Time course of IL-6 expression in experimental CNS ischemia.

Interleukin-6 (IL-6) appears to be an important modulator of the inflammatory response associated with CNS ischemia. Clinically, IL-6 values obtained in the first week post-stroke have been shown to correlate with infarct size and outcome. In this study we used a focal reversible stroke model to investigate the time course and relationship to outcome of IL-6 production in plasma, brain and CSF. Reversible middle cerebral artery occlusion or sham surgery was produced in 50 adult Swiss Webster mice by advancing an 8-0 filament into the internal carotid artery for 2 h (sham 1 min). At 3, 6, 12, 24, and 72 h (8 each ischemia; 2 each sham) groups of animals were evaluated on a 28 point clinical scale, blood and CSF obtained, and the brains were evaluated for infarct volume and IL-6 mRNA levels. Serum levels of IL-6 (ELISA mean +/- SD; undetectable in controls) overall sham group, 102 +/- 87; 3 h, 908 +/- 494* pg ml-1; 6 h, 1079 +/- 468* pg ml-1; 12 h, 980 +/- 221* pg ml-1; pg ml-1; 24 h, 320 +/- 314* pg ml-1; 72 h, 20 +/- 30* pg ml-1 (*p < or = 0.05 to sham). CSF levels (ELISA) overall sham group, 10 +/- 18; 3 h, 379 +/- 210* pg ml-1; 6 h, 157 +/- 61* pg ml-1; 12 h, 136 +/- 88* pg ml-1; 24 h, 127 +/- 99 pg ml-1; 72 h, 72 +/- 9* pg ml-1 (*p < or = 0.05 to sham). Brain IL-6 mRNA levels overall sham group, 20; 3 h, 480; 6 h, 599; 12 h, 7960; 24 h, 20267; 72 h, 0. There was an overall R2 of 0.20 between plasma and CSF IL-6. There was an overall R2 of 0.13 and 0.20 between infarct size and serum and CSF IL-6 level respectively, and an overall R2 of 0.10 and 0.17 between neurologic function and serum and CSF IL-6 level respectively. These findings confirm that IL-6 values increase following CNS ischemia with peak serum and CSF levels occurring before brain values. CSF IL-6 levels had a stronger correlation with neurologic function and infarct size than serum.     

Cerebrospinal fluid levels of interleukin-6 and interleukin-12 in children with meningitis

Purpose  Certain cytokines play important roles in the pathophysiology of meningitis. The main purpose of this study was to investigate if the levels of interleukin-6 (IL-6) and interleukin-12 (IL-12) in cerebrospinal fluid (CSF) could be diagnostic predictors of bacterial meningitis in children. Methods  CSF was obtained from 95 patients suspected with meningitis. These cases were classified to the bacterial meningitis (n = 12), aseptic meningitis (n = 41), and nonmeningitis (n = 42) groups. The levels of IL-6 and IL-12 in CSF were measured using the enzyme-linked immmunosorbent assays test. Results  The CSF IL-6 levels in the bacterial meningitis group (45.2 ± 50.0 pg/ml) were significantly higher than those in the aseptic meningitis group (12.9 ± 10.2 pg/ml) and the nonmeningitis group (6.5 ± 7.8 pg/ml; p < 0.05). The CSF IL-12 levels in the bacterial meningitis group (69.8 ± 67.1 pg/ml) were significantly higher than those in the aseptic meningitis group (22.9 ± 10.8 pg/ml) and the nonmeningitis group (15.3 ± 11.2 pg/ml; p < 0.05). With regard to diagnosis, the measurement of CSF IL-6 and IL-12 levels showed sensitivities of 96% and 96%, respectively, and specificities of 51% and 75%, respectively. Conclusion  It is suggested that the CSF IL-6 and IL-12 levels are useful markers for distinguishing bacterial meningitis from aseptic meningitis.     

Effects of thromboxane synthetase inhibitor (RS-5186) on experimentally-induced cerebral vasospasm

Abstract

RS-5186, which inhibits thromboxane A2 (TXA2) synthetase activity, ameliorated delayed cerebral vasospasm in a canine two-hemorrhage model. Subarachnoid hemorrhage was induced in 15 dogs, which were divided into two groups. In the RS-5186-treated group (9 dogs), 50 mg kgof RS-5186 was administered twice a day for seven days. The remaining six dogs without administration of RS-5186 were used as a control group. In the RS-5186-treated group, the angiographic diameter of the basilar artery on Day 7 after subarachnoid hemorrhage was constricted to 60.9% ± 11.6% fn = 9, mean±SD) of that on Day 0, before subarachnoid hemorrhage. The corresponding value was 42.8%±6.1% (n = 6) in the control group. There was a statistically significant difference between these percentages. In the RS-5186-treated group, plasma thromboxane B2 level on Day 7 was 144.3 ± 28.1 pg mh1 fn = 4), which was lower than the 815.5± 162.0 pg ml^–1 fn = 4) in the control group (p < 0.0005). The plasma 6-keto-prostaglandin F1a level on Day 7 was 180.5 ± 66.5 pg ml*1 fn = 4J in the RS-5186-treated group, and higher than 107.3± 12.4 pg mh1 fn = 4) in the control group fp = 0.0734). Thus, administration of RS-5186 reduced TXA2 plasma level and had a beneficial effect on angiographically-detected delayed vasospasm. [Neurol Res 1999; 21: 513–516]     

CSF levels of a set of neurotrophic factors (brain-derived neurotrophic factor,nerve growth factor) and neuropeptides (neuropeptide Y,galanin) in epileptic children

This paper aims to investigate the possible roles of a set of neurotrophic factors (brain-derived neurotrophic factor-BDNF, nerve growth factor-NGF) and neuropeptides (neuropeptide Y-NPY, and galanin) in children with active epileptogenesis. The cerebrospinal fluid (CSF) levels of BDNF, NPY, NGF and galanin were measured with enzyme-linked immunosorbent assays in epileptic children (n = 73) and controls (n = 64). There were no significant alterations in the CSF levels of BDNF, NPY and NGF in epileptic children with active clinical seizures compared with the levels of controls. However profoundly depressed galanin levels were found in infants with epileptic encephalopathy (mean ± SD:0.63 ± 0.19 pg/ml) and significantly increased galanin levels were measured in children with drug resistant epilepsy during the period of status epilepticus (mean ± SD: 6.92 ± 1.19, pg/ml pg/ml) compared with the levels of controls. Depressed levels of galanin might reflect a defective anti-epileptogenic effect of galanin in infants with epileptic encephalopathy. On the contrary, increased CSF levels of galanin might be a result of anti-epileptogenic effects of this peptide in epileptic children with status epilepticus.     

Nonenzymatic derived lipid peroxide, 8-iso-PGF2α, participates in the pathogenesis of delayed cerebral vasospasm in a canine SAH model

Abstract

We studied whether 8-iso-PGF_2α, nonenzymatic arachidonyl peroxide, participated in the pathogenesis of delayed vasospasm using a canine subarachnoid hemorrhage (SAH) model. Fourteen adult mongrel dogs were divided into two groups, two-hemorrhage SAH group (n = 8) and control group (n = 6). The contents of 8-iso-PGF _2α in CSF, the basilar artery segment, and subarachnoid clot were measured by enzyme immunoassay kit. The CSF 8-iso-PGF_2α content on Day 7 in the SAH group was 67.9 ± 29.9 pg ml^-1 (n = 8), which was significantly higher than 27.1 ± 13.8 (n = 8) on Day 0 in the SAH group, and 33.2 ± 14.4 pg ml^-1 (n = 5) on Day 7 in the control group. The 8-iso-PGF_2α content in the basilar artery segment with spasm on Day 7 in the SAH group was 13.5 ± 1.9 pg mg^-1 wet weight (n = 8), significantly higher than 8.7 ± 1.9 (n = 6) in the control group. The 8-iso-PGF_2α content in subarachnoid clot was 1.7 ± 1.4 ng g^-1 wet weight (n = 8). Significant elevation of the 8-iso-PGF_2α contents in the CSF and the basilar artery segment occurred on Day 7 in the SAH group. The subarachnoid clot enclosed the basilar artery on Day 7, contained a considerable amount of 8-iso-PGF_2α. These results suggested that 8-iso-PGF_2α could play a crucial role in the pathogenesis of the delayed cerebral vasospasm. [Neurol Res 2002; 24: 301-306]     

Intrathecal levels of IL-6, IL-11 and LIF in Alzheimer's disease and frontotemporal lobar degeneration

Cerebrospinal fluid (CSF) levels of interleukin (IL)-6, IL-11 and leukaemia inhibitory factor (LIF) were evaluated in 43 patients with Alzheimer's disease (AD) and 24 patients with frontotemporal lobar degeneration (FTLD) as compared with 30 agematched controls (CON), and correlated with clinical and demographic data and with CSF biomarkers amyloid beta (Aβ)42, total tau and tau phosphorylated at position 181 (P-tau). CSF IL-11 mean levels were significantly increased in AD and FTLD as compared with CON (6.5 ± 4.6 and 6.6 ± 5.1 versus 3.1 ± 3.3 pg/ml, P = 0.009). IL-6 mean levels did not differ between patients and CON (P > 0.05),whereas LIF levels were not detectable in patients or in CON. In AD patients, a significantly positive correlation between MMSE scores and IL-11 CSF concentration was observed (r = 0.344, P = 0.028). No correlations with CSF Aβ42, total tau and P-tau were found. IL-11, but not IL-6 levels are increased in AD and FTLD, and the highest peaks were observed in patients with a less severe degree of cognitive deterioration, therefore suggesting a role of this cytokine in early phases of neurodegeneration.     

Interleukin-1β is increased in the cerebrospinal fluid of patients with small infarcts

Background and purpose:  Interleukin-1beta (IL-1β) and interleukin-6 (IL-6) are involved in inflammatory responses during large vessel occlusion in animal models. The aim of this study was to investigate the intrathecal levels of cytokines in patients with acute small infarcts.
Methods:  Forty patients with acute minor stroke and 32 non-stroke patients (including 29 age- and gender-matched subjects) who received operations with spinal anesthesia were studied prospectively and underwent measurements of cerebrospinal fluid (CSF) IL-1β and IL-6 levels.
Results:  After an age- and gender-matched analysis of 58 patients (29 pairs), the mean intrathecal levels of IL-1β were 0.80 pg/ml in patients with small infarcts and 0.59 pg/ml in non-stroke patients ( P  <   0.0001). In addition, the mean CSF levels of IL-6 were 21.54 pg/ml and 7.52 pg/ml in the stroke and control groups, respectively ( P  =   0.38). These results were consistent with the data without matching. The CSF levels of IL-1β in the 40 stroke patients were significantly higher than in the 32 non-stroke controls ( P  <   0.0001).
Conclusions:  The proinflammatory cytokine IL-1β, but not IL-6, remained elevated in the CSF of patients in the acute stage of small infarcts.     

Cerebrospinal fluid F2-isoprostane levels are increased in Alzheimer's disease

Postmortem studies have associated Alzheimer's disease (AD) with regionally increased oxidative damage to brain. Lacking, however, is a specific marker of oxidative damage to brain that may be measured during life. We tested the hypothesis that cerebrospinal fluid (CSF) concentrations of F₂-isoprostanes (F₂-IsoPs), stable products of arachidonate peroxidation, are increased in CSF of AD patients. CSF from lateral ventricles (VF) was analyzed from 11 AD patients and 11 control subjects who participated in a rapid autopsy program. VF F₂-IsoP concentrations were significantly elevated in AD patients compared with control subjects (72 ± 7 vs 46 ± 4 pg/ml) and were significantly linearly correlated with brain weight (–0.3 pg/ml/g, r² = 0.32). These results suggest that quantification of CSF F₂-IsoP concentrations may provide a useful biomarker of central nervous system oxidative damage in AD.     

Hypothalamic versus pituitary dysfunction in Down's syndrome as cause of growth retardation

We have found that some children with Down's syndrome (DS) have growth retardation secondary to grovrth hormone (GH) deficiency. To test the hypothesis that hypothalamic dysfunction is the primary cause for GH deficiency and grovirth retardation, hypothalamic-pituitary responses of serum GH concentrations to levodopa and clonidine as well as pituitary responses in serum GH concentrations to growth-hormone-releasing hormone (GHRH) were analysed in 14 prepubertal children with DS. Levodopa and clonidine were given, and blood was drawn for determining serum GH levels. Seven prepubertal control children had both levodopa and clonidine tests done. The A serum GH during levodopa was 5.7±6.3 ng ml^?1 in DS and 13.1 ± 9.8 ng ml^?1 in controls. The Δ serum GH during clonidine administration was 3.0±3.2 ng ml^?1 in DS and 17.3±5.6 ng ml^?1 in controls. Children with DS had a significantly lower response to levodopa and clonidine, compared with controls by the Mann-Whitney U-test (P<0.03 and P<0.009, respectively). Growth-hormone-releasing hormone was given at 1 μg kg^?1 i.v. bolus and bloods for GH were drawn at -15, 0, 15, 30, 60, 90 and 120 min in 14 subjeas with DS and 24 normal controls, both groups prepubertal. The mean A serum GH concentration in DS was 53.6±38.3 ng ml^?1, and it was 35.6±25.l ng ml^?1 in controls with P<0.23 non-significant by the Mann-Whitney U-test. These results indicate that levodopa and clonidine (drugs stimulating hypothalamic GHRH release and secondary pituitary GH release in normal individuals) do not stimulate GH release in DS. Furthermore, normal GH response to GHRH in DS indicates normal pituitary function (normal somatotroph response to GHRH) and supports hypothalamic dysfunction in DS.     

Soluble intercellular adhesion molecule-1 in cerebrospinal fluid: An indicator for the inflammatory impairment of the blood-cerebrospinal fluid barrier

A soluble form of the intercellular adhesion molecule- (sICAM-1) was measured in paired cerebrospinal fluid (CSF)/blood samples from 123 patients with differenr neurological diseases. Mean levels of circulating ICAM-1 in the blod were mean ±SD = 423 ± 184.6 ng ml⁻¹ (range 44–1115 ng ml⁻¹). Considerable differences of sICAM-1 in the CSF of patients wre observed between disease groups. In accute bacterial maningitis, sICAM-1 levels as high as of the serum concentration were detected in the CSF (n = 24; mean ± SD = 33.0 ± 23.7 ng ml⁻¹; range: 4.8–93.9 ng ml⁻¹). These changes coincided with a sever blood-CSF barrier dysfunction as indicated by a high CSF/blood ration for albumin (mean ± SD = 46.7 ± 52.2; range: 16.8–249.3). In patients with polyradiculitits (n = 9; mean ± SD = 14.5 ± 11.9 ng ml⁻¹; range: 2.6–43.7 ng ml⁻¹) a similar convariation between the albumin and sICAM CSF/blood ratios was detected. In patients with multiple sclerosis (n = 9; mean ± SD = 5 ± 4.3; arange: 0–12.7 ng ml⁻¹ or HIV infection with neurological symptoms (n = 18; mean ± SD = 4.9 ± 3.2; range; 1–11.9 ng ml⁻¹) low levels of sICAM-1 were detected in the CSG associated with intact blood-CSF barrier function in most patients. Among 13 patients with viral meningitis, only four had detectable levels of sICAM-1 in their CSF (mean ± SD = 1.0 ± 1.5 ng ml⁻¹; range: 0–3.7). Interestingly, in a groupof patients with non-inflammatory disorders of the CNS soluble ICAM-1 was present only in three out of 50 CSF samples despite indication for blood-CSF barrier dysfunction in most cases. Repeated lumbar punctures revealed that persistent high CSF/serum ratios for sICAM-1 were associated with poor outcome. In patients with inflammatory diseases of the CNS, a signoficant correlation was observed between CSF/serumratios for albumin and sICAM-1 ([ifn = 169; r = 0.67; P < 0.001), whereas no relation between these parameters was detected in patients with non-inflammatory diseases These results indicate that sICAM-1 is a reliable marker for an inflammatory process within non-inflammatory process within the CNS which is associated with blood-CSF barrier distrubance.     

A radioimmunoassay for thrombospondin, used in a comparative study of thrombospondin, β-thromboglobulin and platelet factor 4 in healthy volunteers

A radioimmunoassay was developed for the platelet α-granule protein thrombospondin; concentrations of thrombospondin as low as 3 ng ml^?1 could be measured. There was no interference from other components of human biological fluids and no crossreactivity with β-thromboglobulin (β-TG) or platelet factor 4 (PF4). Plasma samples were stable when stored at ?20°C. Normal human plasma contained 105.0 ± 31.0 ng thrombospondin ml^?1 compared with β-TG concentrations of 37.2 ± 10.9 ng ml^?1 and PF4 concentrations of 14.7 ± 10.1 ng ml^?1 when samples were carefully taken into a platelet inhibitor cocktail and processed at 0–4°C. Release of thrombospondin during clotting of blood occurred at the same time as that of β-TG and PF4 and resulted in a serum concentration of 17.5 ± 5.5 μg ml^?1. Assay of whole blood gave a platelet thrombospondin content of 89.1 ± 28.3 ng/ 10⁶ platelets. The concentration in normal urine fluctuated widely from 3 to 22.5 ng ml^?1, and was unrelated to urine flow. The half-life of thrombospondin $\text{in vivo}$ was about 9 h, much longer than that of either β-TG or PF4. Unlike PF4, it was not released into the blood following an intravenous heparin injection. Bovine, ovine, canine and porcine sera contained thrombospondin which crossreacted immunologically with the human molecule; these species would be suitable animal models for the study of thrombospondin and its value as a platelet release marker.     

Decreased levels of interleukin-10 and transforming growth factor-beta2 in cerebrospinal fluid of patients with high grade astrocytoma

Abstract

Objective: Glioma cells can produce anti-inflammatory cytokines such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β) which inhibit T cell and monocyte function. It is unknown if production of these cytokines is limited to the site of tumor or these molecules are also released to cerebrospinal fluid and blood. The goal of our study was to determine if patients with astrocytoma have increased levels of IL-10 and TGF-β2 in cerebrospinal fluid (CSF) and serum.

Methods: CSF and serum samples were taken from 16 patients with astrocytoma of grade III or grade IV according to the WHO classification and from 28 age- and gender-matched controls (patients with normal pressure hydrocephalus or with lumbar disk herniation). Cytokine concentrations were measured using ELISA methods.

Results and discussion: There was no difference in serum levels of IL-10 and TGF-β2 between groups. Patients with astrocytoma had decreased levels of IL-10 (0.9 ± 1.2 versus 3.5 ± 9.2 pg/ml, p=0.01) and TGF-β2 (0.0 ± 0.0 versus 5.4 ± 9.4 pg/ml, p=0.05) in CSF compared to controls. Because serum IL-10 and TGF-β2 levels are similar in patients with astrocytoma and in controls, these cytokines are probably not directly involved in peripheral monocyte and T cell deactivation.     

Increased levels of inflammatory chemokines in amyotrophic lateral sclerosis

Background and purpose:  Amyotrophic lateral sclerosis (ALS) is classically assumed to be a neurodegenerative disorder. Inflammation has been observed in CNS tissue in ALS patients. We investigated the expression and prognostic relevance of proinflammatory chemokines in ALS.
Methods:  We analyzed nine chemokines, eotaxin, eotaxin-3, IL-8, IP-10, MCP-1, MCP-4, macrophage derived chemokine (MDC), macrophage inflammatory protein-1β (MIP-1β), and serum thymus and activation- regulated chemokine (TARC) in serum and cerebrospinal fluid (CSF) of 20 ALS- and 20 non-inflammatory neurological disease (NIND)-patients.
Results:  MCP-1 and IL-8 levels in CSF in ALS were significantly higher than in NIND (1304 pg/ml vs. 1055 pg/ml, P  = 0.013 and 22.7 pg/ml vs. 18.6 pg/ml, P  = 0.035). The expression of MCP-1 and IL-8 were higher in CSF than in serum ( P  < 0.001). There was a trend towards higher MCP-1 CSF levels in ALS patients with shorter time between first symptoms and diagnosis ( r  = −0.407; P  = 0.075).
Conclusions:  We confirmed previous findings of increased MCP-1 levels in CSF of ALS patients. Furthermore, increased levels of IL-8 in CSF suggest a stimulation of a proinflammatory cytokine cascade after microglia activation. We found a tendency for higher MCP-1 values in patients with a shorter diagnostic delay, who are known to have also a shorter survival. This may suggest an association of higher MCP-1 levels with rapidly progressing disease.     

Shunt-Dependent Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage: The Role of Intrathecal Interleukin-6

Object

Aneurysmal subarachnoid hemorrhage (SAH) has been reported to induce an intrathecal inflammatory reaction reflected by cytokine release, particularly interleukin-6 (IL-6), which correlates with early brain damage and poor outcome. The present study examines intrathecal IL-6 production together with clinical parameters, as a predictor of posthemorrhagic shunt dependency.

Methods

Among 186 SAH patients admitted between July 2010 and December 2012, 82 received external ventricular drainage due to acute hydrocephalus. In these patients, cerebrospinal fluid (CSF) concentrations of IL-6 were measured within the first 14 days after SAH. Patients whose IL-6 values were not determined regularly and those who did not survive until discharge were excluded. The peak value of IL-6, ventricular infection during the hospital stay, microbial CSF culture, patient’s age and sex, Hunt and Hess grade, and aneurysm location were assumed as predictive for shunt dependency.

Results

Sixty-nine patients were included, 24 of whom underwent shunt surgery. Peak IL-6 values of ≥10,000 pg/ml were significantly associated with a higher incidence of shunt dependency (p = 0.009). Additional risk factors were aneurysm location on the anterior cerebral artery and its branches or in the posterior circulation (p = 0.025), and age ≥60 years (p = 0.014). In a multivariate analysis, IL-6 ≥10,000 pg/ml appeared to be the only independent predictor for shunt dependency (p = 0.029)

Conclusion

CSF IL-6 values of ≥10,000 pg/ml in the early post-SAH period may be a useful diagnostic tool for predicting shunt dependency in patients with acute posthemorrhagic hydrocephalus. The development of shunt-dependent posthemorrhagic hydrocephalus remains a multifactorial process.     

Contribution of nitric oxide to exercise-induced hypotension in human sympathetic denervation

The cardiovascular, catecholamine, and nitrate/nitrite (NO_x) responses to bicycle exercise were measured in 14 normal subjects (controls) and two groups with sympathetic denervation; 14 with peripheral autonomic failure (pure autonomic failure [PAF]); and 13 with central autonomic failure (multiple system atrophy [MSA]). With exercise, blood pressure increased in control subjects by 40±7/24±5 mm Hg (p<0.001) and fell in PAF by 24±8/24±5 mm Hg (p<0.02 and p<0.007) and MSA by 31±7/11±3 mm Hg (p<0.005 and p<0.04). With exercise, the increase in heart rate was greater in control subjects (60±3 to 111±4/min; p<0.0001) than in PAF (69±3 to 86±4/min; p<0.0001) and MSA (70±4 to 90±4; p<0.001). Resting plasma noradrenaline levels were similar in controls (291±51 pg ml⁻¹) and MSA (257±49 pg ml⁻¹), but lower in PAF (82±14 pg ml⁻¹). With exercise, plasma noradrenaline increased in controls but was unchanged in PAF and MSA. Resting NO_x was similar in controls (50±5 nmol/L; range, 23.3–87.6 nmol/L) and PAF patients (59±8 nmol/l; range, 19.3–116.4 nmol/L), but was higher in MSA patients (87±14 nmol/L; p<0.025, range 15.4–157.2 nmol/L). With exercise, NO_x was unchanged in control subjects and increased by 10% and 17% in PAF and MSA, respectively; these changes were not statistically significant. This study suggests that circulating changes in NO_x levels do not exert a major role in exercise-induced hypotension in subjects with sympathetic denervation.     

Decreased concentration of klotho and increased concentration of FGF23 in the cerebrospinal fluid of patients with narcolepsy

Objectiveto explore the status of concentration of klotho and fibroblast growth factor 23 (FGF23) in cerebrospinal fluid (CSF) of patients with narcolepsy.Patients/methods59 patients with narcolepsy and 17 control individuals were enrolled. We used radioimmunoassay, human klotho enzyme-linked immunosorbent assay (ELISA), human intact FGF23 ELISA and spectrophotometry to measure hypocretin-1, klotho, FGF-23 and phosphorus, respectively. T-Student Test was used to compare klotho and phosphate concentrations, Mann–Whitney U Test were used to compare FGF-23 levels between groups. ANOVA Test was used to compare klotho and phosphate CSF concentrations among narcolepsy patients with CSF hypocretin-1 <110 pg/ml (HCRT-) and narcolepsy patients with CSF hypocretin-1 >110 pg/ml (HCRT+) versus control subjects.ResultsKlotho and phosphorus CSF levels were lower in narcoleptic patients than in control (908.18 ± 405.51 versus 1265.78 ± 523.26 pg/ml; p = 0.004 and 1.34 ± 0.25 versus 1.58 ± 0.23 mg/dl; p = 0.001, respectively). We found higher FGF-23 levels in narcoleptic patients (5.51 versus 4.00 pg/mL; p = 0.001). Klotho and phosphorus CSF levels were lower in both HCRT- and HCRT+ than controls. Moreover, there were higher FGF-23 levels in both HCRT-/HCRT+ groups versus controls. However, we did not find differences comparing HCRT- and HCRT+ groups, analyzing CSF klotho, FGF-23 or phosphorus levels.ConclusionsPatients with narcolepsy have decreased CSF concentration of klotho and increased CSF levels of FGF-23. These findings may play a role in understanding the pathogenesis of narcolepsy.     

Dopamine-β-hydroxylase activities in serum and cerebrospinal fluid of aged and demented patients

Age-related changes in dopamine-β-hydroxylase (DBH) activities in serum and cerebrospinal fluid (CSF) were determined. In normal subjects, serum DBH activity increased gradually from the 3rd to the 8th decade, but decreased prominently in the 9th decade. DBH activity in CSF did not differ between younger and older subjects.Serum DBH activity decreased significantly in senile dementia of Alzheimer's type (SDAT, $\text{12.2 ± 8.8}\text{nmoles/min/ml}$, $\text{P < 0.05}$), but not in multi-infarct dementia (MID, $\text{13.9 ± 9.1}\text{nmoles/min/ml}$) compared to control subjects ($\text{17.1 ± 9.5}\text{nmoles/min/ml}$). The decrease of serum DBH in SDAT was more prominent in patients with severe dementia and/or severe brain atrophy. DBH activity in CSF was much lower than that in serum and did not correlate with each other. DBH activity in CSF obained from SDAT patients ($\text{1.60 ± 0.94}\text{nmoles/h/ml}$) and from MID patients ($\text{2.01 ± 0.99}\text{nmoles/h/ml}$) were both lower than that from other neurological diseases without dementia ($\text{4.04 ± 3.81}\text{nmoles/h/ml}$). DBH in CSF from SDAT patients was significantly lower ($\text{P < 0.05}$) than that from controls, but that from MID did not differ from controls.Noradrenergic nervous dysfunction is partly associated with pathophysiology and life expectancy of senile dementia of Alzheimer's type (SDAT).     

Intracerebroventricular infusion but not bolus injection of vasopressin increases the cerebrospinal fluid pressure in awake rabbits

The effect of intracerebroventricular infusion or injection of arginine vasopressin (AVP) was examined in awake rabbits with permanent ventricular cannulae. Intracerebroventricular infusion of artificial cerebrospinal fluid (CSF) 43 μl min^–1 containing AVP concentrations exceeding 0.4 ng ml^–1, equivalent to an AVP infusion rate of 17.2 pg min^–1, caused a dose-dependent increase in intracranial pressure (ICP) of 3 to 5 mmHg after 30-50 min of AVP infusion. Intracerebroventricular bolus injection of equivalent doses of AVP did not provoke changes in ICP. At the end of the experiments cisternal CSF concentrations of AVP were higher after infusion of AVP than after injection of the same amount of AVP. The mean arterial blood pressure increased slightly in the group of animals infused with AVP at rates above 17.2 pg min^–1. It is concluded that intracerebroventricular infusion of AVP increases ICP in awake rabbits but the mechanism responsible for the elevation of ICP remains speculative.     

Predictive value of serum interleukin-6 level in influenza virus-associated encephalopathy

OBJECTIVE: In Japan, >200 children with influenza virus-associated encephalopathy were reported in 1999 and the mortality rate was high. The levels of tumor necrosis factor-alpha (TNFalpha) and interleukin-6 (IL-6) in both CSF and serum were significantly increased in severe cases. The authors found a correlation between elevated serum cytokine levels and mortality and neurologic morbidity. METHODS: TNFalpha, IL-6, soluble tumor necrosis factor receptor 1 (sTNF-R1), interferon-gamma (IFNgamma), and IL-2 were measured by the ELISA method in sera from six children with encephalopathy before and during therapy, and in six age-matched controls with influenza type A virus infection. RESULTS: The increases in the serum TNFalpha, IL-6, and sTNF-R1 levels were statistically significant at the onset of symptoms before therapy, but the IL-6 level was most useful for diagnosis. The serum IL-6 levels were >6,000 pg/mL in children with brain stem dysfunction, about 150 pg/mL in children without brain stem dysfunction, and <80 pg/mL in controls. The time course of the serum IL-6 level also reflected the clinical condition. Once the serum IL-6 level was increased to >15,000 pg/mL, none of the children survived. The lower the maximal serum IL-6 level, the milder the CNS sequelae. CONCLUSION: The serum IL-6 level may be the most useful indicator for the diagnosis and the clinical severity of influenza virus-associated encephalopathy.     

Plasma amyloid levels within the Alzheimer's process and correlations with central biomarkers

Introduction

Diagnostic relevance of plasma amyloid β (Aβ) for Alzheimer's disease (AD) process yields conflicting results. The objective of the study was to assess plasma levels of Aβ₄₂ and Aβ₄₀ in amnestic mild cognitive impairment (MCI), nonamnestic MCI, and AD patients and to investigate relationships between peripheral and central biomarkers.