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Diagnostics
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Advances in Cerebrospinal Fluid Diagnostics
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Advances in Cerebrospinal Fluid Diagnostics

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 March 2023) | Viewed by 8193

Special Issue Editors

Dr. Elisabeth Kapaki

E-Mail Website
Guest Editor
Neurochemistry and Biomarker Unit, 1st Department of Neurology, Eginition Hospital, National and Kapodistrian University of Athens, Athens, Greece
Interests: CSF; biomarkers; dementia; neurodegenerative diseases; Alzheimer; tau; p-tau; amyloid
Dr. Fotini Boufidou

E-Mail Website
Co-Guest Editor
Neurochemistry and Biological Markers Unit, 1st Department of Neurology, Eginition Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Interests: CSF; neuroimmunology; psychoimmunology; ELISA; biomarkers

Special Issue Information

Dear Colleagues,

Since the first in vivo lumbar puncture (LP), carried out by Heinrich Quincke in 1891 (mainly performed for therapeutic reasons), the parallel analysis of cerebrospinal fluid (CSF) has been a determinative fact. Quincke’s CSF studies involved the measurement of intracranial pressure, the determination of protein and glucose levels, as well as cytological and bacteriological analyses; thus, establishing the first crucial milestones in CSF diagnostics.

Incorporating previous progress in the field of microbiology, such as bacteria cultures, Gram and Ziehl–Neelsen staining methods in CNS analysis, allowed for the diagnosis of infections to be possible and accurate. Immunological methods came into play afterwards, namely, immunoglobulin determination and oligoclonal bands, further advancing CSF diagnostics with the latest discovery of an ever-growing list of antibodies for autoimmune/paraneoplastic disorders.

In the last 30 years, great progress has been achieved in dementia and particularly Alzheimer’s disease diagnosis through the use of biological markers with the molecular specificity of amyloid pathology, neurofibrillary tangle pathology, prion protein pathological misfolding, along with nonspecific biomarkers of neurodegeneration.

Moreover, “omic” approaches, including proteomics, metabolomics, transcriptomics and microRNA analysis, are continuously explored, expanding the potential of CSF diagnostics.

The aim of the present Special Issue is to highlight these important advances in CSF diagnostics through a constellation of articles focusing on the above issues.

Dr. Elisabeth Kapaki
Dr. Fotini Boufidou
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 diagnostics
  • CNS infections
  • demyelinating diseases
  • neuroinflammation
  • neurodegenerative diseases
  • dementias
  • autoimmune encephalopathies
  • methodological issues in CSF analysis

Published Papers (4 papers)

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15 pages, 1699 KiB  
Article
Assessment of Aggregated and Exosome-Associated α-Synuclein in Brain Tissue and Cerebrospinal Fluid Using Specific Immunoassays
by Dimitrios Anagnostou, Garifalia Sfakianaki, Katerina Melachroinou, Miltiadis Soutos, Vassilios Constantinides, Nishant Vaikath, Ioanna Tsantzali, George P. Paraskevas, Omar El Agnaf, Kostas Vekrellis and Evangelia Emmanouilidou
Diagnostics 2023, 13(13), 2192; https://doi.org/10.3390/diagnostics13132192 - 27 Jun 2023
Viewed by 2017
Abstract
Even though it is currently well-established that α-synuclein aggregation is closely associated with the pathological events in Parkinson’s disease (PD) and several other neurodegenerative disorders, collectively called synucleinopathies, the mechanistic link between α-synuclein aggregates and the onset and progression of neurodegeneration in these [...] Read more.
Even though it is currently well-established that α-synuclein aggregation is closely associated with the pathological events in Parkinson’s disease (PD) and several other neurodegenerative disorders, collectively called synucleinopathies, the mechanistic link between α-synuclein aggregates and the onset and progression of neurodegeneration in these diseases remain unclear. The process of aggregation initiates from a structurally distorted monomer that gradually oligomerizes to generate a repertoire of fibrillar and oligomeric multimers that deposit within diseased cells in the brain. Total α-synuclein has been proposed as a potential biomarker in PD, but most of the studies do not discriminate between distinct α-synuclein conformers. To correlate protein measurements to disease pathology, we have developed a conformation-specific ELISA method that selectively detects fibrillar and oligomeric forms of α-synuclein without cross-reacting with monomers. We have used this assay to determine the levels of aggregated α-synuclein in human and mouse brain tissue as well as in CSF and CSF-derived exosomes from patients with synucleinopathy and control subjects. Our results verify the ability of the new assay to detect aggregated α-synuclein in complex matrices and support the idea that the levels of these conformers are related to the age of onset in PD patients, while CSF analysis showed that these species exist in low abundance in CSF and CSF-derived exosomes. Future studies will be required to fully assess the diagnostic usefulness of this ELISA in synucleinopathies. Full article
(This article belongs to the Special Issue Advances in Cerebrospinal Fluid Diagnostics)
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13 pages, 876 KiB  
Article
CSF Aβ42 and Aβ42/Aβ40 Ratio in Alzheimer’s Disease and Frontotemporal Dementias
by Vasilios C. Constantinides, George P. Paraskevas, Fotini Boufidou, Mara Bourbouli, Efstratios-Stylianos Pyrgelis, Leonidas Stefanis and Elisabeth Kapaki
Diagnostics 2023, 13(4), 783; https://doi.org/10.3390/diagnostics13040783 - 19 Feb 2023
Cited by 9 | Viewed by 2574
Abstract
Background: Alzheimer’s disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy [...] Read more.
Background: Alzheimer’s disease dementia (ADD) may manifest with atypical phenotypes, resembling behavioral variant frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS), phenotypes which typically have an underlying frontotemporal lobar degeneration with tau proteinopathy (FTLD-tau), such as Pick’s disease, corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), or FTLD with TDP-43 proteinopathy (FTLD-TDP). CSF biomarkers total and phosphorylated tau (τT and τP-181), and amyloid beta with 42 and 40 amino acids (Aβ42 and Aβ40) are biomarkers of AD pathology. The primary aim of this study was to compare the diagnostic accuracy of Aβ42 to Aβ42/Aβ40 ratio in: (a) differentiating ADD vs. frontotemporal dementias; (b) patients with AD pathology vs. non-AD pathologies; (c) compare biomarker ratios and composite markers to single CSF biomarkers in the differentiation of AD from FTD; Methods: In total, 263 subjects were included (ADD: n = 98; bvFTD: n = 49; PSP: n = 50; CBD: n = 45; controls: n = 21). CSF biomarkers were measured by commercially available ELISAs (EUROIMMUN). Multiple biomarker ratios (Aβ42/Aβ40; τT/τP-181; τT/Aβ42; τP-181/Aβ42) and composite markers (t-tau: τT/(Aβ42/Aβ40); p-tau: τP-181/(Aβ42/Aβ40) were calculated. ROC curve analysis was performed to compare AUCs of Aβ42 and Aβ42/Aβ40 ratio and relevant composite markers between ADD and FTD, as defined clinically. BIOMARKAPD/ABSI criteria (abnormal τT, τP-181 Aβ42, and Aβ42/Aβ40 ratio) were used to re-classify all patients into AD pathology vs. non-AD pathologies, and ROC curve analysis was repeated to compare Aβ42 and Aβ42/Aβ40; Results: Aβ42 did not differ from Aβ42/Aβ40 ratio in the differentiation of ADD from FTD (AUCs 0.752 and 0.788 respectively; p = 0.212). The τT/Aβ42 ratio provided maximal discrimination between ADD and FTD (AUC:0.893; sensitivity 88.8%, specificity 80%). BIOMARKAPD/ABSI criteria classified 60 patients as having AD pathology and 211 as non-AD. A total of 22 had discrepant results and were excluded. Aβ42/Aβ40 ratio was superior to Aβ42 in the differentiation of AD pathology from non-AD pathology (AUCs: 0.939 and 0.831, respectively; p < 0.001). In general, biomarker ratios and composite markers were superior to single CSF biomarkers in both analyses. Conclusions: Aβ42/Aβ40 ratio is superior to Aβ42 in identifying AD pathology, irrespective of the clinical phenotype. CSF biomarker ratios and composite markers provide higher diagnostic accuracy compared to single CSF biomarkers. Full article
(This article belongs to the Special Issue Advances in Cerebrospinal Fluid Diagnostics)
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12 pages, 1190 KiB  
Article
Antiretroviral Levels in the Cerebrospinal Fluid: The Effect of Inflammation and Genetic Variants
by Jessica Cusato, Valeria Avataneo, Miriam Antonucci, Mattia Trunfio, Letizia Marinaro, Alice Palermiti, Alessandra Manca, Giovanni Di Perri, Jacopo Mula, Stefano Bonora, Antonio D’Avolio and Andrea Calcagno
Diagnostics 2023, 13(2), 295; https://doi.org/10.3390/diagnostics13020295 - 12 Jan 2023
Cited by 4 | Viewed by 1304
Abstract
Neurocognitive impairments are common in people living with HIV. Some conditions, such as chronic inflammation, astrocyte infection and an impaired blood–brain barrier (BBBi), along with host genetic variants in transporter genes, may affect antiretroviral (ARV) exposure in the cerebrospinal fluid (CSF). The aim [...] Read more.
Neurocognitive impairments are common in people living with HIV. Some conditions, such as chronic inflammation, astrocyte infection and an impaired blood–brain barrier (BBBi), along with host genetic variants in transporter genes, may affect antiretroviral (ARV) exposure in the cerebrospinal fluid (CSF). The aim of this study was to evaluate ARV CSF penetration according to compartmental inflammation, BBB permeability and single-nucleotide polymorphisms (SNPs) in drug transporter encoding genes. CSF neopterin (ELISA), plasma and CSF ARV concentrations (HPLC) and host genetic variants in ABCC2, HNF4α, SLCO1A2 and SLC22A6 (real-time PCR) were measured. Bi- and multivariate analyses were performed for single ARV and classes. We included 259 participants providing 405 paired plasma and CSF samples. CSF/plasma ratios (CPR) showed an increase for NRTIs and nevirapine with low penetrations for the majority of ARVs. At bi-variate analysis, several associations, including the effect of BBBi (emtricitabine, raltegravir), age (zidovudine and darunavir), and high CSF neopterin (NRTIs and border-line for PIs) were suggested. An association was found between genetic variants and integrase strand transfer (ABCC2 and HNF4α), non-nucleoside reverse transcriptase inhibitors (SLCO1A2), and protease inhibitors (SLC22A6). At multivariate analysis age, gender, BMI, and altered BBB were independent predictors of nucleoside reverse transcriptase CSF concentrations; age (for protease inhibitors) and body mass index and altered BBB (integrase strand transfer inhibitors) were also associated with ARV CSF exposure. We describe factors associated with CSF concentrations, showing that demographic, BBB integrity and, partially, genetic factors may be predictors of drug passage in the central nervous system. Full article
(This article belongs to the Special Issue Advances in Cerebrospinal Fluid Diagnostics)
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11 pages, 1019 KiB  
Case Report
Cerebrospinal Fluid Anti-Neuronal Autoantibodies in COVID-19-Associated Limbic Encephalitis with Acute Cerebellar Ataxia and Myoclonus Syndrome: Case Report and Literature Review
by Konstantina Yiannopoulou, Aigli G. Vakrakou, Aikaterini Anastasiou, Georgia Nikolopoulou, Athina Sourdi, John S. Tzartos, Constantinos Kilidireas and Antonios Dimitrakopoulos
Diagnostics 2023, 13(12), 2055; https://doi.org/10.3390/diagnostics13122055 - 14 Jun 2023
Cited by 2 | Viewed by 1383
Abstract
Since the outbreak of coronavirus (COVID-19) in 2019, various rare movement disorders and cognitive changes have been recognized as potential neurological complications. The early treatment of some of these allows rapid recovery; therefore, we must diagnose these manifestations in a timely way. We [...] Read more.
Since the outbreak of coronavirus (COVID-19) in 2019, various rare movement disorders and cognitive changes have been recognized as potential neurological complications. The early treatment of some of these allows rapid recovery; therefore, we must diagnose these manifestations in a timely way. We describe the case of a 76-year-old man infected with severe acute respiratory syndrome coronavirus-2 who presented with confusion and hallucinations and was admitted to our hospital 14 days after the onset of symptoms. One day later, he developed generalized myoclonus, dysarthria and ataxia, and tonic clonic seizures and was admitted to the intensive care unit. A diagnosis of COVID-19-associated autoimmune encephalitis with characteristics of limbic encephalitis and immune-mediated acute cerebellar ataxia and myoclonus syndrome was supported by alterations in the limbic system shown in magnetic resonance imaging, lateralized discharges shown in electroencephalography, a slightly elevated protein level in the cerebrospinal fluid (CSF), and indirect immunofluorescence in the CSF with autoantibody binding to anatomical structures of the cerebellum and hippocampus. The patient improved with 2 weeks of corticosteroid treatment and four sessions of plasmapheresis. Our current case study describes a rare case of COVID-19-related limbic encephalitis with immune-mediated acute cerebellar ataxia and myoclonus syndrome (ACAM syndrome) and strengthens the need for tissue-based assays (TBAs) to screen the serum and/or CSF of patients highly suspected to have autoimmune encephalitis. We believe that the timely diagnosis and targeted aggressive immunotherapy were mainly responsible for the patient’s total recovery. Full article
(This article belongs to the Special Issue Advances in Cerebrospinal Fluid Diagnostics)
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