Concentrations In Cerebrospinal Fluid Of Patients Research Articles

Therapeutic drug monitoring of polymyxin B cerebrospinal fluid concentrations in patients with carbapenem-resistant Gram-negative bacteria-induced central nervous system infection.

Central nervous system (CNS) infections caused by carbapenem-resistant Gram-negative bacteria (CR-GNB) present a major health and economic burden worldwide. This multicentre prospective study aimed to assess the feasibility and usefulness of CSF therapeutic drug monitoring (TDM) after intrathecal/intraventricular administration of polymyxin B in patients with CNS infections. Forty-two patients treated with intrathecal/intraventricular administration of polymyxin B against CR-GNB-induced CNS infections were enrolled. CSF trough level (Cmin) was collected beginning on Day 2 post-polymyxin B initiation and thereafter. The primary outcomes were clinical cure and 28-day all-cause mortality. All patients started with intrathecal/intraventricular administration of polymyxin B at a dose of 5 g/day, corresponding to a median CSF Cmin of 2.93 mg/L (range, 0.21-25.74 mg/L). Clinical cure was 71.4%, and the median CSF Cmin of this group was higher than that of clinical failure group [3.31 (IQR, 1.73-5.62) mg/L versus 2.25 (IQR, 1.09-4.12) mg/L; P = 0.011]. In addition, with MICs ≤ 0.5 mg/L, maintaining polymyxin B CSF Cmin above 2.0 mg/L showed a higher clinical cure rate (P = 0.041). The 28-day all-cause mortality rate was 31.0% and had no association with CSF Cmin. After intrathecal/intraventricular administration of polymyxin B, CSF concentrations fluctuated considerably inter- and intra-individual. Polymyxin B CSF Cmin above 2.0 mg/L was associated with clinical cure when MICs were ≤ 0.5 mg/L, and the feasibility of TDM warrants additional clinical studies.

Elevated cerebrospinal fluid glucose levels and diabetes mellitus are associated with activation of the neurotoxic polyol pathway

Aims/hypothesisDuring hyperglycaemia, some glucose bypasses glycolysis and is metabolised via the potentially neurotoxic polyol pathway, in which glucose is metabolised to sorbitol and fructose. Increased polyol concentrations have been demonstrated in the cerebrospinal fluid (CSF) of neurological patients with and without diabetes mellitus. However, polyol levels in patients without evident neurological abnormalities have not been investigated so far. The aim of this study was to determine CSF polyol concentrations in patients without major neurological disease with normal or elevated CSF glucose concentrations.MethodsThis observational cohort study used CSF and plasma analyses, as well as clinical data, from 30 participants of the Anaesthetic Biobank of Cerebrospinal Fluid study. Biomaterial was collected from adult patients scheduled for elective surgery under spinal anaesthesia. CSF polyol concentrations were measured by GC/flame ionisation detector in ten patients with normal CSF glucose levels (group 1), ten patients with elevated CSF glucose levels (group 2) and ten patients with elevated CSF glucose levels and type 2 diabetes (group 3). We compared the concentrations of plasma glucose, CSF glucose, sorbitol and fructose, and CSF polyol/glucose ratios between the three groups, and determined the correlation between plasma glucose levels and CSF glucose, sorbitol and fructose levels.ResultsGroups 2 and 3 had significantly higher CSF fructose levels compared with group 1 (p=0.036 and p<0.001, respectively). Group 3 showed significant differences compared with groups 1 and 2 for CSF sorbitol (p<0.001 and 0.036, respectively). Moreover, patients with diabetes had a significantly higher CSF sorbitol/glucose ratio compared with patients without diabetes. There was a strong positive correlation between plasma glucose and CSF glucose, sorbitol and fructose. Finally, age, sex, CSF/plasma albumin ratio and preoperative cognitive function scores were significantly correlated with plasma glucose and CSF glucose, sorbitol and fructose levels.Conclusions/interpretationHyperglycaemia causes a proportional increase in polyol concentrations in CSF of patients without major neurological disease. Furthermore, this study provides the first indication of upregulation of the cerebral polyol pathway in patients with diabetes without evident neurological abnormalities.Graphical abstract

Cerebrospinal Fluid Concentrations of Meropenem and Vancomycin in Ventriculitis Patients Obtained by TDM-Guided Continuous Infusion.

Effective antibiotic therapy of cerebral infections such as meningitis or ventriculitis is hindered by low penetration into the cerebrospinal fluid (CSF). Because continuous infusion of meropenem and vancomycin and routine therapeutic drug monitoring (TDM) have been proposed to optimize antimicrobial exposure in ventriculitis patients, an individualized dosing strategy was implemented in our department. We present a retrospective analysis of meropenem and vancomycin concentrations in serum and CSF in the first nine ventriculitis patients treated with continuous infusion and TDM-guided dose optimization aiming at 20–30 mg/L. Median initial dosing was 8.8 g/24 h meropenem and 4.25 g/24 h vancomycin, respectively, resulting in median serum concentrations of 21.3 mg/L for meropenem and 24.5 mg/L for vancomycin and CSF concentrations of 3.4 mg/L for meropenem and 1.7 mg/L for vancomycin. Median CSF penetration was 15% for meropenem and 7% for vancomycin. With initial dosing, all but one patient achieved CSF concentrations above 1 mg/L. Dose adjustment according to TDM ensured sufficient CSF concentrations in all patients within 48 h of treatment. Given the limited penetration, continuous infusion of meropenem and vancomycin based on renal function and TDM-guided dose optimization appears a reasonable approach to attain sufficient CSF concentrations in ventriculitis patients.

A Novel Method for the Determination of Vitamin D Metabolites Assessed at the Blood-Cerebrospinal Fluid Barrier.

The brain’s supply with vitamin D is poorly understood. Therefore, the present study aimed to determine 25-hydroxy vitamin D3 (25(OH)D) and 24,25-dihydroxy vitamin D (24,25(OH)2D3) in serum and cerebrospinal fluid (CSF) from individuals with intact and disturbed brain-CSF-barrier (BCB) function. In 292 pairs of serum and CSF samples the vitamin D metabolites were measured with liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF/serum ratios (QALB, Q25(OH)D, Q24,25(OH)2D3) were calculated. Median (IQR) serum concentrations of 25(OH)D and 24,25(OH)2D3 were 63.8 (43.4–83.9) nmol/L and 4.2 (2.2–6.2) nmol/L. The CSF concentrations of both metabolites accounted for 3.7 and 3.3% of the respective serum concentrations. Serum 25(OH)D correlated inversely with Q25(OH)D and Q24,25(OH)2D3 implying a more efficient transport of both metabolites across the BCB when the serum concentration of 25(OH)D is low. In patients with BCB dysfunction, the CSF concentrations and the CSF/serum ratios of both vitamin D metabolites were higher than in individuals with intact BCB. The CSF concentrations of 25(OH)D and 24,25(OH)2D3 depend on BCB function and the respective serum concentrations of both metabolites. Higher vitamin D metabolite concentrations in CSF of patients with impaired BCB function may be due to passive diffusion across the BCB.

Alzheimer's disease: Elevated pigment epithelium-derived factor in the cerebrospinal fluid is mostly of systemic origin

Pigment-epithelium derived factor (PEDF) is a neurotrophic factor with neuroprotective, anti-tumorigenic, and anti-angiogenic effects. Elevated levels of PEDF have previously been proposed as a cerebrospinal fluid (CSF) biomarker for Alzheimer's disease. However, the origin of PEDF in CSF, i.e. whether it is derived from the brain or from the systemic circulation, and the specificity of this finding hitherto remained unclear. Here, we analyzed levels of PEDF in paired CSF and serum samples by ELISA in patients with Alzheimer's disease (AD, n=12), frontotemporal dementia (FTD, n=6), vascular dementia (n=4), bacterial meningitis (n=8), multiple sclerosis (n=32), pseudotumor cerebri (n=36), and diverse non-inflammatory neurological diseases (n=19). We established CSF/serum quotient diagrams to determine the fraction of intrathecally synthesized PEDF in CSF. We found that PEDF is significantly increased in CSF of patients with AD, FTD, and bacterial meningitis. Remarkably, PEDF concentrations were also significantly elevated in serum of patients with AD. CSF/serum quotient diagrams demonstrated that elevated PEDF concentrations in CSF of patients with AD are mostly due to elevated PEDF concentrations in serum. These findings underscore the importance of relating concentrations of proteins in CSF to their respective concentrations in serum to avoid erroneous interpretations of increased protein concentrations in lumbar CSF.

Diagnostic Value of Cytokines and Chemokines in Lyme Neuroborreliosis

The aims of the present study were to assess the concentrations of different cytokines and chemokines in blood serum and cerebrospinal fluid (CSF) samples of patients with Lyme neuroborreliosis and to identify the possible marker(s) that would enable a distinction between clinically evident and suspected Lyme neuroborreliosis, as well as between Lyme neuroborreliosis and tick-borne encephalitis (TBE). Our additional interest was to evaluate the relationship between cytokine and chemokine concentrations and Borrelia burgdorferi sensu lato isolation from CSF, as well as intrathecal synthesis of specific borrelial antibodies. We found that higher concentrations of CXCL13 and lower concentrations of interleukin 10 (IL-10) in serum were associated with higher odds for clinically evident Lyme neuroborreliosis compared to suspected Lyme neuroborreliosis, as well as to TBE. The concentrations of IL-2, IL-5, IL-6, IL-10, and CXCL13 in the CSF were higher in patients with evident Lyme neuroborreliosis than in those who were only suspected to have the disease. A comparison of CSF cytokine and chemokine levels in patients with and without intrathecal synthesis of specific borrelial antibodies revealed that CXCL13 CSF concentration is significantly associated with intrathecal synthesis of borrelial antibodies. A comparison of the cytokine and chemokine CSF concentrations in patients with clinically evident Lyme neuroborreliosis according to CSF culture results revealed that higher concentrations of gamma interferon (IFN-γ) were associated with lower odds of Borrelia isolation. Although several differences in the blood serum and CSF concentrations of various cytokines and chemokines between the groups were found, the distinctive power of the majority of these findings is low. Further research on well-defined groups of patients is needed to appraise the potential diagnostic usefulness of these concentrations.

Influence of Lithium Treatment on GDNF Serum and CSF Concentrations in Patients with Early Alzheimers Disease

Preclinical and clinical studies gave evidence that lithium could be useful in the treatment of Alzheimer's disease (AD). One possible mechanism of action might be the induction of neurotrophins. Recently, we found a significant increase of brain-derived neurotrophic factor (BDNF) serum levels in AD patients treated with lithium and a significant decrease of ADAS Cog sum scores in comparison to placebo-treated patients. In another previous study we have shown that glial cell line-derived neurotrophic factor (GDNF) levels in CSF of patients with early AD are increased most probably due to an upregulated expression in CNS as an adaptive process of the impaired brain to enhance neurotrophic support at least in early stages of disease. Here we assessed the influence of a lithium treatment on GDNF serum and cerebrospinal fluid (CSF) concentrations in a subset of a greater sample recruited for a randomized, single-blinded, placebo-controlled, parallel-group multicenter 10-week study, investigating the efficacy of lithium treatment in AD patients. We found a significant negative correlation of lithium concentration in serum with GDNF concentration in CSF at the end of treatment (r = -0.585, p = 0.036) and with the difference of GDNF concentration in CSF before and after treatment (r = - 0.755, p = 0.003). However, we could not show a difference in GDNF concentrations between the patients after the treatment with lithium or placebo (serum, mean ± standard deviation: 434.3 ± 117.9 pg/ml versus 543.8 ± 250.0 pg/ml, p = 0.178; CSF, 62.3 ± 37.4 pg/ml versus 72.8 ± 43.9 pg/ml, p = 0.511). The findings of the present investigation indicated that beneficial effects of the lithium treatment might reduce the necessity of enhanced GDNF expression in the CNS in early AD.

Cerebrospinal Fluid Brain Derived Neurotrophic Factor in the Children with Bacterial Meningitis

Meningitis is an inflammation of the membranes that surround the brain and spinal cord, thereby involving the arachnoid, the pia mater and the interposed cerebrospinal fluid (CSF). The examination of CSF samples may provide information about causative microorganism. CSF contains growth factors including brain derived growth factor (BDNF) which is present under specific pathological and physiological conditions. As CSF is in close contact with the extracellular space of the brain, biochemical brain modifications could be reflected in the CSF and analysis of cytokines and growth factors might identify biomarkers of meningitis. Thus, it is important to study the biochemistry of CSF in order to find a reliable biomarker. The aim of this study was to analyze the level of BDNF in the CSF of the children with bacterial meningitis using ELISA. A total of 66 samples of CSF from normal and meningitis were collected by lumbar puncture. BDNF concentration in the CSF of normal subjects and patients with bacterial meningitis was measured using enzyme linked immunosorbent assay (ELISA). It was shown that the concentration 0f BDNF in the CSF samples with meningitis was higher than in normal CSF. The mean BDNF concentration in CSF of patients with meningitis amounted to 49.22 ± 7.12 pg/ml, which was significantly higher than that of normal, i.e. 9.15 ± 2.26 pg/ml. In conclusion, the data from this study suggests that BDNF could be involved in the pathophysiology of meningitis. The results of our study indicate that BDNF may have neuroprotective properties in meningitis.

Proteomic Analysis of Cerebrospinal Fluid in Pneumococcal Meningitis Reveals Potential Biomarkers Associated with Survival

Patients with pneumococcal meningitis often die or have severe neurological damage despite optimal antibiotic therapy. New or improved therapy is required. The delivery of new interventions will require an improved understanding of the disease pathogenesis. Our objective was to learn more about the pathophysiology of severe meningitis through the interpretation of differences in the proteomic profile of cerebrospinal fluid (CSF) from patients with meningitis. Two-dimensional polyacrylamide gel electrophoresis of CSF from normal subjects (controls, n = 10) and patients with pneumococcal meningitis (n = 20) was analyzed. Spot differences were compared and identified between controls, nonsurvivors (n = 9), and survivors (n = 11). Protein concentration in CSF of patients with meningitis was 4-fold higher than in CSF of control subjects (7.0 mg/mL vs 0.23 mg/mL; P < .01). A mean of 2466 discrete protein spots was present in CSF of patients with meningitis. Thirty-four protein spots were differentially expressed in CSF of nonsurvivors, compared with survivors. None of these protein spots were observed in CSF of control subjects. Proteomic screening of CSF yields potential biomarkers capable of differentiating control subjects from nonsurvivors and survivors of meningitis. Proteins involved in the inflammatory process and central metabolism were represented in the differentially expressed protein repertoire.

Intravenous Anakinra can Achieve Experimentally Effective Concentrations in the Central Nervous System within a Therapeutic Time Window: Results of a Dose-Ranging Study

The naturally occurring antagonist of interleukin-1, IL-1RA, is highly neuroprotective experimentally, shows few adverse effects, and inhibits the systemic acute phase response to stroke. A single regime pilot study showed slow penetration into cerebrospinal fluid (CSF) at experimentally therapeutic concentrations. Twenty-five patients with subarachnoid hemorrhage (SAH) and external ventricular drains were sequentially allocated to five administration regimes, using intravenous bolus doses of 100 to 500 mg and 4 hours intravenous infusions of IL-1RA ranging from 1 to 10 mg per kg per hour. Choice of regimes and timing of plasma and CSF sampling was informed by pharmacometric analysis of pilot study data. Data were analyzed using nonlinear mixed effects modeling. Plasma and CSF concentrations of IL-1RA in all regimes were within the predicted intervals. A 500-mg bolus followed by an intravenous infusion of IL-1RA at 10 mg per kg per hour achieved experimentally therapeutic CSF concentrations of IL-1RA within 45 minutes. Experimentally, neuroprotective CSF concentrations in patients with SAH can be safely achieved within a therapeutic time window. Pharmacokinetic analysis suggests that IL-1RA transport across the blood–CSF barrier in SAH is passive. Identification of the practicality of this delivery regime allows further studies of efficacy of IL-1RA in acute cerebrovascular disease.

Soluble amyloid precursor proteins in the cerebrospinal fluid as novel potential biomarkers of Alzheimer's disease: a multicenter study

In this report, we present the results of a multicenter study to test analytic and diagnostic performance of soluble forms of amyloid precursor proteins alpha and beta (sAPP alpha and sAPP beta) in the cerebrospinal fluid (CSF) of patients with different forms of dementing conditions. CSF samples were collected from 188 patients with early dementia (mini-mental state examination >or=20 in majority of cases) and mild cognitive impairment (MCI) in 12 gerontopsychiatric centers, and the clinical diagnoses were supported by neurochemical dementia diagnostic (NDD) tools: CSF amyloid beta peptides, Tau and phospho-Tau. sAPP alpha and sAPP beta were measured with multiplexing method based on electrochemiluminescence. sAPP alpha and sAPP beta CSF concentrations correlated with each other with very high correlation ratio (R=0.96, P<0.001). We observed highly significantly increased sAPP alpha and sAPP beta CSF concentrations in patients with NDD characteristic for Alzheimer's disease (AD) compared to those with NDD negative results. sAPP alpha and sAPP beta highly significantly separated patients with AD, whose diagnosis was supported by NDD findings (sAPP alpha: cutoff, 117.4 ng ml(-1), sensitivity, 68%, specificity, 85%, P<0.001; sAPP beta: cutoff, 181.8 ng ml(-1), sensitivity, 75%, specificity, 85%, P<0.001), from the patients clinically assessed as having other dementias and supported by NDD untypical for AD. We conclude sAPP alpha and sAPP beta might be regarded as novel promising biomarkers supporting the clinical diagnosis of AD.

Association of Matrix Metalloproteinase-9 and Tissue Inhibitors of Metalloproteinase-4 in Cerebrospinal Fluid with Blood-Brain Barrier Dysfunction in Patients with Eosinophilic Meningitis Caused by Angiostrongylus cantonensis

To evaluate possible blood-brain barrier (BBB) dysfunction caused by matrix metalloproteinase-9 (MMP-9) and its regulation by tissue inhibitors of metalloproteinase (TIMPs) in patients with eosinophilic meningitis caused by infection with Angiostrongylus cantonensis, 40 patients and 28 controls were included in this study. Concentrations of MMP-2, MMP-9, TIMP-1, and cerebrospinal fluid (CSF):serum albumin ratios (Q(Alb) values) were significantly increased in patients compared with controls. However, concentrations of TIMP-4 were significantly lower in patients. In contrast to MMP-2, proteolytic activity of MMP-9 detected by gelatin zymography was only observed in patients with eosinophilic meningitis. We detected higher levels of antibodies specific for A. cantonensis and higher Q(Alb) values and MMP-9 concentrations in CSF of patients with eosinophilic meningitis, Furthermore, the increase in the Q(Alb) value was significantly correlated with the increase in MMP-9 in patients. In parallel with CSF MMP-9, patients also showed an increase in CSF leukocyte counts. Gradual decreases in levels of Q(Alb), MMP-9, and TIMP-1 and increases in levels of TIMP-4 were observed in six patients during recovery from eosinophilic meningitis. These results suggest that the source of MMP-9 in CSF of patients with eosinophilic meningitis was probably associated with leukocytes migrating from peripheral blood to CSF. Activity of MMP-9 in CSF of patients could not be completely inhibited because of the decrease of TIMP-4, which may cause BBB dysfunction, as shown by higher Q(Alb) values in patients.

Activin A concentrations in human cerebrospinal fluid are age-dependent and elevated in meningitis

Objective Activin A, and its binding protein, follistatin (FS), are expressed in the central nervous system (CNS). We have previously shown elevated concentrations of FS in the cerebrospinal fluid (CSF) of patients with meningitis and increased concentrations of activin A in the CSF of rabbits with bacterial meningitis. Methods We measured CSF and serum concentrations of activin A and FS in normal subjects and in patients with various neurological diseases using previously validated immunoassays specific for activin A or FS. Results In healthy persons, serum concentrations of both activin A and FS were age-dependent. In CSF, concentrations of activin A ranged from 0.03 to 0.33 ng/ml and were strongly correlated with age in both sexes, whereas FS CSF concentrations were below the assay detection limit in most of the patients. Activin A concentrations in CSF of patients with various neurological diseases, including meningitis, chronic inflammatory CNS diseases, neurodegenerative diseases, tumors in the CNS, cerebral ischemia, intracerebral/subarachnoid hemorrhages, subdural hemorrhages and epileptic seizures, were compared with age- and sex-matched control patients. The comparisons revealed significantly elevated concentrations of activin A in patients with meningitis ( P = 0.017). Serum concentrations of activin A or FS were not affected by any of the neurological diseases examined. Conclusions Our results show for the first time that in normal subjects concentrations of activin A in CSF are correlated with age, and furthermore, that activin A CSF concentrations are elevated in patients with meningitis. The latter underlines a role for activin A in acute inflammatory processes within the CNS.

CEREBROSPINAL FLUID CONCENTRATIONS OF ANTI-INFLAMMATORY MEDIATORS IN EARLY-PHASE SEVERE TRAUMATIC BRAIN INJURY

In our previous study of patients with early-phase severe traumatic brain injury (TBI), the anti-inflammatory interleukin (IL)-10 concentration was lower in cerebrospinal fluid (CSF) than in serum, whereas proinflammatory IL-1beta and tumor necrosis factor (TNF)-alpha concentrations were higher in CSF than in serum. To clarify the influence of additional injury on this disproportion between proinflammatory and anti-inflammatory mediators, we compared their CSF and serum concentrations in patients with severe TBI with and without additional injury. All 35 study patients (18 with and 17 without additional injury) had a Glasgow Coma Scale score of 8 or less upon admission. With the exception of additional injury, clinical characteristics did not differ significantly between groups. CSF and serum concentrations of two proinflammatory mediators (IL-1beta and TNF-alpha,) and three anti-inflammatory mediators (IL-1 receptor antagonist [IL-1ra], soluble TNF receptor-I [sTNFr-I], and IL-10) were measured and compared at 6 h after injury. CSF concentrations of proinflammatory mediators were much higher than the corresponding serum concentrations in both patient groups (P < 0.001). In contrast, serum concentrations of anti-inflammatory mediators were much higher than the paired CSF concentrations in patients with additional injury (P < 0.001), but serum concentrations were lower than or equal to the corresponding CSF concentrations in patients without additional injury. CSF concentrations of IL-1beta, IL-1ra, sTNFr-I, and IL-10 were significantly higher (P < 0.01 for all) in patients with high intracranial pressure (ICP; n = 11) than in patients with low ICP (n = 24), and were also significantly higher (P < 0.05 for all) in patients with an unfavorable outcome (n = 14) than in patients with a favorable outcome (n = 21). These findings indicate that increased serum concentrations of anti-inflammatory mediators after severe TBI are mainly due to additional extracranial injury. We conclude that anti-inflammatory mediators in CSF may be useful indicators of the severity of brain damage in terms of ICP as well as overall prognosis of patients with severe TBI.

Reduced CSF PLTP activity in Alzheimer's disease and other neurologic diseases; PLTP induces ApoE secretion in primary human astrocytes in vitro

Phospholipid transfer protein (PLTP) plays a pivotal role in cellular lipid efflux and modulation of lipoprotein metabolism. PLTP is distributed widely in the central nervous system (CNS), is synthesized by glia and neurons, and is active in cerebrospinal fluid (CSF). The aims of this study were to test the hypothesis that patients with Alzheimer's disease (AD) have altered PLTP-mediated phospholipid transfer activity in CSF, and to examine the potential relationship between PLTP activity and apolipoprotein E (apoE) levels in CSF. We assessed PLTP activity and apoE concentration in CSF of patients with probable AD (n = 50), multiple sclerosis (MS; n = 9), other neurologic diseases (n = 21), and neurologically healthy controls (n = 40). PLTP activity in AD was reduced compared to that in controls (P < 0.001), with approximately half of the AD patients with PLTP activity values below all controls. Patients with MS had lower PLTP activity than AD patients (P < 0.001). PLTP activity was highly correlated with PLTP mass, as estimated by Western blot (r = 0.006; P < 0.01). CSF PLTP activity positively correlated with apoE concentration in AD (R = 0.435; P = 0.002) and controls (R = 0.456; P = 0.003). Anti-apoE immunoaffinity chromatography and Western blot analyses indicated that some CSF PLTP is associated with apoE-containing lipoproteins. Exogenous addition of recombinant PLTP to primary human astrocytes significantly increased apoE secretion to the conditioned medium. The findings of reduced PLTP activity in AD CSF, and the observation that PLTP can influence apoE secretion in astrocytes suggest a potential link between alterations in the brain lipid metabolism and AD pathogenesis.

Altered kallikrein 7 and 10 concentrations in cerebrospinal fluid of patients with Alzheimer's disease and frontotemporal dementia

Background: The role of various proteases in the pathogenesis of Alzheimer's disease is well documented. Recently, many members of the human tissue kallikrein family, a group of 15 secreted serine proteases, were found to be highly expressed in the central nervous system (CNS). Some of these enzymes can be measured in cerebrospinal fluid (CSF) by using ELISA-type methodologies. Methods: We quantified various kallikreins in CSF of 20 patients with Alzheimer's disease (AD), 16 patients with frontotemporal dementia (FTD), and 15 controls. We then correlated the levels of various kallikreins with presence of AD or FTD. Among all kallikreins measured, detectable levels in CSF were identified for kallikreins hK6, hK7, and hK10. Other tested kallikreins (hK5, hK8, hK11, and hK13) were unmeasurable. The most notable differences between kallikrein levels in CSF and the three groups of subjects were seen between controls and FTD patients for hK6 (decrease in FTD; P = 0.017), controls and FTD patients for hK7 (decrease in FTD; P < 0.001), and controls and AD patients for hK7 (decrease in AD; P = 0.019). In addition, significant differences were seen between FTD patients or control subjects and patients with AD patients for hK10 (increase in AD; P < 0.02). Approximately half of the AD patients had CSF hK10 levels that were higher than all patients with FTD except one and all control subjects except two. Various kallikrein concentrations in CSF were correlated, the strongest correlation seen between hK6 and hK7 ( r s = 0.58). We also observed a statistically significant association between decreasing hK7 concentration in CSF and possession of one or two ApoE4 alleles ( P = 0.014). Conclusions: We demonstrate for the first time significant alterations of hK6, hK7, and hK10 concentration in CSF of patients with AD and FTD. Notably, all three kallikreins (hK6, hK7, and hK10) are decreased in CSF of FTD patients and hK10 is increased in CSF of AD patients, in comparison to control subjects. The possible connection between these enzymes and the pathogenesis and progression of AD and FTD needs to be further investigated.

Nasal drug delivery to the cerebrospinal fluid: transport of a lipophilic compound

The aim of this study was to investigate the possibility of direct transport of drugs from the olfactory area to the cerebrospinal fluid (CSF) by intranasal administration (i.n.) of a lipophilic drug in human volunteers. In a large number of animal studies evidence has been found for drug transport via the nose to the brain [1]. Human studies are suggesting such a transport, for instance for i.n. midazolam [2], on pharmacodynamic grounds, but pharmacokinetic evidence is as yet missing. This study evaluates drug CSF concentrations in patients at the neurosurgery department after i.n. and intravenous (i.v.) administration of melatonin, used in this study as a lipophilic model compound. It has been chosen because it is an endogenous relatively safe compound, for which a very good nasal absorption has been reported [3]. In a pharmacokinetic study, patients at the neurosurgery department with an external cerebrospinal drain were recruited. Three patients were included. Each patient received on one day melatonin i.n. as a dose of 400 μg (200 μg in each nostril) and on another day 200 μg melatonin i.v. Blood samples and CSF samples were collected just before and at 5, 10, 20, 0, 40, 60, 120 and 180 min after drug administration. Melatonin concentrations were measured with h.p.l.c. Concentration–time curves of the plasma and CSF concentrations of melatonin were compared after i.n. and i.v. administration. The nasal absorption of melatonin in blood is fast and efficient. Peak plasma concentrations after i.n. are reached within 20 min and are comparable with those reached after i.v. administration. The AUCCSF:AUCplasma after i.n. administration was in all three patients not larger than after i.v. administration. In the three investigated patients the increase in CSF melatonin concentration after i.n. administration appeared to be comparable with that after i.v. administration (Table 1). Table 1 AUC (0, 180 min) of melatonin in CSF after i.n. and i.v. administration. The increase of the melatonin concentrations in the CSF does not differ largely in the period 0–180 min, whether the drug is administered i.n. or i.v., indicating that the drug enters the CSF via the systemic circulation and the blood–brain barrier. It is evident that i.n. administration of a lipophilic compound could be an interesting alternative route of administration, giving high blood and also high CSF concentrations, but the results of this study provide no indication for an additional transport mechanism of the lipophilic compound directly from the nose to the CSF.

Decreased concentration of annexin V in parkinsonian cerebrospinal fluid: speculation on the underlying cause.

Circumstantial evidence suggests that increased apoptosis is responsible for the loss of dopaminergic nigrostriatal neurons in Parkinson's disease (PD). It is impossible to perform high-quality studies on human postmortem material because of the low quality of tissue preservation, and the fact that apoptosis has a duration of only hours, and that the duration of the agonal period itself will lead to massive neuronal cell death. We measured, as epiphenomenon of neuronal cell death ex vivo, the Annexin V concentration in cerebrospinal fluid (CSF) in patients with PD and control subjects. The Annexin V concentration in CSF of patients with PD was significantly lower compared with control subjects. Annexin V concentrations of the CSF did not correlate with dementia, duration of symptoms, age, sex, or treatment of PD. The rationale for measurement of Annexin V in CSF is the fact that Annexin V adheres to dying cells. It is tempting to suppose that the decrease of Annexin V in CSF of PD is the result of consumption of this protein during neuronal apoptosis as has been demonstrated to occur in the midbrain in PD.

Concentrations of zinc, iron, molybdenum, arsenic, and lithium in cerebrospinal fluid of patients with brain tumors.

We used flameless atomic absorption spectrophotometry to measure concentrations of Fe, Mo, Li, As, and Zn in cerebrospinal fluid (CSF) of patients with malignant brain tumors benign brain tumors, non-brain malignant tumors and control (non-neoplastic disease) patients. Mean (and SD) concentrations (microgram/L) of these elements in the control group were 62.7 (28.7) for Fe, 6.8 (4.8) for Mo, 0.7 (2.0) for Li, 1.3 (0.7) for As, 7 (5.9) for Zn. We could detect Li in less than 53% of controls. Zn concentrations in CSF of patients with astrocytoma (malignant brain tumor), benign brain tumors, or non-brain tumors were significantly (p less than 0.05) less than in control patients; the ratios for mean concentrations of Zn in tumor patients/control patients for the above groups were 0.3, 0.20, and 0.17, respectively. Concentrations of As in CSF of patients with non-brain malignant tumors were significantly (p less than 0.05) higher than in the controls; the ratio for mean CSF concentration of As in patients with non-brain tumors/control patients was 2.9. Differences in the concentrations of Fe, Li, or Mo among the various groups were nonsignificant.

Moxalactam epimer kinetics in children

The kinetics of the R and S epimers of moxalactam were followed after single intravenous doses of 50 mg/kg to 12 patients, 8 to 45 mo old, with cellulitis or epiglottitis. High-pressure liquid chromatography was used to determine serum concentrations. Total body clearance and apparent volume of distribution of the R epimer were higher than those of the S epimer (P less than 0.004). Total body clearance of R, S, and R + S moxalactam ranged from 29.01 to 183.7, 19.00 to 79.95, and 23.34 to 113.6 ml/min/m2. Mean elimination half-lives of R, S, and R + X moxalactam were 2.04, 2.26, and 2.24 hr. The higher incidence of the more active R epimer and the 500% interpatient variation in clearance may indicate a need for monitoring serum and cerebrospinal fluid concentrations in patients with severe unresponsive central nervous system infectious treated with moxalactam.