Cerebrospinal Spinal Fluid Research Articles

Trospium chloride has no effect on memory testing and is assay undetectable in the central nervous system of older patients with overactive bladder

Muscarinic receptors in the brain play an important role in cognitive function, especially memory, and there is growing awareness that specific antimuscarinic drugs for overactive bladder (OAB) may have adverse central nervous system (CNS) effects. Selection of an antimuscarinic OAB drug with reduced potential for CNS effects could be especially beneficial in the elderly people, in whom even the modest cognitive impairment may negatively affect independence. The purpose of the study is to determine if trospium chloride is assay detectable in the CNS of older adults with OAB and to assess whether deterioration of memory occurs in these individuals. Twelve cognitively intact older adults (>or=65-75 years old) with OAB were given extended-release trospium chloride 60 mg once daily over a 10-day period to achieve plasma steady-state levels. Standardised memory testing (Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised) was performed predose and postdose. Cerebrospinal spinal fluid (CSF) and plasma samples were drawn on day 10 and assayed for trospium chloride. Predose (day 0) and postdose (day 10) results on the memory tests were compared using a reliable change index to assess a meaningful change in learning or memory. Trospium chloride levels in all the CSF samples (n = 72) of all participants were assay undetectable (<40 pg/ml) on day 10 at steady-state peak plasma concentration concurrent with measureable peak plasma values (C(max) = 925 pg/ml). Repeat memory testing revealed no significant net drug effect on learning or recall. This is the first study to investigate for the presence of an OAB antimuscarinic in the human brain, performed by assaying for concentrations of trospium chloride and correlating with simultaneous clinical cognitive safety measures. The results of both pharmacological and neuropsychological testing support the hypothesis of a lack of detectable CNS penetration for the quaternary amine trospium chloride.

MSQ: a tool for quantification of proteomics data generated by a liquid chromatography/matrix‐assisted laser desorption/ionization time‐of‐flight tandem mass spectrometry based targeted quantitative proteomics platform

Mass spectrometry (MS)-based quantitative proteomics has become a critical component of biological and clinical research for identification of biomarkers that can be used for early detection of diseases. In particular, MS-based targeted quantitative proteomics has been recently developed for the detection and validation of biomarker candidates in complex biological samples. In such approaches, synthetic reference peptides that are the stable isotope labeled version of proteotypic peptides of proteins to be quantitated are used as internal standards enabling specific identification and absolute quantification of targeted peptides. The quantification of targeted peptides is achieved using the intensity ratio of a native peptide to the corresponding reference peptide whose spike-in amount is known. However, a manual calculation of the ratios can be time-consuming and labor-intensive, especially when the number of peptides to be tested is large. To establish a liquid chromatography/matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry (LC/MALDI TOF/TOF)-based targeted quantitative proteomics pipeline, we have developed a software named Mass Spectrometry based Quantification (MSQ). This software can be used to automate the quantification and identification of targeted peptides/proteins by the MALDI TOF/TOF platform. MSQ was applied to the detection of a selected group of targeted peptides in pooled human cerebrospinal spinal fluid (CSF) from patients with Alzheimer's disease (AD) in comparison with age-matched control (OC). The results for the automated quantification and identification of targeted peptides/proteins in CSF were in good agreement with results calculated manually.

Efficacy of Etravirine for Treatment of Acute HIV Meningoencephalitis

We describe a patient with human immunodeficiency virus (HIV) and hepatitis C virus coinfection who experienced recurrent episodes of acute HIV meningoencephalitis. The addition of etravirine to the therapeutic regimen completely resolved symptoms, and HIV was no longer detected in cerebrospinal spinal fluid specimens. Etravirine has a satisfactory safety profile and, in this case, was a durable alternative therapy for HIV meningoencephalitis.

Application of Targeted Quantitative Proteomics Analysis in Human Cerebrospinal Fluid Using a Liquid Chromatography Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Tandem Mass Spectrometer (LC MALDI TOF/TOF) Platform

Targeted quantitative proteomics by mass spectrometry aims to selectively detect one or a panel of peptides/proteins in a complex sample and is particularly appealing for novel biomarker verification/validation because it does not require specific antibodies. Here, we demonstrated the application of targeted quantitative proteomics in searching, identifying, and quantifying selected peptides in human cerebrospinal spinal fluid (CSF) using a matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometer (MALDI TOF/TOF)-based platform. The approach involved two major components: the use of isotopic-labeled synthetic peptides as references for targeted identification and quantification and a highly selective mass spectrometric analysis based on the unique characteristics of the MALDI instrument. The platform provides high confidence for targeted peptide detection in a complex system and can potentially be developed into a high-throughput system. Using the liquid chromatography (LC) MALDI TOF/TOF platform and the complementary identification strategy, we were able to selectively identify and quantify a panel of targeted peptides in the whole proteome of CSF without prior depletion of abundant proteins. The effectiveness and robustness of the approach associated with different sample complexity, sample preparation strategies, as well as mass spectrometric quantification were evaluated. Other issues related to chromatography separation and the feasibility for high-throughput analysis were also discussed. Finally, we applied targeted quantitative proteomics to analyze a subset of previously identified candidate markers in CSF samples of patients with Parkinson's disease (PD) at different stages and Alzheimer's disease (AD) along with normal controls.

Changing pattern of primary cerebral lymphoma in the highly active antiretroviral therapy era

Before the introduction of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV)-related primary central nervous system lymphoma (PCNSL) represented one of the most prevalent causes of focal brain lesions in HIV-infected people. The prognosis of PCNSL was very poor, with median survival time not exceeding 2 months. Brain biopsy was the method of choice for the definitive diagnosis, but it was and remains an invasive procedure with morbidity and mortality as well as considerable costs in terms of patients' management and quality of life. The strict association between AIDS-PCNSL and Epstein-Barr virus led to the suggestion that EBV DNA in cerebrospinal spinal fluid (CSF) might serve as a diagnostic marker, reducing the time required for diagnosis and allowing a minimally invasive approach. The clinical usefulness of this methodology has been largely demonstrated through clinical practice. After the introduction of HAART in clinical practice, a survival benefit has been observed for most persons with acquired immunodeficiency syndrome (AIDS)-associated opportunistic infections and cancers. In particular, for patients with non-Hodgkin lymphoma, a higher likelihood of response to chemotherapy as well as a longer survival has been found as a consequence of the use of combined antiretroviral therapy. Although larger studies did not show significant changes in survival of HIV-infected patients with PCNSL in the era of HAART, small case series and anecdotal reports showed the benefit of HAART in the treatment of PCNSL. Nevertheless, these patients' survival still remains very poor and it could be hypothesized that, other than specific cancer prognostic determinants and severe immunodeficiency, viral pathogenesis as well as EBV-specific immunologic dysfunction may be responsible.

Giant pseudoaneurysm in adolescent

Intracranial pseudoaneurysms, infrequent vascular lesion in children and adolescents, are characterized by the presence of organizing hematoma and fibrosis outside the true lumen instead of normal vascular elements. Because most pseudoaneurysms result from eminent insults such as major trauma or grave infection, development without preceding incident is extremely rare. Giant pseudoaneurysms in younger population, albeit unexceptionally unusual, are symptomatic in most instances and exhibit very high risk of rupture. Clinical manifestation as chronic headache without hemorrhage or neural compression is very unlikely. Once identified, only prompt surgical treatment guarantees favorable prognosis. We report a case of a 17-year-old boy with a giant pseudoaneurysm arising at distal middle cerebral artery. He complained of headache that had become apparent 3 years ago and medically intractable 3 months ago. Brain computed tomographic scan and lumbar cerebrospinal spinal fluid study revealed no trace of recent hemorrhage. However, digital subtraction angiography revealed a huge aneurysmal dilatation along the right distal middle cerebral artery with the features of delayed filling and emptying of contrast agent. Surgical obliteration of the corresponding aneurysm with tandem clipping and aneurysmectomy made him free of headache postoperatively. We could not uncover the actual cause of formation and precise mechanism of clinical presentation for this unique aneurysm; nevertheless, we suggest that blunt head injury of fairly long history caused such a lesion, and repeated minute bleeding elicited headache. This assumption was possible only after full consideration of the histopathology.

Amino acids and transaminases activity in ventricular CSF and in brain of normal and Alzheimer patients

The present study was conducted to determine the concentration of amino acids in the cerebrospinal spinal fluid (CSF) and the activities of two tramsaminases: glutamic oxaloacetate transaminase (GOT) and glutamic pyruvate transaminase (GPT) in human Alzheimer disease (AD) and normal brain. l-Glutamic acid, l-glutamine and l-alanine are the most abundant amino acids in the CSF (50–55% of total amino acids). l-Glutamine occurs at much higher levels in Alzheimer CSF compared to the normal CSF (229 ± 91.8 nmol/ml in AD versus 107 ± 47.2 nmol/ml in normal; P = 0.0041). In contrast, l-aspartate occurs at significantly lower concentrations in Alzheimer CSF than normal CSF (46.1 ± 25.7 nmol/ml in Alzheimer versus 95.2 ± 52.6 nmol/ml in normal; P = 0.020). In Alzheimer brain (frontal, parietal and occipital cortices) GOT is present at significantly higher activities than in normal brain cortices (about 1.5 times higher; P < 0.01). No significant differences for GPT activity occurred between normal and AD brain. Since CSF receives amino acids from brain tissues, and since GOT catalyzes the conversion of l-aspartate to l-glutamate, the higher concentrations of l-glutamine (which is derived from l-glutamate), and the lower concentrations of l-aspartate found in Alzheimer CSF could be considered as a consequence of the higher activity of GOT that occurs in Alzheimer brain.

A spontaneous giant pseudoaneurysm presenting with chronic headache in adolescent

Intracranial pseudoaneurysms are rare vascular lesions, particularly in children and adolescents, and are characterized by the presence of organizing hematoma and fibrosis outside the true lumen, instead of true vascular elements. Most pseudoaneurysms result from an eminent insult, such as major trauma or grave infectious illness. Development of pseudoaneurysm without antecedent incident is rare. Furthermore, clinical manifestation with only a headache is also unusual in this age group. We now describe one patient who had a giant pseudoaneurysm arising at the distal middle cerebral artery. A 17-year-old boy complained of headache that had become apparent 3 years ago and intractable to medicine 3 months ago. Brain computed tomographic scan and lumbar cerebrospinal spinal fluid study revealed no trace of recent hemorrhage. However, digital subtraction angiography revealed a huge aneurysmal dilatation along the right M2 segment with the features of delayed filling and emptying of contrast agent. Surgical obliteration of the corresponding aneurysm with tandem clipping and aneurysmectomy rendered him free of headache thereafter. The actual cause and mechanisms of this case are not certain; nonetheless, we suggest that traumatic cause produced such a lesion, and minor repeated bleeding also elicited headache, albeit no evidence of recent major injury.

Calcitonin-like immunoreactivity in the subcommissural organ and Reissner's fiber in the teleost Clarias batrachus, frog Rana tigrina and lizard Calotes versicolor

In the CNS of vertebrates, although the subcommissural organ (SCO) has been identified as an ependymal brain gland and Reissner's fiber (RF) as a condensed product of its secretion, the exact nature of the secretory substances has remained elusive. In the present study, immunocytochemical application of polyclonal antibodies against calcitonin revealed intense immunoreactivity in the cells, cell processes and cerebrospinal spinal fluid (CSF)-contacting apical terminals of the columnar ependymal cells of the SCO in the teleost, Clarias batrachus. Intense immunoreactivity was also seen throughout the length of the RF as it extended along the Sylvian aqueduct, fourth ventricle and central canal of the spinal cord. Control procedures were employed to confirm the specificity of the immunoreaction. The results for the first time suggest that calcitonin-like substance may be the synthetic and secretory product of the SCO that may be released into the CSF or stored in the RF. Presence of calcitonin-like immunoreactivity in the SCO-RF complex of the frog Rana tigrina and the lizard Calotes versicolor underscores wider significance of the phenomenon. In view of the potentials of these findings, it is felt that investigations aimed at establishing the precise nature of calcitonin-like immunoreative material in the SCO-RF complex may be rewarding. © 1997 Elsevier Science B.V. All rights reserved.

Evaluation of Neonatal Intracranial Hemorrhage by Computerized Tomography

Computerized tomographic (CT) brain scan was performed on 28 infants with unexplained cardiorespiratory and neurologic deterioration and bloody lumbar cerebrospinal spinal fluid. Fourteen of 20 with intraventricular hemorrhage (IVH) died; the six infants with lesser degrees of IVH survived. Significant subarachnoid hemorrhage (SAH) was demonstrable in three infants and three had negative scans despite bloody CSF. We have found that CT scans provide useful information about the size and extent of neonatal IVH and distinguished it from SAH. It also confirms the diagnosis of post-hemorrhagic hydrocephalus in these infants. Continued use of the CT scan will help us to understand the natural history and the effects of neonatal intracranial hemorrhage among the survivors of intensive care.

Comparative Ultrastructure of the Cerebrospinal Fluid-Contacting Neurons

Publisher Summary The structure of the cerebrospinal spinal fluid (CSF)-contacting endings differs in the two parts of the nervous system. In the hypothalamus, the CSF contacting dendritic terminals are characterized by an atypical cilium and those in the central canal by a kinocilium and numerous stereocilia. These structures express different functional tasks to be solved in the two main areas of the CSF-contacting neuronal system. The CSF-contacting endings are formed by the dendritic processes of the neurons. Their dendritic nature is proved by the presence of the endoplasmic reticulum, ribosomes, and Golgi areas, as well as by the lack of synaptic vesicles. The number of CSF-contacting neurons is large in the hypothalamus of lower vertebrates, while in higher vertebrates the number of dendritic CSF-contacting terminals decreases. Light and electron microscope studies are used to derive morphological results on CSF contacting neurons and neuronal system. It is the task of further morphophysiological examinations to clarify the functional relations of the CSF-contacting neuronal system.