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Biomarkers and Diagnostics in Neurological Diseases

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Clinical Neurology".

Deadline for manuscript submissions: 25 March 2026 | Viewed by 9379

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Dr. Maria Ioanna Stefanou

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Second Department of Neurology, "Attikon" University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
Interests: transcranial magnetic stimulation; neurophysiology; stroke; COVID-19; neuroimmunology

Special Issue Information

Dear Colleagues,

Over the past decade, significant progress has been achieved in implementing novel biomarkers for diagnosing neurological diseases. Technological advancements have expedited the transition of biomarkers from bench to bedside, enabling their integration into diagnostic and therapeutic algorithms for diverse neurological conditions, including cerebrovascular, neurodegenerative, and neuroimmunological disorders.

This Special Issue highlights current research and fosters discussions on the evolving role of biomarkers in neurological diseases. Biomarkers are currently indispensable tools for neurologists, contributing to differential diagnosis, prognostic assessment, and treatment monitoring. Their sensitivity, specificity, and clinical validity remain critical areas of investigation.

Topics of interest include diagnostic biomarkers across neuroimaging, neurophysiology, serology, and cerebrospinal fluid (CSF) domains. Examples encompass the following:

(i) Established serum and CSF biomarkers, such as Aβ and tau peptides, facilitating early Alzheimer’s disease diagnosis;
(ii) Emerging biomarkers for differential diagnosis and treatment monitoring in neurodegenerative (e.g., amyotrophic lateral sclerosis) and neuroimmunological disorders (e.g., multiple sclerosis);
(iii) Lipoprotein(a) as a cerebrovascular biomarker for intracranial and extracranial atherosclerosis;
(iv) Inflammatory cytokines, Schwann cell‐specific proteins, and microRNAs for peripheral neuropathies;
(v) Neuroimaging biomarkers, including amyloid PET, tau PET, and advanced modalities like spectroscopy;
(vi) Translational neurophysiological biomarkers, such as transcranial magnetic stimulation (TMS)-evoked potentials for consciousness disorders;
(vii) Artificial intelligence (AI) applications for identifying reliable neurological biomarkers.

This Special Issue aims to advance understanding and clarify the clinical utility of biomarkers in neurology.

Dr. Maria Ioanna Stefanou
Guest Editor

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Keywords

biomarkers
neurological diseases
diagnosis
lipoprotein(a)
neurofilament protein
tau peptide
neuroimaging

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Published Papers (6 papers)

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Research

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12 pages, 3141 KB

Open AccessArticle

Evolution of Retinal Morphology Changes in Amyotrophic Lateral Sclerosis

by Valeria Koska, Stefanie Teufel, Aykut Aytulun, Margit Weise, Marius Ringelstein, Rainer Guthoff, Sven G. Meuth and Philipp Albrecht

J. Clin. Med. 2026, 15(1), 258; https://doi.org/10.3390/jcm15010258 (registering DOI) - 29 Dec 2025

Abstract

Background/Objectives: To compare changes in the thickness of retinal layers between patients with amyotrophic lateral sclerosis (ALS) and healthy controls using optical coherence tomography. Amyotrophic lateral sclerosis is a degenerative disease of the upper and lower motoneurons with a rapidly progressive course, but non-motor symptoms such as decreased ocular motility and reduced visual acuity have also been reported. Specific biomarkers or surrogate parameters assessing neurodegeneration in ALS are of interest. Methods: In a retrospective, longitudinal study using optic coherence tomography of the retinal layers, we compared changes in the thickness of the layers between patients with ALS and healthy controls. Correlations to clinical scores, such as the modified ranking scale, were analyzed. Results: In our cohort of patients with early ALS (disease duration 5.15 ± 21.4 months at baseline), we neither observed differences in retinal layer thickness at baseline nor did the thickness changes in any retinal layer differ in comparison to healthy controls at baseline. Moreover, we observed no significant thickness changes over the course of the observational period in our patients with ALS. However, a correlation analysis revealed a negative association of the thickness change rates in the complex of ganglion cell and inner plexiform layer and the inner nuclear layer with a higher modified Rankin scale at follow-up. Conclusions: This study adds to the notion that OCT may not be a suitable tool to monitor atrophy and disease progression in ALS. However, further longitudinal studies with longer follow-up times and larger cohorts are warranted. Full article

(This article belongs to the Special Issue Biomarkers and Diagnostics in Neurological Diseases)

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11 pages, 222 KB

Open AccessArticle

Clinical Features, Antibody Profiles, and Prognostic Factors in Autoimmune Encephalitis: A Single-Center Study

by Bedriye Karaman, Gülcan Neşem Baskan, Merve Yavuz, Ayşe Güler, Özgül Ekmekci, Nur Yüceyar and Rasim Tunçel

J. Clin. Med. 2025, 14(19), 6806; https://doi.org/10.3390/jcm14196806 - 26 Sep 2025

Viewed by 1253

Abstract

Background/Objectives: Autoimmune encephalitis (AIE) comprises a heterogeneous group of inflammatory central nervous system (CNS) disorders characterized by variable clinical presentations and antibody profiles. This study aimed to identify poor prognostic factors in AIE by retrospectively evaluating patients diagnosed based on clinical, radiological, and serological findings. Methods: Forty-four patients diagnosed with AIE between 2014 and 2024 were included. Demographic, clinical, radiological, and serological data were collected retrospectively. Patients were grouped based on antibody localization (intracellular, surface, and seronegative) and classified by treatment response. Poor prognosis was defined as a lack of objective clinical improvement to treatment or death. Results: The mean age was 57.8 ± 13.6 years, with a female-to-male ratio of approximately 1:1. Limbic encephalitis (LE) was the most common clinical presentation (43.2%). Malignancy was detected in 33.3% of patients, most frequently in those with SOX1 (83.3%), anti-Hu (60.0%), and anti-Yo (50.0%) antibodies. Anti-SOX1 positivity was significantly associated with both malignancy (OR = 27.5, p = 0.007) and mortality (OR = 13.2, p = 0.009), while anti-LGI1 positivity correlated with the absence of malignancy (p = 0.036). Patients with LE showed significantly better treatment responses (OR = 14.0, p = 0.019). Mortality was 20.1% overall and highest among anti-SOX1-positive patients (66.7%). The presence of multiple antibodies was associated with higher mortality and poorer prognosis, although not statistically significantly. Conclusions: Anti-SOX1 positivity is a key indicator of poor prognosis in AIE and is strongly associated with both malignancy and mortality. In contrast, LE presentation was linked to a better treatment response. Antibody profile, clinical features, and malignancy screening are critical for risk stratification and guiding management in AIE. Full article

(This article belongs to the Special Issue Biomarkers and Diagnostics in Neurological Diseases)

18 pages, 4022 KB

Open AccessArticle

Glymphopathy and Reduced Processing Speed in Community-Dwelling Adults with Silent Cerebral Small Vessel Disease: A DTI-ALPS Study

by Zaw Myo Hein, Muhammad Faqhrul Fahmy Arbain, Muhammad Danial Che Ramli, Usman Jaffer and Che Mohd Nasril Che Mohd Nassir

J. Clin. Med. 2025, 14(17), 6039; https://doi.org/10.3390/jcm14176039 - 26 Aug 2025

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Abstract

Background/Objectives: Cerebral small vessel disease (CSVD) often manifests as enlarged perivascular spaces (ePVS), which are linked to reduced processing speed even in asymptomatic individuals. Glymphatic dysfunction (or glymphopathy) has been proposed as a mechanism underlying ePVS, with the diffusion tensor image analysis along the perivascular space (DTI-ALPS) index serving as a potential non-invasive surrogate marker. This study aimed to examine the association between DTI-ALPS index, ePVS burden, and processing speed in community-dwelling adults without overt neurological symptoms, stratified by QRISK3 cardio-cerebrovascular risk prediction score. Methods: Sixty young-to-middle-aged adults (aged 25–65 years), classified as low-to-moderate QRISK3 scores, underwent brain 3T diffusion magnetic resonance imaging (MRI) to evaluate ePVS burden and calculate DTI-ALPS indices. Processing speed index (PSI) was assessed using the Wechsler Adult Intelligence Scale—Version IV (WAIS-IV). Results: Approximately 43% of subjects reported having ePVS with significantly lower DTI-ALPS indices and PSI compared to those without ePVS. The DTI-ALPS index was inversely correlated with ePVS burden and positively correlated with PSI. Mediation analysis showed that the lower DTI-ALPS partially mediated the association between ePVS burden and slower processing speed. Conclusions: Visible ePVS in our cohort may reflect early glymphopathy and subtle cognitive slowing, while the DTI-ALPS index may serve as an early biomarker for preclinical CSVD-related cognitive vulnerability, supporting targeted prevention strategies. Full article

(This article belongs to the Special Issue Biomarkers and Diagnostics in Neurological Diseases)

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Review

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25 pages, 671 KB

Open AccessReview

Serum Biomarkers in Acute Ischemic Stroke: Clinical Applications and Emerging Insights

by Anthi Tsogka, John Ellul, Elisabeth Chroni, Apostolos Safouris, Klearchos Psychogios, Dimitra Veltsista and Odysseas Kargiotis

J. Clin. Med. 2025, 14(21), 7748; https://doi.org/10.3390/jcm14217748 - 31 Oct 2025

Viewed by 1256

Abstract

Acute ischemic stroke (AIS) remains a major cause of long-term disability and death worldwide, posing significant challenges to healthcare systems. Timely diagnosis is crucial, as acute phase therapeutic options are highly time-sensitive and most effective when administered early in the disease course. In this context, serum biomarkers have emerged as a promising and complementary tool to aid in the rapid and accurate diagnosis, prognosis, and therapeutic monitoring of AIS. This narrative review aims to provide a comprehensive overview of the current landscape of serum biomarkers relevant to AIS. These biomarkers are categorized based on the underlying pathophysiological mechanisms they reflect, including markers of inflammation and oxidative stress, neuronal and endothelial injury, and those related to hemostasis and fibrinolysis. Their biological significance is evaluated through the spectrum of their diagnostic sensitivity and specificity and their potential integration into clinical practice. In addition, many of these biomarkers offer prognostic insights, helping to predict the likelihood of complications, recurrent stroke, or poor functional recovery. Furthermore, their role as a potential tool for the differential diagnosis of patients presenting with minor or nonspecific neurological symptoms and therapeutic monitoring is emphasized. Despite the promising potential of these biomarkers, their translation into routine clinical use remains limited. Full article

(This article belongs to the Special Issue Biomarkers and Diagnostics in Neurological Diseases)

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22 pages, 1486 KB

Open AccessReview

Lipoprotein(a) as a Stroke Biomarker: Pathophysiological Pathways and Therapeutic Implications

by Evangelos Panagiotopoulos, Lina Palaiodimou, Aikaterini Theodorou, Georgia Papagiannopoulou, Eleni Bakola, Maria Chondrogianni, Klearchos Psychogios, Odysseas Kargiotis, Apostolos Safouris, Charalambos Vlachopoulos, Sotirios Giannopoulos, Marios Themistocleous, Vaia Lambadiari, Georgios Tsivgoulis and Maria-Ioanna Stefanou

J. Clin. Med. 2025, 14(9), 2990; https://doi.org/10.3390/jcm14092990 - 25 Apr 2025

Cited by 9 | Viewed by 3301

Abstract

Lipoprotein(a) [Lp(a)] has attracted widespread interest as a potential biomarker for cerebrovascular diseases due to its genetically determined and stable plasma concentration throughout life. Lp(a) exhibits pro-atherogenic and pro-thrombotic properties that contribute to vascular pathology in both extracranial and intracranial vessels. Elevated Lp(a) levels are strongly associated with large-artery atherosclerotic stroke, while data on its role in other ischemic subtypes and hemorrhagic stroke remains limited and inconsistent. Recent advances in Lp(a)-lowering therapies, such as antisense oligonucleotides and RNA-based agents, have demonstrated significant efficacy in reducing plasma Lp(a) levels. These advances have prompted increasing research into their potential application in the prevention and treatment of cerebrovascular diseases, aiming to determine whether Lp(a) reduction may translate into a reduced risk of stroke and large-artery atherosclerosis. This narrative review summarizes the current evidence on the association between Lp(a) and stroke, focusing on its utility in patient risk stratification. It also highlights existing knowledge gaps and outlines directions for future research, particularly in understanding subtype-specific effects and evaluating the clinical benefits of Lp(a)-targeted therapies. Full article

(This article belongs to the Special Issue Biomarkers and Diagnostics in Neurological Diseases)

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Other

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16 pages, 2545 KB

Open AccessSystematic Review

Cognitive Impairment in Newly Diagnosed Patients with Multiple Sclerosis: A Systematic Review of Related Molecular Biomarkers and a Meta-Analysis of Associated Demographic and Disease-Related Characteristics

by Konstantina Stavrogianni, Vasileios Giannopapas, Dimitrios K. Kitsos, Niki Christouli, Vassiliki Smyrni, Athanasios K. Chasiotis, Alexandra Akrivaki, Evangelia-Makrina Dimitriadou, John S. Tzartos, Georgios Tsivgoulis, George P. Paraskevas, Dimitrios Peschos, Konstantinos I. Tsamis and Sotirios Giannopoulos

J. Clin. Med. 2025, 14(8), 2630; https://doi.org/10.3390/jcm14082630 - 11 Apr 2025

Cited by 2 | Viewed by 1816

Abstract

Background/Objectives: Neuropsychological impairment (NI) is common in newly diagnosed patients with multiple sclerosis (pwMS). This study has two main objectives; the systematic review aims to describe the relationship between NI and molecular biomarkers in newly diagnosed pwMS, and the meta-analysis aims to explore the relationship between NI, age, disability status, and disease duration in this patient group. Methods: We conducted a systematic review, with 20 studies meeting the inclusion criteria. Out of these, 12 studies were included in the meta-analysis. We analyzed three key cognitive measures—the Symbol Digit Modalities Test (SDMT), the Paced Auditory Serial Addition Test (PASAT), and the Selective Reminding Test–long-term storage (SRT-LTS)—in relation to demographic and MS-related characteristics. Results: Neurofilament light chain (NfL) levels were consistently associated with NI, especially a slower information processing speed (IPS). Other biomarkers, including chitinase 3-like 1 (CHI3L1), brain-derived neurotrophic factor (BDNF), apolipoprotein E4 allele (APOE4), and vitamin D, also showed promising correlations with NI. A meta-regression analysis of 2380 pwMS indicated a negative association between SDMT score and disability status (p = 0.01). No significant associations were found for the PASAT with age, disability status, or disease duration (p > 0.05). Conclusions: These findings highlight the role of NfL as a biomarker related to NI in newly diagnosed pwMS and the association between IPS and disability status. Further research is needed with more homogeneous samples in terms of the disease duration, along with standardized cognitive assessments and a broader range of biomarkers, to improve our understanding and management of cognitive difficulties in the early stages of MS. Full article

(This article belongs to the Special Issue Biomarkers and Diagnostics in Neurological Diseases)

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