulated in TMEV-IDD mice. We also demonstrated an increased level of intrathecal Ig synthesis as well as a marked infiltration of late differentiated B cells, including antibody secreting cells (ASC), in the spinal cord of TMEV-IDD, but not R-EAE mice. An intact blood-brain barrier in TMEV-IDD mice along with higher CSF levels of CXCL13, CXCL12, and CCL19 provides evidence for an intrathecal synthesis of chemokines mediating B cell localization to the central nervous system (CNS).ConclusionsOverall, these findings, showing increased concentrations of intrathecally produced Igs, substantial infiltration of ASC, and the presence of B cell supporting chemokines in the CNS of TMEV-IDD mice, but not R-EAE mice, suggest a potentially important role for Igs and ASC in the chronic progressive phase of demyelinating diseases.

598: Assessment of blood-brain-barrier integrity and neuroinflammation in preeclampsia

Circulating inflammatory factors may predispose to blood-brain-barrier impairment and neuroinflammation in preeclampsia, but human data is limited. We tested the hypothesis that peripheral inflammatory mediators (complement factors and cytokines) access cerebrospinal fluid (CSF) through a leaky blood-brain-barrier in preeclampsia. Prospective case-control study of pregnant women with a non-anomalous gestation >24 weeks, with indicated spinal anesthesia or combined spinal epidural analgesia. Women were enrolled in three groups: 1) Healthy controls; 2) Chronic or gestational hypertension and; 3) Preeclampsia with or without severe features. Blood and urine were collected before delivery, with CSF collected during spinal placement. In blood and CSF, we measured biomarkers using enzyme linked immunosorbent assays: albumin, C5a, C5b-9, TNF-α, and IL-6. Albumin and complement factors were also measured in urine. The CSF/plasma albumin quotient was used to assess blood-brain-barrier integrity. Clinical data was abstracted from the medical record. Differences were assessed by ANOVA, chi-squared test, or test of medians, with α=0.05. In total, 48 subjects enrolled (16 per arm) and summary characteristics are detailed in Table 1. Plasma, urine and CSF measurements for albumin, C5a, C5b-9, TNF-α, and IL-6 are shown in Table 2. Preeclampsia was associated with increased plasma levels of terminal complement effector C5b-9 (membrane attack complex) and pro- inflammatory cytokine IL-6. Marked urinary excretion of C5b-9 in preeclampsia (p<0.001) confirmed end-organ effects in the kidney. Despite systemic complement activation and end-organ injury in preeclampsia, C5b-9 remained undetectable in CSF. Levels of IL-6 were detectable in CSF, but they did not increase in conjunction with rising plasma levels in preeclampsia. Likewise, albumin was detectable in CSF, but the CSF/plasma albumin quotient did not increase in preeclampsia (p=0.78, vs. controls). Moreover, CSF albumin levels were not increased in the subset of 8 preeclampsia subjects with severe features [median 16.0 mg/dl, interquartile range (12.5-17.0)]. We find that the integrity of the blood-brain-barrier is maintained in preeclampsia despite evidence of systemic inflammation and terminal complement activation.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

Population Pharmacokinetics of Vancomycin in Postoperative Neurosurgical Patients

Neurosurgical procedures may damage the blood-brain barrier to allow more vancomycin distribution into the cerebrospinal fluid (CSF) from blood after intravenous administration. However, a large intersubject variability in CSF vancomycin concentration was observed. We aimed to develop a population pharmacokinetic model to guide vancomycin dosing in patients after neurosurgical operation. Blood and CSF samples were collected and determined from postoperative neurosurgical patients after vancomycin administration. A three-compartment (central, peripheral, and CSF) model was proposed to characterize the pharmacokinetics of vancomycin. A nonlinear mixed-effects modeling approach was applied to fit the blood and CSF data simultaneously. The covariate analysis found that the CSF albumin level was strongly associated with the clearance between central and CSF compartment. Visual predictive check indicated that the proposed population pharmacokinetic model agrees well with the observed vancomycin concentrations. Individualized vancomycin dosage regimens could be developed for postoperative neurosurgical patients with different CSF albumin levels through model simulations. The CSF albumin level is a determinant of CSF vancomycin concentration.

Free Radical Injury and Blood-Brain Barrier Permeability in Hypoxic-Ischemic Encephalopathy

The purpose of this work was to evaluate the extent of free radical injury in newborns with hypoxic ischemic encephalopathy by measuring plasma levels of malondialdehyde and nitric oxide and to assess the blood-brain barrier permeability by measuring the cerebrospinal fluid albumin/plasma albumin ratio. This prospective observational study was conducted over a period of 2 years at Sir Sundarlal Hospital, Banaras Hindu University. The study population consisted of 43 term neonates with perinatal asphyxia who subsequently developed hypoxic ischemic encephalopathy. Twenty normal gestational age- and gender-matched healthy infants without any perinatal asphyxia served as control subjects. Peripheral venous blood samples were analyzed for malondialdehyde, total plasma nitrates/nitrites, and albumin levels between 12 and 24 hours of life. To assess the blood-brain barrier permeability, the cerebrospinal fluid albumin/plasma albumin ratio was measured. Correlation among the levels of malondialdehyde, nitrates/nitrites, and blood-brain barrier permeability was calculated. Data were analyzed by using SPSS 10 software. Plasma malondialdehyde and nitrate/nitrite levels were significantly higher in infants with hypoxic ischemic encephalopathy compared with control subjects. Although there was a progressive increment in plasma levels of malondialdehyde with increasing severity of hypoxic ischemic encephalopathy, the differences were not statistically significant. Plasma nitrate/nitrite levels were almost similar in all stages of hypoxic ischemic encephalopathy. Plasma albumin levels were comparable in infants with hypoxic ischemic encephalopathy and control subjects, whereas cerebrospinal fluid albumin levels and blood-brain barrier permeability were significantly higher in infants with hypoxic ischemic encephalopathy. Significant correlation was observed between plasma malondialdehyde and nitrate/nitrite levels with blood-brain barrier permeability. Increased plasma levels of malondialdehyde and nitrates/nitrites are found to be associated with hypoxic ischemic encephalopathy, indicating the possible role of free radical injury in its causation. Increased blood-brain barrier permeability may be another contributory factor to the progression of the disease.

Serum Matrix Metalloproteinase-2 Levels Indicate Blood–CSF Barrier Damage in Patients with Infectious Meningitis

Protein components in cerebrospinal fluid (CSF) are maintained at a specific concentration by a dynamic gradient between the capillary and intrathecal spaces via the blood-cerebrospinal fluid barrier (BCB) in the brain and spinal cord. Permeability to proteins increases when there is structural damage to the BCB. Matrix metalloproteinase-2 (MMP-2; gelatinase A) has been shown to degrade type IV collagen, a major component of the cellular basement membrane. We analyzed alpha2 macroglobulin (alpha2M) indices and evaluated the relationship between alpha2M, as an indicator of BCB permeability, and MMP-2, which degrades the extra-cellular matrix in patients with infectious meningitis. Albumin levels in CSF or serum were determined by turbidimetric immunoassay, or bromcresol green assay, respectively. alpha2M levels in CSF or serum were measured with enzyme-linked immunosorbent assay, or laser-nephelometry, respectively. Serum MMP-2 levels were determined by enzyme immuno assay. We calculated the alpha2M index, i.e. the ratio of alpha2M (CSF / serum) to albumin (CSF / serum; alpha2M in CSF / alpha2M in serum x albumin in serum / albumin in CSF). alpha2M indices were significantly increased in infectious meningitis compared to healthy controls (p < 0.05). They were highest in bacterial meningitis, and there was a significant difference between viral or mycotic and bacterial meningitis (p < 0.05). Serum MMP-2 levels were increased in infectious meningitis, being highest in bacterial meningitis, where they were significantly different from healthy controls (p < 0.05). There was a significant positive correlation between serum MMP-2 levels and alpha2M indices (r = 0.64, p < 0.0001). Markedly increased levels of serum MMP-2 in infectious, especially bacterial, meningitis may reflect the degree of damage to the BCB.

Approaching an individual methotrexate regimen in leptomeningeal carcinomatosis

Background Chemotherapeutic effects in leptomeningeal carcinomatosis (LC) vary widely between patients, presumably in part because drug elimination from cerebrospinal fluid (CSF) differs between individuals. An individual dosing, adapted to elimination, may improve treatment efficacy. Objective To discuss the feasibility of easily accessible elimination parameters for an individual dosing of chemotherapy in LC. Materials and methods The elimination of intrathecally applied methotrexate (Mtx) was tested in 14 LC patients and compared to the literature data. Plasma drug levels and CSF albumin levels are suggested as elimination parameters. Results and discussion Mtx disappeared from CSF and appeared in plasma with an expected wide variation (interindividual range of coefficients of variation (CV) of CSF Mtx levels 158–189%, intraindividual range of CV of plasma Mtx levels 35–64%). Our data together with reported data suggest that plasma Mtx levels mirror closely the Mtx elimination from CSF. The levels of CSF albumin and of plasma Mtx at defined sample times correlated negatively ( r = − 0.7), which reflects their largely common elimination from CSF. Conclusion Both parameters seem appropriate to describe the Mtx elimination from CSF. They should allow to individually adapt Mtx dosing towards an improvement of Mtx availability in CSF and of treatment efficacy.

What determines the CSF concentrations of albumin and plasma-derived IgG?

Objectives: To estimate the mean influence of the main determinants of the cerebrospinal fluid (CSF) concentration of albumin and plasma-derived immunoglobulin G (IgG). Methods: Correlations of serum and CSF concentrations of albumin and IgG and assumptions of the mode of action of the determinants (plasma concentration, barrier permeability, and CSF flow) are used to quantify the determinants' influences in a sample of 1700 patients. Results: We estimated in patients with normal CSF albumin that the serum concentrations of albumin and IgG explained 3.3% and 23% of the variation of the respective CSF concentrations, whereas the barrier permeability accounted for 41.9% and 22.2%, and CSF flow for 54.8%. In patients with pathologic CSF albumin concentration, the serum concentrations were estimated to explain 0.2% and 8.2% of the variation of the respective CSF concentrations, the barrier permeability 19.7% and 11.7%, and CSF flow 80.1%. Conclusions: CSF flow had the strongest mean influence, especially at elevated CSF albumin levels. The serum concentrations and barrier permeabilities of albumin and IgG influenced the respective CSF concentrations quite differently, which should be due to the different physicochemical properties of the two molecules. Mean influences from large patient samples, as explored here, can give only an overview. Understanding the determinants in individuals will need further specific measurements, especially of CSF flow.

Transforming growth factor-beta1 in the cerebrospinal fluid of patients with subarachnoid hemorrhage: titers derived from exogenous and endogenous sources.

Transforming growth factor-beta1 (TGF-beta1) is a fibrogenic cytokine that is involved in postinjury repair and is implicated in the etiology of postsubarachnoid hemorrhage (SAH) chronic communicating hydrocephalus. TGF-beta1 was measured by enzyme-linked immunosorbant assay (ELISA) in sequential samples of cerebrospinal fluid (CSF) in 11 patients with hydrocephalus after SAH; levels were seen to be biphasically elevated and sources were investigated. TGF-beta1 levels were compared with albumin levels that estimated CSF blood content. Control samples from nonhemorrhagic hydrocephalics were tested similarly. Mean total TGF-beta1 levels were elevated to 4400+/-3435 (+/-SD) pg/mL greater than control levels of 97+/-42 at 1 to 2 days posthemorrhage. Thereafter, levels fell to 714+/-401 by 5 to 6 days posthemorrhage, then rose to a second peak of 1667+/-774 at 9 to 10 days posthemorrhage, remaining significantly increased until 19 days posthemorrhage (P = 0.007). The first peak probably derived from extravasated platelets and correlated with increased albumin levels in the CSF. The second TGF-beta1 peak rose greater than CSF albumin levels that had stabilized at this time, and thus was attributed to a tissue-specific response rather than a re-bleed. TGF-beta1 was detected in the choroid secretory epithelium from controls, but levels were greater in SAH patients at 10 to 12 days posthemorrhage. The authors conclude that the elevated levels of TGF-beta1 in CSF after SAH are derived initially from blood and later from endogenous sources such as the choroid plexus.

Changes with aging of steroidal levels in the cerebrospinal fluid of women

Objective: Age-related changes of steroid levels in the central nervous system (CNS) are not well understood. To investigate whether steroidal conditions in the CNS of women change with aging and menopause, steroid levels have been measured in serum and cerebrospinal fluid (CSF), and examined correlations with aging. Methods: Serum and CSF concentrations of estradiol (E 2), cortisol, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS) and albumin were measured in 80 female patients who underwent operations for benign gynecological diseases. They had no endocrinological or neurological disorders and were aged 17–71 years; 62 patients were in premenopause and 18 were in postmenopause. Results: Serum levels of E 2 decreased markedly after menopause, while levels of DHEA and DHEAS decreased gradually with age. There was no significant change with age of serum cortisol levels. The CSF concentrations of E 2 (0.2–3 pg/ml) decreased with age [correlation coefficient ( r)=0.31, P<0.01]. The CSF DHEA levels (0.1–0.8 ng/ml) did not change with age although not significantly, but CSF cortisol levels (0.1–0.6 μg/dl) increased with age ( r=0.35, P<0.01). The CSF DHEAS concentrations were below the sensitivity of the radioimmunoassay (RIA) (1 ng/ml). The CSF/serum ratios of cortisol increased with age ( r=0.30, P<0.01), as did those of DHEA ( r=0.55, P<0.01). Although serum albumin levels did not change throughout life, CSF albumin levels and CSF/serum albumin ratios increased gradually with age ( r=0.28, P=0.052; r=0.23, P=0.114, respectively), but there was no significance. There were marked decreases of serum E 2 and DHEA levels and CSF E 2 levels in postmenopausal women ( P<0.05), but CSF cortisol levels increased ( P<0.05) and DHEA levels in CSF were maintained after menopause. Conclusion: These results indicate that steroids in CSF become cortisol dominated and deficient in estrogens with aging, especially after menopause.

Levels of interleukin-6, CRP and alpha 2 macroglobulin in cerebrospinal fluid (CSF) and serum as indicator of blood-CSF barrier damage.

We measured the levels of interleukin-6 (IL-6), albumin, C-reactive protein (CRP) and alpha 2 macroglobulin (alpha 2M), all of which have different spectrums of molecular weight, in the cerebrospinal fluid (CSF) and serum in 121 patients to evaluate damage to the blood-cerebrospinal fluid barrier (BCB) in meningitis. There was an extraordinary high level of IL-6 in the CSF when patients had bacterial or viral meningitis, but the level returned to a normal range within a week in almost all of these cases. There were no significant differences in CSF albumin levels among the different disease groups. The CRP level in CSF is considered to correlate with the serum level, and CSF CRP was higher in bacterial meningitis than in viral meningitis, however, CRP in CSF was increased in some of the infectious diseases without meningitis. The alpha 2M in CSF, which tends to be at extraordinarily high levels when there is damage to the BCB, correlated highly with CSF cell counts. CSF IL-6 seemed to be a useful indicator to identify the acute active phase of meningitis. CRP and alpha 2M in CSF are considered to be useful to differentiate bacterial meningitis, bacterial infection without meningitis and viral meningitis. Extraordinarily high levels of alpha 2M, which has a high molecular weight, in CSF is indicative of BCB damage.

Prednisone effects on blood-brain barrier permeability and CNS IgG synthesis in healthy humans

Corticosteroids reportedly decrease blood-brain barrier (BBB) permeability and/or CNS IgG synthesis in patients with multiple sclerosis or brain tumors. However, these effects have not been studied in healthy humans. We investigated the effects of prednisone, 80 mg/day for five days, on the ratio of cerebrospinal fluid (CSF) albumin/serum albumin, a measure of blood-brain barrier (BBB) permeability, and on CSF and serum IgG levels in six healthy, normal volunteers. We found significant steroid-induced decreases in serum and CSF albumin levels and in serum IgG levels. However, we found only a nonsignificant decrease in BBB permeability and no significant change in CNS IgG synthesis. These findings, based on a small number of volunteers, suggest that it may be difficult to further decrease BBB permeability and CNS IgG synthesis in medically healthy subjects.

Experimental bacterial meningitis in the rabbit: cerebrospinal fluid changes and its relation to leukocyte response.

This study was focused on cerebrospinal fluid (CSF) manifestations in experimental Streptococcus pneumoniae and Escherichia coli meningitis in rabbits. An increased (p less than 0.001) CSF lactate concentration was found in infected animals, mostly not accompanied by a decrease in CSF glucose concentrations. Despite a marked difference in CSF cellular response between the 2 etiological groups no significant difference in CSF lactate levels was found. Neither did CSF lactate levels correlate to CSF polymorphonuclear cell counts. CSF concentrations of albumin were with large variations above control levels in all infected animals. Also a small or moderate increase in CSF albumin levels was generally associated with a marked increase in CSF lactate concentration. The concentration of total amino acids in the CSF was above control values (mean + 2 SD) in 9/21 infected animals. Halothane/N2O anesthesia for 25 min increased (p less than 0.05) CSF levels of glucose, partly independent of alterations in plasma glucose concentrations, in both infected rabbits and in controls.