Reduction In Cerebrospinal Fluid Research Articles

Rituximab reduces B cells and T cells in cerebrospinal fluid of multiple sclerosis patients

Effects of B cell depletion by rituximab, a monoclonal antibody to CD20, were studied in patients with relapsing MS that had not responded optimally to standard immunomodulatory therapies. Flow cytometry demonstrated reduced cerebrospinal fluid (CSF) B cells and T cells in most patients at 6 months post-treatment. ELISAs demonstrated modest reductions in serum antibodies to myelin oligodendrocyte glycoprotein and myelin basic protein in some subjects. Beta-interferon neutralizing antibodies were reduced in three subjects, but developed anew after treatment in three others, suggesting caution in considering rituximab as a means to eliminate NABs. In summary, rituximab depleted B cells from CSF at 24 weeks after initial treatment, and this B cell depletion was associated with a reduction in CSF T cells as well.

Cerebrospinal and peripheral human immunodeficiency virus type 1 load in a multisite, randomized, double-blind, placebo-controlled trial ofd-Ala1-peptide T-amide for HIV-1-associated cognitive-motor impairment

D-Ala1-peptide T-amide (DAPTA) has shown neuroprotection in vitro against gp120-induced loss of dendritic arborization and is promulgated as a CCR5 antagonist. A multisite, randomized, double-blind clinical trial of DAPTA versus placebo prior to combination antiretroviral therapy conducted with human immunodeficiency virus (HIV)-1 seropositive participants having cognitive impairment showed no overall cognitive effect, though subgroups with greater impairment and CD4 cell counts of 201 to 500 cells/mm3 at baseline showed significant improvement. The objective of this study was to examine whether intranasal administration of DAPTA at a dose of 2 mg three times per day (tid) was associated with a reduction of cerebrospinal fluid (CSF) and peripheral (plasma and serum) viral load among a subgroup of participants completing 6 months of treatment. Baseline and 6-month CSF (n = 92) and peripheral (plasma n = 33; serum n = 24) viral load were measured by the Roche Ultrasensitive assay, version 1.5, with reflexive use of the AMPLICOR assay and preservation of the blind. A DAPTA treatment indicator variable was tested using generalized linear models on change in viral load. Peripheral load (combined plasma and serum) was significantly reduced in the DAPTA-treated group. No group differences in CSF viral load were found. This retrospective study on a limited subgroup of the original trial sample indicated that DAPTA treatment may reduce peripheral viral load without concomitant CSF effects. Future studies should be undertaken to confirm the existence of this result and the CSF-periphery dissociation observed with respect to HIV-1-associated cognitive-motor impairment.

β-Amyloid (Aβ) protein in cerebrospinal fluid as a biomarker for Alzheimer’s disease

With the arrival of symptomatic treatment (acetylcholine esterase inhibitors) and the promise of drugs that may delay disease progression, development of diagnostic biomarkers for Alzheimer’s disease (AD) are important. β-Amyloid (Aβ) protein is the main component of senile plaques. A marked reduction in cerebrospinal fluid (CSF)-Aβ42 in AD has been found in numerous studies. Importantly, reduced CSF-Aβ42 is also found very early in the disease process, before the onset of clinical symptoms. Recent studies suggest that CSF-Aβ42 have a satisfactory performance when used as a diagnostic marker for AD in clinical routine. This paper reviews CSF-Aβ42 as a biomarker for AD.

Carbon dioxide and the cerebral circulation.

Carbon dioxide and the cerebral circulation.

Intrathecal adenosine analog administration reduces substance P in cerebrospinal fluid along with behavioral effects that suggest antinociception in rats.

Adenosine and adenosine analogs induce analgesia in humans and presumed antinociception in animal models when administered both systemically and intrathecally. In the present investigation in rats, we studied the effects of intrathecally administered adenosine analogs, with or without systemic coadministration of an adenosine antagonist (theophylline), on substance P (SP) and calcitonin gene-related peptide (CGRP) concentrations in cerebrospinal fluid (CSF). In parallel, nociceptive reflex testing (tail immersion latency) and motor function were evaluated. The potent unselective adenosine receptor agonist N-ethylcarboxamide-adenosine (NECA) and the relatively adenosine A1 receptor selective agonist R-phenyl-isopropyl-adenosine (R-PIA) both reduced SP-like immunoreactivity (-LI) by 50%, whereas CGRP-LI remained unchanged. There was a dose-dependent increase in tail immersion latency. This effect was present without motor impairment when R-PIA was administered in doses up to 5 nmol. R-PIA (10-100 nmol), as well as 1-100 nmol of the unselective agonist NECA, produced dose-dependent motor impairment. The reduction of SP-LI as well as the behavioral effects were reversed by theophylline. We conclude that SP reduction in CSF, which possibly reflects reduced SP turnover after adenosine receptor stimulation, provides an additional possible mechanism of action for the analgesic effects of adenosine. We studied the interactions between the known pain mediator substance P and substances with effects similar to the endogenous pain modulator adenosine in rats. The results suggest that the pain-reducing effect of adenosine is, at least partly, due to a reduction of substance P in cerebrospinal fluid.

Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease.

In this clinical study the cerebrospinal fluid (CSF) level of a novel form of the beta-amyloid peptide (A beta) extending to position 42 (A beta 42) was determined in patients with Alzheimer's disease (AD) as well as controls. In addition to measurement of CSF A beta 42 levels, total A beta peptides, microtubule-associated protein tau, and apolipoprotein E (ApoE) genotype were also assessed. It is interesting that CSF A beta 42 levels were found to be significantly lower in AD patients relative to controls, whereas total A beta levels were not. A beta 42 has recently been shown to preferentially deposit in the brain tissue of patients with AD, suggesting that diminished clearance may account for its reduction in CSF. As previously reported, tau levels were increased in AD patients; however, neither A beta 42 nor tau levels were apparently influenced by the ApoE genotype.

The effects of high-dose methylprednisolone on gadolinium-enhanced magnetic resonance imaging and cerebrospinal fluid measurements in multiple sclerosis

Blood-brain barrier (BBB) disruption is probably the first event in the lesion development in multiple sclerosis (MS). This stage can be visualized by gadolinium-enhanced magnetic resonance (MR) imaging of the brain. Serial MR imaging studies have indicated a continuous spectrum of disease activity with waxing and waning of acute lesions, even in clinically stable MS patients. High-dose intravenous methylprednisolone (MP) has a beneficial clinical effect; reduces gadolinium enhancement, indicating improvement of BBB integrity; and, in MS patients, decreases intrathecal immunoglobulin synthesis with reduction of cerebrospinal fluid (CSF) myelin basic protein (MBP). A correlative triad is noted between gadolinium enhancement, clinical improvement, and decrease of CSF MBP following MP treatment, indicating a relationship between restoration BBB integrity, clinical improvement and decrease of myelin breakdown. It is not clear whether MP interferes primarily with the process of demyelination or reacts non-specifically with its mediators.

Fibrinolytic activity after subarachnoid haemorrhage and the effect of tranexamic acid

Seventy-four patients with recent subarachnoid haemorrhage were randomly allocated to placebo or tranexamic acid treatment. Fibrinolytic activity in the blood and cerebrospinal fluid was assessed before treatment, one week later and two weeks later. The natural history of fibrinolysis following subarachnoid haemorrhage was obtained from analysis of the placebo group. Following subarachnoid haemorrhage, fibrin degradation products and plasminogen activity in the cerebrospinal fluid were elevated. Subsequently, fibrin degradation products in the cerebrospinal fluid fell progressively over the following 2 weeks. Changes in cerebrospinal fluid plasminogen activity correlated with those of blood plasminogen activity. Complications such as rebleeding, hydrocephalus or cerebral thrombosis could not be predicted from analysis of fibrinolytic activity. Tranexamic acid treatment resulted in a reduction in cerebrospinal fluid and blood plasminogen activity. The relevance of fibrinolysis in cerebrospinal fluid and blood to the management of subarachnoid haemorrhage is discussed.

CSF production in acute ventriculitis.

Clinically, there appears to be a significant reduction in cerebrospinal fluid (CSF) formation during acute ventriculitis--an observation that has not been well documented by experimental studies. To examine this phenomenon, an inoculum of Escherichia coli was injected into the lateral ventricles of New Zealand White rabbits. Approximately 18 hours later, the survivors (64%) underwent a 3-hour ventriculocisternal perfusion of carbon-14-dextran (MW 7 X 10(4)) as a reference marker for CSF formation. On the average, CSF formation in this experimental group was reduced by one-half to two-thirds of normal, confirming the clinical observation. Histologically, the stroma of the choroid plexus was the site of an extensive inflammatory infiltrate. Meningitis, ependymitis, and focal encephalitis completed the picture. Vasculitis was not present in the choroid plexus. The epithelium of the choroid plexus underwent patchy cellular swelling or frank necrosis and destruction. It is postulated that the changes in the choroid plexus caused by the inflammatory process were responsible for the diminished CSF formation in this acute setting. Reduced choroidal blood flow and/or enterotoxin may play a role in these alterations.

CSF dynamics in patients with subarachnoid and/or intraventricular hemorrhage.

The purpose of this study was to examine the extent to which reduction of cerebrospinal fluid (CSF) absorption contributes to raised intracranial pressure (ICP) in patients with acute subarachnoid hemorrhage (SAH). Seventeen patients suffering from SAH and/or intraventricular hemorrhage were studied; all were admitted in Grades II to V according to Hunt and Hess. Eleven patients had a proven aneurysm. The ICP, monitored via an intraventricular catheter, was above 15 mm Hg (2 kPa) during part of the monitoring period in all patients. B-waves at 1/min were noted in all patients. Resistance to outflow of CSF was determined by the following techniques: 1) bolus injection; 2) constant-rate steady-state infusion; or 3) controlled withdrawal ("inverse infusion"). Resistance to outflow of CSF was increased in all patients, ranging from 11.5 to 85 mm Hg/ml/min. The ICP was linearly correlated with outflow resistance. Four (50%) of the eight survivors required a shunt. Neither the presence of hydrocephalus on admission, nor the level of ICP, nor the magnitude of resistance to outflow of CSF was clearly related to the requirement of a permanent CSF diversion.

Comparative Studies between Hemofiltration and Hemodialysis on Urea and Isotope-Labelled Sodium Kinetics

Comparative studies on urea and sodium kinetics were performed between hemodialysis (HD) and hemofiltration (HF). 10 patients on HF were examined and 11 patients on HD were then selected to match the HF group on the basis of age, body weight and height. The urea concentration of serum, cerebrospinal fluid (CSF) and total urea removed were measured during HD and HF. The slope of regression line of the serum urea concentration during the 5 h of treatment was significantly higher for HD, while the total urea removed was comparable between the two. On the contrary, CSF reduction in urea was significantly greater after HF, resulting in a smaller urea concentration gradient between serum and CSF. The sodium kinetics during the procedures were estimated using 22Na. Although the total 22Na removed was significantly larger in HF than in HD and body weight loss was comparable between the two groups, the slope of regression line for 22Na was significantly less with HF whereas total serum Na levels for HF equaled HD. The above results indicate that urea and sodium equilibrated more efficiently between the compartments of body fluid in HF. This resulted in a smaller decrease in osmolality as well as in solute concentration gradients between plasma and CSF.

On the importance of CSF Na in the regulation of renal sodium excretion and renin release.

Infusions (20 microliters/min) of isotonic (0.27 M) mannitol dissolved in Na-free artificial cerebrospinal fluid (CSF) were made for 2 h into the lateral cerebral ventricle (IVT) of conscious 68 h dehydrated sheep. The IVT infusion induced a conspicuous drop in renal sodium excretion and marked rise in plasma renin concentration (PRC). The antinatriuretic response to the IVT infusion was not altered by the intravenous administration of ADH or te converting enzyme blocker (SQ 14225, Captopril). Surgical bilateral renal denervation did not change the antinatriuretic response while the increase in PRC was extinguished. Samples of CSF were collected prior to, and 15 min after the end of the infusion. These showed a reduction in CSF [Na], while CSF osmolality remained unchanged. The study supports the view that sodium sensitive receptors close to the cerebral ventricular system participate in the regulation of renal sodium excretion and renin release, it also suggests that renal sodium excretion is affected by an unknown hormonal factor of cerebral origin, while the release of renin seen in response to a reduction in CSF [Na] is mediated by the renal nerves.

Intrathecal arabinosyl cytosine in meningeal leukemia

Intrathecal arabinosyl cytosine was administered on a twice weekly schedule, in a dosage range of 5 to 70 mg per square meter of body surface area, to 13 children with meningeal leukemia. Eleven children with acute lymphocytic leukemia had been previously treated with intrathecal methotrexate, and 7 had received cranial or craniospinal radiotherapy. Seven of these 11 children responded with relief of symptoms and reduction of cerebrospinal fluid (CSF) cell count to less than 10 mononuclear cells per mm3 of CSF and less than 2 leukemic cells on one smear of CSF sediment. The median duration of response was 28 days. Vomiting occurred in 5 children after treatment, headache in 2, and fever in one. Neither leukopenia nor other systemic toxicity was observed. It is concluded that intrathecal arabinosyl cytosine has therapeutic activity against meningeal leukemia.