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Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 20 June 2026 | Viewed by 11194

Special Issue Editors

Prof. Dr. David Gurwitz

E-Mail Website
Guest Editor
Department of Human Molecular Genetics and Biochemistry, Faculty of Health and Medical Sciences, Tel Aviv University, Tel Aviv 69978, Israel
Interests: pharmacogenomics; RNA biomarkers; psychiatric disorders; autism spectrum disorder; Alzheimer’s disease; health aging
Special Issues, Collections and Topics in MDPI journals
Dr. Chiara Villa

E-Mail Website
Guest Editor
Department of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
Interests: genetics; Alzheimer’s disease; non-coding RNAs; neurodegeneration; epilepsy; brain; biomarkers
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

IJMS is pleased to announce a Special Issue titled “Molecular Advances in Biomarkers of Central Nervous System Diseases”.

For this Special Issue, our Guest Editors, Prof. Dr. David Gurwitz and Dr. Chiara Villa, will consider articles exploring novel biomarkers for early diagnosis, prognosis, differential diagnosis of disease subtypes, and personalized treatment choice for CNS diseases and disorders. Topics of interest include Alzheimer’s disease, Parkinson’s disease, stroke, epilepsy, and metabolic or genetic disorders affecting CNS function.

This Special Issue encompasses original research, opinion, and review articles. Studies with either human samples from patients and matched controls or established animal models of CNS diseases and disorders are particularly encouraged.

Biomarkers may include DNA methylation profiles, modified expression levels of mRNA, microRNAs, or other non-coding RNAs affecting CNS disease risk, age of onset, severity, prognosis, or response to approved or experimental therapeutics. In addition to DNA and RNA biomarkers, studies may include protein, metabolome, microbiome, and mitochondrial biomarkers affecting the aforementioned parameters of CNS diseases and disorders.

Reports on approved clinical trials will be considered when based on new mechanisms for a given CNS disease or disorder.

Prof. Dr. David Gurwitz
Dr. Chiara Villa
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 250 words) can be sent to the Editorial Office for assessment.

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • RNA biomarkers
  • CNS disorders
  • autism spectrum disorder
  • precision medicine

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Published Papers (7 papers)

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Research

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17 pages, 2590 KB  
Article
Serum Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Differential Biomarkers of Response to Dimethyl Fumarate and Ocrelizumab in Multiple Sclerosis
by Alessandra Mingione, Andrea Corona, Corinne Monzani, Alen Zollo, Carola Cirocco, Tiziana Zaccone, Mariangela Scavone, Gian Marco Podda, Paola Signorelli, Monica Miozzo, Alberto Priori and Filippo Martinelli-Boneschi
Int. J. Mol. Sci. 2026, 27(3), 1441; https://doi.org/10.3390/ijms27031441 - 31 Jan 2026
Viewed by 930
Abstract
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Quantifying neuronal damage is a critical step for patient care. Neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are the most promising serum biomarkers reflecting neuronal damage and astroglial activation, respectively. [...] Read more.
Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease. Quantifying neuronal damage is a critical step for patient care. Neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are the most promising serum biomarkers reflecting neuronal damage and astroglial activation, respectively. This study analyzed sNfL and sGFAP in 177 MS patients and 71 healthy controls (HCs) using SIMOA technology, classifying patients as responders (Rs) or non-responders (NRs) based on “No Evidence of Disease Activity 3” (NEDA-3) status during two years of treatment. Longitudinal analyses were performed for Dimethyl fumarate (DMF) and Ocrelizumab (OCRE) treatment. Biomarker–age correlation analysis in HCs confirmed correlation between both NfL and GFAP, with age and cut-off values specific for age decades being calculated. Both biomarkers were higher in MS patients compared to HCs. sNfL showed a significant increase in NR patients overall. In contrast, sGFAP was elevated in the low-to-moderate-efficacy treatment agents (LETAs) NR group and also in the DMF NR subgroup, suggesting that it monitors persistent astrogliosis. Longitudinal analysis showed that both biomarkers decreased during DMF treatment after one year. During OCRE treatment, sNfL rapidly reduced to HC levels within one year, while sGFAP decreased only after two years. This highlights that OCRE acts differently on the pathological processes linked to the two biomarkers. Full article
(This article belongs to the Special Issue Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders)
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24 pages, 21759 KB  
Article
Lysosomal Network Defects in Early-Onset Parkinson’s Disease Patients Carrying Rare Variants in Lysosomal Hydrolytic Enzyme Genes
by Alba Pascual, Thaleia Moulka, Oriol de Fàbregues, Roberta Repossi, Pedro J. García-Ruiz, Saida Ortolano, Marisel De Lucca, Lydia Vela-Desojo, Marta Alves-Villar, Marcos Frías, Cici Feliz-Feliz, Mònica Roldán, Jonathan Olival, Guerau Fernàndez, Francesc Palau, Jordi Pijuan and Janet Hoenicka
Int. J. Mol. Sci. 2025, 26(19), 9454; https://doi.org/10.3390/ijms26199454 - 27 Sep 2025
Viewed by 4191
Abstract
Despite significant advances in understanding the genetics of Parkinson’s disease (PD) and Parkinsonism, the diagnostic yield remains low. Pathogenic variants of GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase and causes recessive Gaucher dis-ease, are recognized as the most important genetic risk factor [...] Read more.
Despite significant advances in understanding the genetics of Parkinson’s disease (PD) and Parkinsonism, the diagnostic yield remains low. Pathogenic variants of GBA1, which encodes the lysosomal enzyme β-glucocerebrosidase and causes recessive Gaucher dis-ease, are recognized as the most important genetic risk factor for PD in heterozygous carriers. This study focuses on the functional genomics of rare genetic variations in other lysosomal hydrolytic enzymes genes in patient-derived fibroblasts. We examined 49 early-onset PD patients using whole exome sequencing and in silico panel analysis based on a curated PD gene list. Two patients were found to carry the p.Asp313Tyr variant in the X-linked GLA gene (encoding GALA, typically associated with Fabry disease), and one patient carried the p.Arg419Gln variant in GLB1 (encoding β-Gal, linked to the recessive GM1 gangliosidosis and mucopolysaccharidosis type IVB). The in silico study of both variants supports a potentially damaging impact on the encoded protein function and structural destabilization. Additional candidate variants were found related to lysosomes, Golgi apparatus and neurodegeneration, suggesting a multifactorial contribution to the disease. However, none of these variants met diagnostic standards. Functional assays showed a significant decrease in GALA expression and partial retention of the enzyme in the trans-Golgi network in fibroblasts with GLA:p.Asp313Tyr, while altered Golgi morphology was observed in fibroblasts with GLB1:p.Arg419Gln. Moreover, all patients exhibited abnormalities in lysosomal morphology, altered lysosomal pH, and impaired autophagic flux. Our findings suggest that rare, heterozygous variants in lysosomal-related genes, even when individually insufficient for monogenic disease, can converge to impair lysosomal homeostasis and autophagic flux in EOPD. The underlying genetic and cellular heterogeneity among patients emphasizes the importance of combining genetic and functional approaches to better understand the mechanisms behind the EOPD, which could enhance both diagnosis and future treatments. Full article
(This article belongs to the Special Issue Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders)
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19 pages, 967 KB  
Article
Real-World Laboratory Analysis of Molecular Biomarkers in Multiple Sclerosis Centers in Central-Eastern European Countries Covering 107 Million Inhabitants
by Anett Járdánházy, Thomas Berger, Harald Hegen, Bernhard Hemmer, Halina Bartosik-Psujek, Vanja Basic Kes, Achim Berthele, Jelena Drulovic, Mario Habek, Dana Horakova, Alenka Horvat Ledinek, Eva Kubala Havrdova, Melinda Magyari, Konrad Rejdak, Cristina Tiu, Peter Turcani, Krisztina Bencsik, Zsigmond Tamás Kincses and László Vécsei
Int. J. Mol. Sci. 2025, 26(17), 8274; https://doi.org/10.3390/ijms26178274 - 26 Aug 2025
Viewed by 2071
Abstract
A multicenter molecular biomarker survey was conducted in Multiple Sclerosis (MS) centers across Central-Eastern European countries, encompassing a population of 107 million. Our aim was to provide a “snapshot” for future studies investigating the use of molecular biomarkers in MS. A self-report questionnaire [...] Read more.
A multicenter molecular biomarker survey was conducted in Multiple Sclerosis (MS) centers across Central-Eastern European countries, encompassing a population of 107 million. Our aim was to provide a “snapshot” for future studies investigating the use of molecular biomarkers in MS. A self-report questionnaire was distributed via email to MS centers in seven Central-Eastern European countries (Croatia, Czech Republic, Poland, Romania, Serbia, Slovakia, and Slovenia) and to four reference centers (two in Austria, one in Germany, and one in Denmark), focusing on cerebrospinal fluid (CSF) analysis and molecular biomarkers in MS. Responding centers routinely request CSF oligoclonal band (OCB) testing in suspected MS cases, although no consensus exists on the number of CSF-restricted bands required to define OCB positivity, either within or between countries. More than half of the surveyed centers in the Czech Republic, Slovakia, Slovenia, and the reference centers request kappa free light chain (κFLC) testing in patients with suspected MS. Neurofilament light chain (NfL) is frequently used as a molecular biomarker for MS in Romania, Slovakia, and the reference centers. In summary, besides the use of CSF-specific OCB there is no consensus among the surveyed countries regarding the use of molecular biomarkers in MS. Full article
(This article belongs to the Special Issue Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders)
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Review

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31 pages, 2194 KB  
Review
Elucidating the Neurobiological Underpinnings of Mild Behavioral Impairment in Tauopathies: Clinical and Molecular Insights
by Efthalia Angelopoulou, John Papatriantafyllou, Sokratis Papageorgiou and Chiara Villa
Int. J. Mol. Sci. 2026, 27(7), 3341; https://doi.org/10.3390/ijms27073341 - 7 Apr 2026
Viewed by 776
Abstract
Mild behavioral impairment (MBI) is a clinical syndrome characterized by the late-life onset and persistence of neuropsychiatric symptoms (NPSs), representing a change from longstanding behavior or personality and considered a potential prodrome of neurodegenerative disease. MBI is classified into five domains: decreased motivation, [...] Read more.
Mild behavioral impairment (MBI) is a clinical syndrome characterized by the late-life onset and persistence of neuropsychiatric symptoms (NPSs), representing a change from longstanding behavior or personality and considered a potential prodrome of neurodegenerative disease. MBI is classified into five domains: decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and psychotic symptoms. In this narrative review, we synthesize clinical, neuroanatomical, and molecular evidence linking MBI to the spectrum of tauopathies, including Alzheimer’s disease (AD), frontotemporal spectrum disorders (FTSDs), and primary four-repeat tauopathies such as progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Emerging evidence suggests that early behavioral symptoms associated with MBI may reflect the selective vulnerability of frontolimbic, salience, default mode, and frontostriatal networks to tau-mediated neurodegeneration. Mechanistically, converging findings support roles for tau-related synaptic dysfunction, including synaptotoxic soluble tau species, cytoskeletal and axonal transport disruption, monoaminergic neurotransmitter imbalance in brainstem systems, and neuroinflammatory and glial pathways. We also highlight genotype-related behavioral profiles in genetic frontotemporal lobar degeneration and discuss how scalable blood-based biomarkers, including neurofilament light chain, glial fibrillary acidic protein, and plasma phospho-tau species, may complement MBI-based phenotyping for differential diagnosis and prognostic stratification in clinical research. Full article
(This article belongs to the Special Issue Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders)
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28 pages, 2043 KB  
Review
Phosphatase Signaling as a Therapeutic Strategy in Schizophrenia
by Lauren E. Molony and Lutz Tautz
Int. J. Mol. Sci. 2026, 27(6), 2822; https://doi.org/10.3390/ijms27062822 - 20 Mar 2026
Viewed by 517
Abstract
Cognitive impairment in schizophrenia remains insufficiently addressed by existing treatments. Current FDA-approved therapies primarily modulate neurotransmitter systems, resulting in incomplete symptom control and substantial adverse effects. There is therefore a critical need for therapeutic strategies that more directly address the intracellular signaling mechanisms [...] Read more.
Cognitive impairment in schizophrenia remains insufficiently addressed by existing treatments. Current FDA-approved therapies primarily modulate neurotransmitter systems, resulting in incomplete symptom control and substantial adverse effects. There is therefore a critical need for therapeutic strategies that more directly address the intracellular signaling mechanisms underlying synaptic dysfunction and cognitive deficits in schizophrenia. Protein phosphatases represent an essential but historically underexplored class of signaling enzymes that regulate phosphorylation-dependent control of synaptic receptor trafficking, plasticity, and neuronal circuit function. Although multiple phosphatases have been implicated in schizophrenia through genetic, post-mortem, and functional studies, their therapeutic targeting has been limited by challenges related to selectivity, cellular permeability, and pleiotropy. Here, we review the etiology of schizophrenia and limitations of current pharmacological approaches, synthesize evidence linking specific protein phosphatases to schizophrenia pathophysiology, and discuss emerging strategies, including allosteric modulation and targeted protein degradation, that may enable selective intervention in phosphatase-driven signaling pathways. We highlight the striatal-enriched tyrosine phosphatase STEP (PTPN5) as a case study illustrating how selective phosphatase modulation can restore synaptic signaling in schizophrenia-relevant models. Full article
(This article belongs to the Special Issue Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders)
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35 pages, 2527 KB  
Review
Extracellular Vesicle-Based Biomarkers in Spinal Cord Injury: A State-of-the-Art Review on Diagnostic and Prognostic Advances
by Trung Nhan Vo, Hae Eun Shin, Yeji Kim and Inbo Han
Int. J. Mol. Sci. 2026, 27(4), 2079; https://doi.org/10.3390/ijms27042079 - 23 Feb 2026
Cited by 1 | Viewed by 880
Abstract
Spinal cord injury (SCI) is a devastating neurological disorder that can result in permanent disability and reduced quality of life, characterized by heterogeneous injury mechanisms and limited tools for accurate early diagnosis and prognostic stratification. The clinical course of SCI is driven not [...] Read more.
Spinal cord injury (SCI) is a devastating neurological disorder that can result in permanent disability and reduced quality of life, characterized by heterogeneous injury mechanisms and limited tools for accurate early diagnosis and prognostic stratification. The clinical course of SCI is driven not only by the initial mechanical insult but also by complex secondary injury cascades involving neuroinflammation, axonal degeneration, demyelination, and maladaptive repair responses. Current diagnostic and prognostic approaches, which rely largely on neurological examination and imaging, provide limited insight into these dynamic molecular processes. In this context, extracellular vesicles (EVs) have emerged as a biologically compelling source of biomarkers for SCI. EVs are released by neurons, glial cells, endothelial cells, and immune cells and carry molecular cargo that reflects cellular stress, injury severity, and endogenous repair activity. Increasing evidence indicates that EV-associated proteins and regulatory microRNAs (miRNAs) encode injury-specific signatures related to neuronal and glial damage, inflammatory signaling, metabolic stress, and functional recovery potential. In this review, we summarize the current knowledge on EV biology in SCI and discuss emerging evidence supporting EV-derived proteins and miRNAs as promising tools for refining diagnosis and prognosis. Our aim is not only to consolidate established findings but also to highlight EV-based molecular signatures as a developing framework for precision biomarker discovery in SCI. Full article
(This article belongs to the Special Issue Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders)
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26 pages, 604 KB  
Review
Signaling Molecules and Diagnosis of Cognitive Disorders: Current State and Prospects
by Igor Kvetnoy, Oleg Kheyfets, Lazar Safaniev, Vladimir Kheifets, Ekaterina Mironova, Tatiana Kvetnaia, Gianluigi Mazzoccoli, Kiryl Prashchayeu and Anna Gavrilova
Int. J. Mol. Sci. 2026, 27(1), 372; https://doi.org/10.3390/ijms27010372 - 29 Dec 2025
Cited by 1 | Viewed by 672
Abstract
Cognitive disorders present significant medical and social challenges nowadays, due to their high prevalence, progressive course and a lack of effective methods for treatment of neurodegenerative diseases and comorbid pathologies. An important area of research is the identification of molecular biomarkers that reflect [...] Read more.
Cognitive disorders present significant medical and social challenges nowadays, due to their high prevalence, progressive course and a lack of effective methods for treatment of neurodegenerative diseases and comorbid pathologies. An important area of research is the identification of molecular biomarkers that reflect early pathophysiological changes and facilitate a more accurate biological characterization of cognitive impairment. This study provides an overview of the most relevant signaling molecules for diagnosing cognitive disorders. It presents data on the effectiveness of using comprehensive panels of molecular biomarkers in clinical practice, including β-amyloid, CD34, claudin, DRP1, endothelin-1, NF-kB, PINK1, RAGE, S100, α-synuclein, and tau protein, in patients with Alzheimer’s disease (AD) and vascular dementia (VD). The study results demonstrate that cumulative changes in the expression of signaling molecules reflect various neurodegenerative and vascular-associated biological processes. The data obtained are comparative in nature and require further validation before potential clinical application. Full article
(This article belongs to the Special Issue Molecular Advances in Biomarkers of Central Nervous System Diseases and Disorders)
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