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Metabolites
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Cerebrospinal Fluid Biomarkers for Understanding Disease Pathogenesis
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Cerebrospinal Fluid Biomarkers for Understanding Disease Pathogenesis

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Advances in Metabolomics".

Deadline for manuscript submissions: closed (28 February 2022) | Viewed by 17884

Special Issue Editors

Dr. Byong Chul Yoo

E-Mail Website
Guest Editor
Division of Translational Science, National Cancer Center, Goyang, Korea
Interests: cerebrospinal fluid; Meningeal Carcinomatosis; Cancer Biology; proteomics; Metabolomics
Prof. Ho-Shin Gwak

E-Mail Website
Guest Editor
Center for Specific Organs Cancer, National Cancer Center, Goyang, Korea
Interests: stereotactic radiosurgery; cancer biology; radiosurgery; astrocytoma; meningeal carcinomatosis; metastatic brain tumor

Special Issue Information

Dear Colleagues, 

Cerebrospinal fluid (CSF) bathes the central nervous system (CNS), carrying various material secreted actively or passively. The blood–brain barrier is not only an obstacle to deliver molecules to CNS, but also makes blood sampling  inappropriate to study CNS disease. Although acquiring a CSF sample is more difficult than blood sampling, lumbar puncture and ventricular reservoir provide repeated access to CNS status. Thus, many researchers have been attempting to discover a biomarker of CNS disease from CSF samples and recent data provides evidence proving that CSF is useful for the diagnostics and monitoring of CNS disease.

However, two barriers remain at large to the achievement solid biomarkers of CNS disease by analyzing CSF materials: CSF is a clear, acellular fluid with a few floating cells captured in cases of active disease such as inflammation or leptomeningeal metastasis. Thus, all extracellular genomic materials and proteins exist on a 1/10~1/1,000 lower scale, compared to in blood or tissues. These difficulties are now being overcome using advanced -omics technology; for example, CSF proteomics can identify thousands of different proteins from 0.2 mL of CSF. Another problem is that, like in serum biomarker, the sources of candidate biomarkers could vary and quantification based on normalization is very difficult. For example, metabolomics have recently been highlighted as having a different profile for its disease status reflecting current activity or cancer cell behavior. However, so many other variables affecting these profiles have still not yet been identified or standardized.

Bringing our data together will provide a base for analyzing conditions that affect CSF profile and help us to understand the unknown pathophysiology of CNS disease with advanced multi-omics approach.

Dr. Byong Chul Yoo
Prof. Ho-Shin Gwak
Guest Editors

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Published Papers (5 papers)

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Research

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20 pages, 1190 KiB  
Article
Folate Related Pathway Gene Analysis Reveals a Novel Metabolic Variant Associated with Alzheimer’s Disease with a Change in Metabolic Profile
by Jaleel Miyan, Charlotte Buttercase, Emma Beswick, Salma Miyan, Ghazaleh Moshkdanian and Naila Naz
Metabolites 2022, 12(6), 475; https://doi.org/10.3390/metabo12060475 - 24 May 2022
Cited by 4 | Viewed by 3860
Abstract
Metabolic disorders may be important potential causative pathways to Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) decreasing output, raised intracranial pressure, and ventricular enlargement have all been linked to AD. Cerebral folate metabolism may be a key player since this is significantly affected by [...] Read more.
Metabolic disorders may be important potential causative pathways to Alzheimer’s disease (AD). Cerebrospinal fluid (CSF) decreasing output, raised intracranial pressure, and ventricular enlargement have all been linked to AD. Cerebral folate metabolism may be a key player since this is significantly affected by such changes in CSF, and genetic susceptibilities may exist in this pathway. In the current study, we aimed to identify whether any single nucleotide polymorphism (SNPs) affecting folate and the associated metabolic pathways were significantly associated with AD. We took a functional nutrigenomics approach to look for SNPs in genes for the linked folate, methylation, and biogenic amine neurotransmitter pathways. Changes in metabolism were found with the SNPs identified. An abnormal SNP in methylene tetrahydrofolate dehydrogenase 1 (MTHFD1) was significantly predictive of AD and associated with an increase in tissue glutathione. Individuals without these SNPs had normal levels of glutathione but significantly raised MTHFD1. Both changes would serve to decrease potentially neurotoxic levels of homocysteine. Seven additional genes were associated with Alzheimer’s and five with normal ageing. MTHFD1 presents a strong prediction of susceptibility and disease among the SNPs associated with AD. Associated physiological changes present potential biomarkers for identifying at-risk individuals. Full article
(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers for Understanding Disease Pathogenesis)
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24 pages, 20302 KiB  
Article
Different Metabolomic and Proteomic Profiles of Cerebrospinal Fluid in Ventricular and Lumbar Compartments in Relation to Leptomeningeal Metastases
by Ji-Woong Kwon, Ji Hye Im, Kyue-Yim Lee, Byong Chul Yoo, Jun Hwa Lee, Kyung-Hee Kim, Jong Heon Kim, Sang Hoon Shin, Heon Yoo and Ho-Shin Gwak
Metabolites 2022, 12(1), 80; https://doi.org/10.3390/metabo12010080 - 14 Jan 2022
Cited by 6 | Viewed by 2694
Abstract
The different molecular profiles of cerebrospinal fluid (CSF) between ventricular and lumbar compartments remain elusive, especially in the context of leptomeningeal metastasis (LM), which affects CSF flow. We evaluated CSF metabolomic and proteomic profiles based on the compartments and the diagnosis of spinal [...] Read more.
The different molecular profiles of cerebrospinal fluid (CSF) between ventricular and lumbar compartments remain elusive, especially in the context of leptomeningeal metastasis (LM), which affects CSF flow. We evaluated CSF metabolomic and proteomic profiles based on the compartments and the diagnosis of spinal LM, proved by MRI from 20 paired ventricular and lumbar CSF samples of LM patients, including 12 spinal LM (+) samples. In metabolome analysis, 9512 low-mass ions (LMIs) were identified—7 LMIs were abundant in all lumbar versus paired ventricular CSF samples, and 3 LMIs were significantly abundant in all ventricular CSF. In comparisons between spinal LM (+) CSF and LM (−) CSF, 105 LMIs were discriminative for spinal LM (+) CSF. In proteome analysis, a total of 1536 proteins were measured. A total of 18 proteins, including complement C3, were more highly expressed in all lumbar CSF, compared with paired ventricular CSF, while 82 proteins, including coagulation factor V, were higher in the ventricular CSF. Of 37 discriminative proteins, including uteroglobin and complement component C8 gamma chain, 4 were higher in all spinal LM (+) CSF versus spinal LM (−) CSF. We further evaluated metabolic pathways associated with these discriminative proteins using the Gene Ontology database. We found that 16/17 spinal LM (+) pathways, including complement activation, were associated with lumbar discriminative proteins, whereas only 2 pathways were associated with ventricular-discriminative proteins. In conclusion, we determined that metabolite and protein profiles differed between paired lumbar and ventricular CSF samples. The protein profiles of spinal LM (+) CSF showed more similarity with the lumbar CSF than the ventricular CSF. Thus, we suggest that CSF LMIs and proteins could reflect LM disease activity and that LM-associated differences in CSF are more likely to be present in the lumbar compartment. Full article
(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers for Understanding Disease Pathogenesis)
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13 pages, 1913 KiB  
Article
Experimental Assessment of Leptomeningeal Metastasis Diagnosis in Medulloblastoma Using Cerebrospinal Fluid Metabolomic Profiles
by Ji Hye Im, Byong Chul Yoo, Jun Hwa Lee, Kyue-Yim Lee, Kyung-Hee Kim, Jong Heon Kim, Hyeon Jin Park, Meerim Park, Sang Hyeon Lee, Ji-Woong Kwon, Sang Hoon Shin, Heon Yoo, Jeyul Yang, Seung Ah Choi, Seung-Ki Kim and Ho-Shin Gwak
Metabolites 2021, 11(12), 851; https://doi.org/10.3390/metabo11120851 - 7 Dec 2021
Cited by 3 | Viewed by 2764
Abstract
Diagnosing leptomeningeal metastasis (LM) in medulloblastoma is currently based on positive cerebrospinal fluid (CSF) cytology or magnetic resonance imaging (MRI) finding. However, the relevance of discordant results has not been established. We evaluated the diagnostic potential of CSF metabolomic profiles in the medulloblastoma [...] Read more.
Diagnosing leptomeningeal metastasis (LM) in medulloblastoma is currently based on positive cerebrospinal fluid (CSF) cytology or magnetic resonance imaging (MRI) finding. However, the relevance of discordant results has not been established. We evaluated the diagnostic potential of CSF metabolomic profiles in the medulloblastoma LM assessment. A total of 83 CSF samples from medulloblastoma patients with documented MRI and CSF cytology results at the time of sampling for LM underwent low-mass ions (LMIs) analysis using liquid chromatography-mass spectrometry. Discriminating LMIs were selected by a summed sensitivity and specificity (>160%) and LMI discriminant equation (LOME) algorithms, evaluated by measuring diagnostic accuracy for verifying LM groups of different MRI/cytology results. Diagnostic accuracy of LM in medulloblastoma was 0.722 for cytology and 0.889 for MRI. Among 6572 LMIs identified in all sample, we identified 27 discriminative LMIs differentiating MRI (+)/cytology (+) from MRI (−)/cytology (−). Using LMI discriminant equation (LOME) analysis, we selected 9 LMIs with a sensitivity of 100% and a specificity of 93.6% for differentiating MRI (+)/cytology (+) from MRI (−)/cytology (−). Another LOME of 20 LMIs significantly differentiated sampling time relative to treatment (p = 0.007) and the presence or absence of LM-related symptoms (p = 0.03) in the MRI (+)/cytology (−) group. CSF metabolomics of medulloblastoma patients revealed significantly different profiles among LM diagnosed with different test results. We suggest that LM patients could be screened by appropriately selected LOME-generated LMIs to support LM diagnosis by either MRI or cytology alone. Full article
(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers for Understanding Disease Pathogenesis)
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17 pages, 3957 KiB  
Article
Transferrin Biosynthesized in the Brain Is a Novel Biomarker for Alzheimer’s Disease
by Kyoka Hoshi, Hiromi Ito, Eriko Abe, Takashi J. Fuwa, Mayumi Kanno, Yuta Murakami, Mitsunari Abe, Takenobu Murakami, Akioh Yoshihara, Yoshikazu Ugawa, Takashi Saito, Takaomi C. Saido, Kana Matsumoto, Yoshiki Yamaguchi, Katsutoshi Furukawa, Hiroyuki Arai, Mitsuyasu Kanai, Masakazu Miyajima, Hajime Arai, Norihiro Ogawa, Hiroyasu Akatsu, Yoshio Hashizume, Hiroaki Tateno, Takashi Honda and Yasuhiro Hashimotoadd Show full author list remove Hide full author list
Metabolites 2021, 11(9), 616; https://doi.org/10.3390/metabo11090616 - 10 Sep 2021
Cited by 19 | Viewed by 3896
Abstract
Glycosylation is a cell type-specific post-translational modification that can be used for biomarker identification in various diseases. Aim of this study is to explore glycan-biomarkers on transferrin (Tf) for Alzheimer’s disease (AD) in cerebrospinal fluid (CSF). Glycan structures of CSF Tf were analyzed [...] Read more.
Glycosylation is a cell type-specific post-translational modification that can be used for biomarker identification in various diseases. Aim of this study is to explore glycan-biomarkers on transferrin (Tf) for Alzheimer’s disease (AD) in cerebrospinal fluid (CSF). Glycan structures of CSF Tf were analyzed by ultra-performance liquid chromatography followed by mass spectrometry. We found that a unique mannosylated-glycan is carried by a Tf isoform in CSF (Man-Tf). The cerebral cortex contained Man-Tf as a major isofom, suggesting that CSF Man-Tf is, at least partly, derived from the cortex. Man-Tf levels were analyzed in CSF of patients with neurological diseases. Concentrations of Man-Tf were significantly increased in AD and mild cognitive impairment (MCI) comparing with other neurological diseases, and the levels correlated well with those of phosphorylated-tau (p-tau), a representative AD marker. Consistent with the observation, p-tau and Tf were co-expressed in hippocampal neurons of AD, leading to the notion that a combined p-tau and Man-Tf measure could be a biomarker for AD. Indeed, levels of p-tau x Man-Tf showed high diagnostic accuracy for MCI and AD; 84% sensitivities and 90% specificities for MCI and 94% sensitivities and 89% specificities for AD. Thus Man-Tf could be a new biomarker for AD. Full article
(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers for Understanding Disease Pathogenesis)
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Review

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15 pages, 15297 KiB  
Review
Metabolites and Biomarker Compounds of Neurodegenerative Diseases in Cerebrospinal Fluid
by Keiji Wakamatsu, Yoichi Chiba, Ryuta Murakami, Yumi Miyai, Koichi Matsumoto, Masaki Kamada, Wakako Nonaka, Naoya Uemura, Ken Yanase and Masaki Ueno
Metabolites 2022, 12(4), 343; https://doi.org/10.3390/metabo12040343 - 12 Apr 2022
Cited by 12 | Viewed by 3551
Abstract
Despite recent advances in diagnostic procedures for neurological disorders, it is still difficult to definitively diagnose some neurodegenerative diseases without neuropathological examination of autopsied brain tissue. As pathological processes in the brain are frequently reflected in the components of cerebrospinal fluid (CSF), CSF [...] Read more.
Despite recent advances in diagnostic procedures for neurological disorders, it is still difficult to definitively diagnose some neurodegenerative diseases without neuropathological examination of autopsied brain tissue. As pathological processes in the brain are frequently reflected in the components of cerebrospinal fluid (CSF), CSF samples are sometimes useful for diagnosis. After CSF is secreted from the choroid plexus epithelial cells in the ventricles, some flows in the brain, some is mixed with intracerebral interstitial fluid, and some is excreted through two major drainage pathways, i.e., the intravascular periarterial drainage pathway and the glymphatic system. Accordingly, substances produced by metabolic and pathological processes in the brain may be detectable in CSF. Many papers have reported changes in the concentration of substances in the CSF of patients with metabolic and neurological disorders, some of which can be useful biomarkers of the disorders. In this paper, we show the significance of glucose- and neurotransmitter-related CSF metabolites, considering their transporters in the choroid plexus; summarize the reported candidates of CSF biomarkers for neurodegenerative diseases, including amyloid-β, tau, α-synuclein, microRNAs, and mitochondrial DNA; and evaluate their potential as efficient diagnostic tools. Full article
(This article belongs to the Special Issue Cerebrospinal Fluid Biomarkers for Understanding Disease Pathogenesis)
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