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Diagnostics
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The Diagnostic Value of Cerebrospinal Fluid
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The Diagnostic Value of Cerebrospinal Fluid

A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 24583

Special Issue Editors

Dr. Katalin Barkovits

E-Mail Website
Guest Editor
Medizinische Proteom-Center (MPC), Ruhr-University Bochum, Bochum, Germany
Interests: neurodegenerative disease; biomarker discovery; CSF and plasma analysis; proteomics; mass spectrometry
Prof. Dr. Katrin Marcus

E-Mail Website
Guest Editor
Medizinische Proteom-Center (MPC), Ruhr-University Bochum, Bochum, Germany
Interests: neurodegenerative disease; biomarker discovery; CSF and plasma analysis; proteomics; mass spectrometry

Special Issue Information

Dear Colleagues,

Cerebrospinal fluid (CSF) is in direct contact with the brain and extends into the spinal cord. The main functions of CSF are to provide physical stability for the central nervous system (CNS), to actively regulate the CNS by supplying hormones and neuropeptides to it, and to remove various CNS metabolites. Due to its direct contact with the CNS, CSF is of great diagnostic importance. Thus, it can serve as a representative for the state of health of the CNS and provide important information on neurological diseases and disorders, which include for instance dementias (e.g. Alzheimer disease and Parkinson's disease), cerebrovascular diseases (e.g. stroke), neurotraum (e.g. spinal cord injury and traumatic brain injury), multiple sclerosis, neuroinfections and brain tumors. The early detection of neurological diseases as well as tools to assess the severity of destruction or predicting recovery is of utmost importance for optimal treatment. Biomarkers such as metabolites, lipids and proteins are suitable for such detections, which can be used as an indicator for biological and pathological processes but also for pharmacological responses to a therapeutic intervention. For a large number of neurological diseases such as meningitis or multiple sclerosis, the examination of CSF is already used for diagnosis and therapy decisions. For other neurological diseases and disorders, however, there is still a lack of diagnostic approaches and therefore there is a great interest in CSF in a scientific context. 

In this Special Issue, we welcome contributions that provide an update on a wide range of topics in CSF diagnostics (e.g. milestones in CSF analysis or the current diagnostic standards). However, this issue also focuses on new and innovative approaches that are important for CSF-based diagnostics.

Dr. Katalin Barkovits
Prof. Dr. Katrin Marcus
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Diagnostics is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cerebrospinal fluid (CSF)
  • biomarker
  • neurological diseases and disorders
  • central nervous system (CNS)
  • diagnostic
  • dementias
  • multiple sclerosis
  • brain tumors
  • neurotrauma
  • neuroinfections

Published Papers (7 papers)

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Research

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12 pages, 663 KiB  
Article
Upregulation of sICAM-1 and sVCAM-1 Levels in the Cerebrospinal Fluid of Patients with Schizophrenia Spectrum Disorders
by Sophie Meixensberger, Hanna Kuzior, Bernd L. Fiebich, Patrick Süß, Kimon Runge, Benjamin Berger, Kathrin Nickel, Dominik Denzel, Miriam A. Schiele, Maike Michel, Simon Maier, Karl Bechter, Katharina Domschke, Ludger Tebartz van Elst and Dominique Endres
Diagnostics 2021, 11(7), 1134; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11071134 - 22 Jun 2021
Cited by 15 | Viewed by 2147
Abstract
Immunological explanatory approaches are becoming increasingly important in schizophrenia research. In this context, the function of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) plays an essential role. Different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell [...] Read more.
Immunological explanatory approaches are becoming increasingly important in schizophrenia research. In this context, the function of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB) plays an essential role. Different adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), are key elements in sustaining the integrity of the BBB and BCSFB. The objectives of this study were to (1) compare the levels of different cell adhesion molecules in the CSF of patients with schizophrenia spectrum disorders to those of patients with unipolar depression and (2) analyze their association with the established markers of the BBB/BCSFB function (CSF total protein and albumin quotient (AQ)). Therefore, a total of 40 patients with schizophrenia spectrum disorder and 39 age- and sex-matched control patients with unipolar depression were analyzed. The levels of soluble ICAM-1 (s-ICAM-1), soluble VCAM-1 (s-VCAM-1), and plasminogen activator inhibitor 1 (PAI-1) in the CSF were measured using a magnetic bead multiplexing immunoassay. The levels of sICAM-1 (p < 0.001), sVCAM-1 (p < 0.001), and PAI-1 (p < 0.001) in the CSF were significantly higher in patients with schizophrenia spectrum disorder than in patients with unipolar depression. In addition, a significant correlation of sVCAM-1 levels with total protein concentrations (r = 0.454, p = 0.003) and AQ levels (r = 0.512, p = 0.001) in patients with schizophrenia spectrum disorders was observed. The results revealed that sICAM-1 and sVCAM-1 levels in the CSF were higher in patients with schizophrenia spectrum disorder than in those with depression. These circulating signaling molecules may indicate endothelial dysfunction causing impaired BBB/BCSFB function in patients with schizophrenia spectrum disorders. Consistent with this view, a highly significant correlation of sVCAM-1 with CSF protein and AQs was detected. Upregulation of these cell adhesion molecules might be indicative of a proinflammatory immune response underlying the BBB/BCSFB disturbance in a subgroup of patients with schizophrenia spectrum disorders. The significance of the study is limited by its retrospective research design and by the absence of a healthy control group. The assay used was not previously established for the measurement of CSF. Further translational and controlled studies of the role of different cell adhesion molecules in schizophrenia are needed. Full article
(This article belongs to the Special Issue The Diagnostic Value of Cerebrospinal Fluid)
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11 pages, 1441 KiB  
Article
Sex-Related Differences in Cerebrospinal Fluid Plasma-Derived Proteins of Neurological Patients
by Massimiliano Castellazzi, Caterina Ferri, Sarah Alfiero, Ilenia Lombardo, Michele Laudisi, Ginevra Tecilla, Michela Boni, Stefano Pizzicotti, Enrico Fainardi, Tiziana Bellini and Maura Pugliatti
Diagnostics 2021, 11(5), 884; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11050884 - 16 May 2021
Cited by 4 | Viewed by 2278
Abstract
Background and aims: Cerebrospinal fluid (CSF) protein content presents a sexual dimorphism in humans. We investigated sex-related differences in CSF IgG levels and in the quantification of intrathecal IgG synthesis (IIS). Methods: CSF, serum albumin and IgG were measured in 1519 neurological patients [...] Read more.
Background and aims: Cerebrospinal fluid (CSF) protein content presents a sexual dimorphism in humans. We investigated sex-related differences in CSF IgG levels and in the quantification of intrathecal IgG synthesis (IIS). Methods: CSF, serum albumin and IgG were measured in 1519 neurological patients and both linear and hyperbolic formulas were used for the quantification of IIS. CSF-restricted oligoclonal IgG bands (OCBs) were used as “gold standard”. Results: The linear IgG Index showed a weak agreement with OCBs in males and females (k = 0.559, k = 0.587, respectively), while the hyperbolic Reiber’s formulas had a moderate agreement with OCBs in females (k = 0.635) and a weak agreement in males (k = 0.565). Higher CSF albumin and IgG levels were found in men than in women in the whole population and in subjects without IIS after adjusting for age and for serum concentrations of albumin and IgG, respectively (Quade statistics, p < 0.000001). CSF and serum albumin and IgG levels positively correlated to age in both sexes. CSF total protein content did not correlate with CSF leukocyte numbers but was higher in patients with marked pleocytosis. Conclusions: In neurological patients, men have higher levels of CSF serum-derived proteins, such as albumin and IgG. Full article
(This article belongs to the Special Issue The Diagnostic Value of Cerebrospinal Fluid)
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Review

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15 pages, 2470 KiB  
Review
Role and Relevance of Cerebrospinal Fluid Cells in Diagnostics and Research: State-of-the-Art and Underutilized Opportunities
by Ferdinand Otto, Christine Harrer, Georg Pilz, Peter Wipfler and Andrea Harrer
Diagnostics 2022, 12(1), 79; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics12010079 - 30 Dec 2021
Cited by 4 | Viewed by 6348
Abstract
Cerebrospinal fluid (CSF) has recently experienced a revival in diagnostics and research. However, little progress has been made regarding CSF cell analysis. For almost a century, CSF cell count and cytomorphological examination have been central diagnostic parameters, with CSF pleocytosis as a hallmark [...] Read more.
Cerebrospinal fluid (CSF) has recently experienced a revival in diagnostics and research. However, little progress has been made regarding CSF cell analysis. For almost a century, CSF cell count and cytomorphological examination have been central diagnostic parameters, with CSF pleocytosis as a hallmark finding of neuroinflammation and cytology offering valuable clues regarding infectious, autoimmune, and malignant aetiologies. A great deal of information, however, remains unattended as modern immune phenotyping technologies have not yet been broadly incorporated into routine CSF analysis. This is a serious deficit considering the central role of CSF cells as effectors in central nervous system (CNS) immune defence and autoimmune CNS processes, and the diagnostic challenges posed by clinically overlapping infectious and immune-mediated CNS diseases. Here, we summarize historical, specimen-intrinsic, methodological, and technical issues determining the state-of-the-art diagnostics of CSF cells and outline future perspectives for this underutilized window into meningeal and CNS immunity. Full article
(This article belongs to the Special Issue The Diagnostic Value of Cerebrospinal Fluid)
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17 pages, 774 KiB  
Review
Next Generation Sequencing of Cerebrospinal Fluid B Cell Repertoires in Multiple Sclerosis and Other Neuro-Inflammatory Diseases—A Comprehensive Review
by Christoph Ruschil, Constanze Louisa Kemmerer, Lena Beller, Gisela Gabernet and Markus Christian Kowarik
Diagnostics 2021, 11(10), 1871; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11101871 - 11 Oct 2021
Cited by 4 | Viewed by 2592
Abstract
During the last few decades, the role of B cells has been well established and redefined in neuro-inflammatory diseases, including multiple sclerosis and autoantibody-associated diseases. In particular, B cell maturation and trafficking across the blood–brain barrier (BBB) has recently been deciphered with the [...] Read more.
During the last few decades, the role of B cells has been well established and redefined in neuro-inflammatory diseases, including multiple sclerosis and autoantibody-associated diseases. In particular, B cell maturation and trafficking across the blood–brain barrier (BBB) has recently been deciphered with the development of next-generation sequencing (NGS) approaches, which allow the assessment of representative cerebrospinal fluid (CSF) and peripheral blood B cell repertoires. In this review, we perform literature research focusing on NGS studies that allow further insights into B cell pathophysiology during neuro-inflammation. Besides the analysis of CSF B cells, the paralleled assessment of peripheral blood B cell repertoire provides deep insights into not only the CSF compartment, but also in B cell trafficking patterns across the BBB. In multiple sclerosis, CSF-specific B cell maturation, in combination with a bidirectional exchange of B cells across the BBB, is consistently detectable. These data suggest that B cells most likely encounter antigen(s) within the CSF and migrate across the BBB, with further maturation also taking place in the periphery. Autoantibody-mediated diseases, such as neuromyelitis optica spectrum disorder and LGI1 / NMDAR encephalitis, also show features of a CSF-specific B cell maturation and clonal connectivity with peripheral blood. In conclusion, these data suggest an intense exchange of B cells across the BBB, possibly feeding autoimmune circuits. Further developments in sequencing technologies will help to dissect the exact pathophysiologic mechanisms of B cells during neuro-inflammation. Full article
(This article belongs to the Special Issue The Diagnostic Value of Cerebrospinal Fluid)
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21 pages, 1965 KiB  
Review
Biological Significance of the Protein Changes Occurring in the Cerebrospinal Fluid of Alzheimer’s Disease Patients: Getting Clues from Proteomic Studies
by Cristina M. Pedrero-Prieto, Javier Frontiñán-Rubio, Francisco J. Alcaín, Mario Durán-Prado, Juan R. Peinado and Yoana Rabanal-Ruiz
Diagnostics 2021, 11(9), 1655; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11091655 - 09 Sep 2021
Cited by 7 | Viewed by 3026
Abstract
The fact that cerebrospinal fluid (CSF) deeply irrigates the brain together with the relative simplicity of sample extraction from patients make this biological fluid the best target for biomarker discovery in neurodegenerative diseases. During the last decade, biomarker discovery has been especially fruitful [...] Read more.
The fact that cerebrospinal fluid (CSF) deeply irrigates the brain together with the relative simplicity of sample extraction from patients make this biological fluid the best target for biomarker discovery in neurodegenerative diseases. During the last decade, biomarker discovery has been especially fruitful for the identification new proteins that appear in the CSF of Alzheimer’s disease (AD) patients together with amyloid-β (Aβ42), total tau (T-tau), and phosphorylated tau (P-tau). Thus, several proteins have been already stablished as important biomarkers, due to an increase (i.e., CHI3L1) or a decrease (i.e., VGF) in AD patients’ CSF. Notwithstanding this, only a deep analysis of a database generated with all the changes observed in CSF across multiple proteomic studies, and especially those using state-of-the-art methodologies, may expose those components or metabolic pathways disrupted at different levels in AD. Deep comparative analysis of all the up- and down-regulated proteins across these studies revealed that 66% of the most consistent protein changes in CSF correspond to intracellular proteins. Interestingly, processes such as those associated to glucose metabolism or RXR signaling appeared inversely represented in CSF from AD patients in a significant manner. Herein, we discuss whether certain cellular processes constitute accurate indicators of AD progression by examining CSF. Furthermore, we uncover new CSF AD markers, such as ITAM, PTPRZ or CXL16, identified by this study. Full article
(This article belongs to the Special Issue The Diagnostic Value of Cerebrospinal Fluid)
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32 pages, 873 KiB  
Review
CSF Diagnostics: A Potentially Valuable Tool in Neurodegenerative and Inflammatory Disorders Involving Motor Neurons: A Review
by Karsten Krause, Maximilian Wulf, Paula Sommer, Katalin Barkovits, Matthias Vorgerd, Katrin Marcus and Britta Eggers
Diagnostics 2021, 11(9), 1522; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11091522 - 24 Aug 2021
Cited by 5 | Viewed by 3292
Abstract
Cerebrospinal fluid (CSF) diagnostics has emerged as a valid tool for a variety of neurological diseases. However, CSF diagnostics has been playing a subordinate role in the diagnosis of many neurological conditions. Thus, in the multitude of neuromuscular diseases in which motor neurons [...] Read more.
Cerebrospinal fluid (CSF) diagnostics has emerged as a valid tool for a variety of neurological diseases. However, CSF diagnostics has been playing a subordinate role in the diagnosis of many neurological conditions. Thus, in the multitude of neuromuscular diseases in which motor neurons are affected, a CSF sample is rarely taken routinely. However, CSF diagnostics has the potential to specify the diagnosis and monitor the treatment of neuromuscular disorders. In this review, we therefore focused on a variety of neuromuscular diseases, among them amyotrophic lateral sclerosis (ALS), peripheral neuropathies, and spinal muscular atrophy (SMA), for which CSF diagnostics has emerged as a promising option for determining the disease itself and its progression. We focus on potentially valuable biomarkers among different disorders, such as neurofilaments, cytokines, other proteins, and lipids to determine their suitability, differentiating between different neurological disorders and their potential to determine early disease onset, disease progression, and treatment outcome. We further recommend novel approaches, e.g., the use of mass spectrometry as a promising alternative techniques to standard ELISA assays, potentially enhancing biomarker significance in clinical applications. Full article
(This article belongs to the Special Issue The Diagnostic Value of Cerebrospinal Fluid)
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9 pages, 1386 KiB  
Review
Neurofilaments as Emerging Biomarkers of Neuroaxonal Damage to Differentiate Behavioral Frontotemporal Dementia from Primary Psychiatric Disorders: A Systematic Review
by Vincent Davy, Julien Dumurgier, Aurore Fayosse, Claire Paquet and Emmanuel Cognat
Diagnostics 2021, 11(5), 754; https://0-doi-org.brum.beds.ac.uk/10.3390/diagnostics11050754 - 22 Apr 2021
Cited by 7 | Viewed by 2697
Abstract
The behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome resulting from various causes of neuronal demises associated with frontotemporal lobar degeneration. Symptoms include behavioral and personality changes, social cognitive impairment, and executive function deficits. There is a significant clinical overlap between [...] Read more.
The behavioral variant of frontotemporal dementia (bvFTD) is a clinical syndrome resulting from various causes of neuronal demises associated with frontotemporal lobar degeneration. Symptoms include behavioral and personality changes, social cognitive impairment, and executive function deficits. There is a significant clinical overlap between this syndrome and various primary psychiatric disorders (PPD). Structural and functional neuroimaging are considered helpful to support the diagnosis of bvFTD, but their sensitivity and specificity remain imperfect. There is growing evidence concerning the potential of neurofilaments as biomarkers reflecting axonal and neuronal lesions. Ultrasensitive analytic platforms have recently enabled neurofilament light chains’ (NfL) detection not only from cerebrospinal fluid but also from peripheral blood samples in FTD patients. In this short review, we present recent advances and perspectives for the use of NfL assessments as biomarkers of neuroaxonal damage to differentiate bvFTD from primary psychiatric disorders. Full article
(This article belongs to the Special Issue The Diagnostic Value of Cerebrospinal Fluid)
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