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Advances in Biomarkers for Neurodegenerative Diseases

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A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 14819

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Special Issue Editor

Dr. Gessica Sala

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Guest Editor

Milan Center for Neuroscience (NeuroMI), University of Milano-Bicocca, Milan, Italy
Interests: study of pathogenic mechanisms (proteotoxicity, autophagy dysfunctions, oxidative stress, excitotoxicity) and discovery of biomarkers in neurodegenerative diseases using ex vivo peripheral cells from patients and in vitro disease models
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Due to the increasing aging population in most countries, the prevalence of neurodegenerative diseases is expected to rise dramatically, with important socio-economic impacts. Among the neurodegenerative diseases, Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the two most common pathologies leading patients to a progressively reduced quality of life and autonomy and then to disability. Although significant progress has been made recently, the identification of new biomarkers for neurodegenerative diseases represents a great need in order to anticipate the diagnosis, improve diagnostic accuracy, monitor drug efficacy in clinical trials, and develop effective disease-modifying and tailored therapies.

Hence, this Special Issue aims to collect the most recent advances in the identification of biomarkers for neurodegenerative disease, with a particular focus on AD, PD and amyotrophic lateral sclerosis (ALS). Contributions on new susceptibility/trait markers, diagnostic/state markers and progression markers for AD, PD, ALS and other neurodegenerative diseases are welcome. Original research articles focusing on either “wet” or “dry” biomarkers for neurodegenerative diseases, deriving from genetic, epidemiologic, biochemical, -omics, epigenetic, histologic, imaging, and other tech-based assessments, will be greatly appreciated, as well as review articles summarizing and discussing the currently available biomarkers for neurodegenerative diseases.

Dr. Gessica Sala
Guest Editor

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. Biomolecules is an international peer-reviewed open access monthly 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 2700 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

risk marker
prodromal marker
clinical marker
wet marker
dry marker
Alzheimer’s disease
Parkinson’s disease
amyotrophic lateral sclerosis
neurodegenerative diseases

Published Papers (11 papers)

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Research

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19 pages, 1538 KiB

Open AccessArticle

The Cerebrospinal Fluid Free-Glycans Hex₁ and HexNAc₁Hex₁Neu5Ac₁ as Potential Biomarkers of Alzheimer’s Disease

by Lynn Krüger, Karina Biskup, Carola G. Schipke, Bianca Kochnowsky, Luisa-Sophie Schneider, Oliver Peters and Véronique Blanchard

Biomolecules 2024, 14(5), 512; https://doi.org/10.3390/biom14050512 - 24 Apr 2024

Viewed by 461

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting a growing number of elderly people. In order to improve the early and differential diagnosis of AD, better biomarkers are needed. Glycosylation is a protein post-translational modification that is modulated in the course of many diseases, including neurodegeneration. Aiming to improve AD diagnosis and differential diagnosis through glycan analytics methods, we report the glycoprotein glycome of cerebrospinal fluid (CSF) isolated from a total study cohort of 262 subjects. The study cohort consisted of patients with AD, healthy controls and patients suffering from other types of dementia. CSF free-glycans were also isolated and analyzed in this study, and the results reported for the first time the presence of 19 free glycans in this body fluid. The free-glycans consisted of complete or truncated N-/O-glycans as well as free monosaccharides. The free-glycans Hex₁ and HexNAc₁Hex₁Neu5Ac₁ were able to discriminate AD from controls and from patients suffering from other types of dementia. Regarding CSF N-glycosylation, high proportions of high-mannose, biantennary bisecting core-fucosylated N-glycans were found, whereby only about 20% of the N-glycans were sialylated. O-Glycans and free-glycan fragments were less sialylated in AD patients than in controls. To conclude, this comprehensive study revealed for the first time the biomarker potential of free glycans for the differential diagnosis of AD. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

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10 pages, 1803 KiB

Open AccessArticle

Elevated Serum Xanthine Oxidase and Its Correlation with Antioxidant Status in Patients with Parkinson’s Disease

by Ratna Dini Haryuni, Takamasa Nukui, Jin-Lan Piao, Takashi Shirakura, Chieko Matsui, Tomoyuki Sugimoto, Kousuke Baba, Shunya Nakane and Yuji Nakatsuji

Biomolecules 2024, 14(4), 490; https://doi.org/10.3390/biom14040490 - 18 Apr 2024

Viewed by 473

Abstract

Parkinson’s disease (PD) is a neurodegenerative movement disorder associated with a loss of dopamine neurons in the substantia nigra. The diagnosis of PD is sensitive since it shows clinical features that are common with other neurodegenerative diseases. In addition, most symptoms arise at the late stage of the disease, where most dopaminergic neurons are already damaged. Several studies reported that oxidative stress is a key modulator in the development of PD. This condition occurs due to excess reactive oxygen species (ROS) production in the cellular system and the incapability of antioxidants to neutralize it. In this study, we focused on the pathology of PD by measuring serum xanthine oxidase (XO) activity, which is an enzyme that generates ROS. Interestingly, the serum XO activity of patients with PD was markedly upregulated compared to patients with other neurological diseases (ONDs) as a control. Moreover, serum XO activity in patients with PD showed a significant correlation with the disease severity based on the Hoehn and Yahr (HY) stages. The investigation of antioxidant status also revealed that serum uric acid levels were significantly lower in the severe group (HY ≥ 3) than in the ONDs group. Together, these results suggest that XO activity may contribute to the development of PD and might potentially be a biomarker for determining disease severity in patients with PD. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

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13 pages, 3299 KiB

Open AccessArticle

Sporadic Amyotrophic Lateral Sclerosis Skeletal Muscle Transcriptome Analysis: A Comprehensive Examination of Differentially Expressed Genes

by Elisa Gascón, Pilar Zaragoza, Ana Cristina Calvo and Rosario Osta

Biomolecules 2024, 14(3), 377; https://doi.org/10.3390/biom14030377 - 20 Mar 2024

Viewed by 1215

Abstract

Amyotrophic lateral sclerosis (ALS) that comprises sporadic (sALS) and familial (fALS) cases, is a devastating neurodegenerative disorder characterized by progressive degeneration of motor neurons, leading to muscle atrophy and various clinical manifestations. However, the complex underlying mechanisms affecting this disease are not yet known. On the other hand, there is also no good prognosis of the disease due to the lack of biomarkers and therapeutic targets. Therefore, in this study, by means of bioinformatics analysis, sALS-affected muscle tissue was analyzed using the GEO GSE41414 dataset, identifying 397 differentially expressed genes (DEGs). Functional analysis revealed 320 up-regulated DEGs associated with muscle development and 77 down-regulated DEGs linked to energy metabolism. Protein–protein interaction network analysis identified 20 hub genes, including EIF4A1, HNRNPR and NDUFA4. Furthermore, miRNA target gene networks revealed 17 miRNAs linked to hub genes, with hsa-mir-206, hsa-mir-133b and hsa-mir-100-5p having been previously implicated in ALS. This study presents new potential biomarkers and therapeutic targets for ALS by correlating the information obtained with a comprehensive literature review, providing new potential targets to study their role in ALS. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

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18 pages, 3071 KiB

Open AccessArticle

Exploring SVA Insertion Polymorphisms in Shaping Differential Gene Expressions in the Central Nervous System

by Lauren S. Hughes, Alexander Fröhlich, Abigail L. Pfaff, Vivien J. Bubb, John P. Quinn and Sulev Kõks

Biomolecules 2024, 14(3), 358; https://doi.org/10.3390/biom14030358 - 17 Mar 2024

Viewed by 1102

Abstract

Transposable elements (TEs) are repetitive elements which make up around 45% of the human genome. A class of TEs, known as SINE-VNTR-Alu (SVA), demonstrate the capacity to mobilise throughout the genome, resulting in SVA polymorphisms for their presence or absence within the population. Although studies have previously highlighted the involvement of TEs within neurodegenerative diseases, such as Parkinson’s disease and amyotrophic lateral sclerosis (ALS), the exact mechanism has yet to be identified. In this study, we used whole-genome sequencing and RNA sequencing data of ALS patients and healthy controls from the New York Genome Centre ALS Consortium to elucidate the influence of reference SVA elements on gene expressions genome-wide within central nervous system (CNS) tissues. To investigate this, we applied a matrix expression quantitative trait loci analysis and demonstrate that reference SVA insertion polymorphisms can significantly modulate the expression of numerous genes, preferentially in the trans position and in a tissue-specific manner. We also highlight that SVAs significantly regulate mitochondrial genes as well as genes within the HLA and MAPT loci, previously associated within neurodegenerative diseases. In conclusion, this study continues to bring to light the effects of polymorphic SVAs on gene regulation and further highlights the importance of TEs within disease pathology. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

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12 pages, 1794 KiB

Open AccessArticle

Olfactory Dysfunction Is Associated with Cerebral Amyloid Deposition and Cognitive Function in the Trajectory of Alzheimer’s Disease

by Sheng-Min Wang, Dong Woo Kang, Yoo Hyun Um, Sunghwan Kim, Chang Uk Lee and Hyun Kook Lim

Biomolecules 2023, 13(9), 1336; https://doi.org/10.3390/biom13091336 - 31 Aug 2023

Cited by 2 | Viewed by 894

Abstract

Olfactory dysfunction is consistently observed in individuals with Alzheimer’s disease (AD), but its association with beta-amyloid (Aβ) deposition remains unclear. This study aimed to investigate the relationship among olfactory function, cerebral Aβ deposition, and neuropsychological profiles in individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI), and AD dementia. A total of 164 participants were included, and olfactory function was assessed using the brief smell identification test (B-SIT). Cerebral Aβ deposition was measured using [¹⁸F]-flutemetamol PET imaging (A-PET). The results show a significant group difference in olfactory function, with the highest impairment observed in the Aβ-positive MCI and AD dementia groups, and the impairment was the lowest in Aβ-negative NCI. Olfactory dysfunction was positively associated with cognitive impairments across multiple domains. Furthermore, individuals with Aβ deposition had lower olfactory function compared to those without Aβ, even within the same neuropsychological stage. The association between olfactory dysfunction and Aβ deposition was observed globally and in specific cortical regions. These findings suggest that olfactory dysfunction is associated with both cognitive function and cerebral Aβ pathology in the trajectory of AD. Olfactory deficits may serve as an additional marker for disease progression and contribute to understanding the underlying mechanisms of AD. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

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16 pages, 3849 KiB

Open AccessArticle

Metformin Prevents NDEA-Induced Memory Impairments Associated with Attenuating Beta-Amyloid, Tumor Necrosis Factor-Alpha, and Interleukin-6 Levels in the Hippocampus of Rats

by Teresa Ponce-Lopez, José Antonio González Álvarez Tostado, Fernando Dias and Keren Happuck Montiel Maltez

Biomolecules 2023, 13(9), 1289; https://doi.org/10.3390/biom13091289 - 24 Aug 2023

Cited by 1 | Viewed by 1424

Abstract

N-nitrosodiethylamine (NDEA) is a potential carcinogen known to cause liver tumors and chronic inflammation, diabetes, cognitive problems, and signs like Alzheimer’s disease (AD) in animals. This compound is classified as probably carcinogenic to humans. Usual sources of exposure include food, beer, tobacco, personal care products, water, and medications. AD is characterized by cognitive decline, amyloid-β (Aβ) deposit, tau hyperphosphorylation, and cell loss. This is accompanied by neuroinflammation, which involves release of microglial cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin 1β (IL-1β), by nuclear factor kappa B (NF-κB) upregulation; each are linked to AD progression. Weak PI3K/Akt insulin-signaling inhibits IRS-1 phosphorylation, activates GSK3β and promotes tau hyperphosphorylation. Metformin, an antihyperglycemic agent, has potent anti-inflammatory efficacy. It reduces proinflammatory cytokines such as IL-6, IL-1β, and TNF-α via NF-κB inhibition. Metformin also reduces reactive oxidative species (ROS) and modulates cognitive disorders reported due to brain insulin resistance links. Our study examined how NDEA affects spatial memory in Wistar rats. We found that all NDEA doses tested impaired memory. The 80 µg/kg dose of NDEA increased levels of Aβ1-42, TNF-α, and IL-6 in the hippocampus, which correlated with memory loss. Nonetheless, treatment with 100 mg/kg of metformin attenuated the levels of pro-inflammatory cytokines and Aβ1-42, and enhanced memory. It suggests that metformin may protect against NDEA-triggered memory issues and brain inflammation. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

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10 pages, 1142 KiB

Open AccessCommunication

Serum and Exosomal miR-7-1-5p and miR-223-3p as Possible Biomarkers for Parkinson’s Disease

by Lorenzo Agostino Citterio, Roberta Mancuso, Simone Agostini, Mario Meloni and Mario Clerici

Biomolecules 2023, 13(5), 865; https://doi.org/10.3390/biom13050865 - 19 May 2023

Cited by 5 | Viewed by 1760

Abstract

The etiology of Parkinson’s disease (PD) is poorly understood, and is strongly suspected to include both genetic and environmental factors. In this context, it is essential to investigate possible biomarkers for both prognostic and diagnostic purposes. Several studies reported dysregulated microRNA expression in neurodegenerative disorders, including PD. Using ddPCR, we investigated the concentrations of miR-7-1-5p, miR-499-3p, miR-223-3p and miR-223-5p—miRNAs involved in the α-synuclein pathway and in inflammation—in the serum and serum-isolated exosomes of 45 PD patients and 49 age- and sex-matched healthy controls (HC). While miR-499-3p and miR-223-5p showed no differences (1), serum concentration of miR-7-1-5p was significantly increased (p = 0.0007 vs. HC) and (2) miR-223-3p serum (p = 0.0006) and exosome (p = 0.0002) concentrations were significantly increased. ROC curve analysis showed that miR-223-3p and miR-7-1-5p serum concentration discriminates between PD and HC (p = 0.0001, in both cases). Notably, in PD patients, both miR-223-3p serum (p = 0.0008) and exosome (p = 0.006) concentrations correlated with levodopa equivalent daily dosage (LEDD). Finally, serum α-synuclein was increased in PD patients compared to HC (p = 0.025), and in patients correlated with serum miR-7-1-5p in (p = 0.05). Our results suggest that both miR-7-1-5p and miR-223-3p, distinguishing PD from HC, have the potential to be useful and non-invasive biomarkers in Parkinson’s disease. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

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Review

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21 pages, 1696 KiB

Open AccessReview

Biomarkers for Managing Neurodegenerative Diseases

by Lara Cheslow, Adam E. Snook and Scott A. Waldman

Biomolecules 2024, 14(4), 398; https://doi.org/10.3390/biom14040398 - 26 Mar 2024

Viewed by 705

Abstract

Neurological disorders are the leading cause of cognitive and physical disability worldwide, affecting 15% of the global population. Due to the demographics of aging, the prevalence of neurological disorders, including neurodegenerative diseases, will double over the next two decades. Unfortunately, while available therapies provide symptomatic relief for cognitive and motor impairment, there is an urgent unmet need to develop disease-modifying therapies that slow the rate of pathological progression. In that context, biomarkers could identify at-risk and prodromal patients, monitor disease progression, track responses to therapy, and parse the causality of molecular events to identify novel targets for further clinical investigation. Thus, identifying biomarkers that discriminate between diseases and reflect specific stages of pathology would catalyze the discovery and development of therapeutic targets. This review will describe the prevalence, known mechanisms, ongoing or recently concluded therapeutic clinical trials, and biomarkers of three of the most prevalent neurodegenerative diseases, including Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease (PD). Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

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18 pages, 365 KiB

Open AccessReview

Blood Biomarkers of Alzheimer’s Disease and Cognition: A Literature Review

by Greta Garcia-Escobar, Rosa Maria Manero, Aida Fernández-Lebrero, Angel Ois, Irene Navalpotro-Gómez, Victor Puente-Periz, José Contador-Muñana, Isabel Estragués-Gazquez, Albert Puig-Pijoan and Joan Jiménez-Balado

Biomolecules 2024, 14(1), 93; https://doi.org/10.3390/biom14010093 - 11 Jan 2024

Viewed by 1733

Abstract

Recent advances in blood-based biomarkers of Alzheimer’s Disease (AD) show great promise for clinical applications, offering a less invasive alternative to current cerebrospinal fluid (CSF) measures. However, the relationships between these biomarkers and specific cognitive functions, as well as their utility in predicting longitudinal cognitive decline, are not yet fully understood. This descriptive review surveys the literature from 2018 to 2023, focusing on the associations of amyloid-β (Aβ), Total Tau (t-Tau), Phosphorylated Tau (p-Tau), Neurofilament Light (NfL), and Glial Fibrillary Acidic Protein (GFAP) with cognitive measures. The reviewed studies are heterogeneous, varying in design and population (cognitively unimpaired, cognitively impaired, or mixed populations), and show results that are sometimes conflicting. Generally, cognition positively correlates with Aβ levels, especially when evaluated through the Aβ₄₂/Aβ₄₀ ratio. In contrast, t-Tau, p-Tau, Nfl, and GFAP levels typically show a negative correlation with cognitive performance. While p-Tau measures generally exhibit stronger associations with cognitive functions compared to other biomarkers, no single blood marker has emerged as being predominantly linked to a specific cognitive domain. These findings contribute to our understanding of the complex relationship between blood biomarkers and cognitive performance and underscore their potential utility in clinical assessments of cognition. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

40 pages, 7475 KiB

Open AccessReview

Advancements in Genetic and Biochemical Insights: Unraveling the Etiopathogenesis of Neurodegeneration in Parkinson’s Disease

by Yashumati Ratan, Aishwarya Rajput, Ashutosh Pareek, Aaushi Pareek, Vivek Jain, Sonia Sonia, Zeba Farooqui, Ranjeet Kaur and Gurjit Singh

Biomolecules 2024, 14(1), 73; https://doi.org/10.3390/biom14010073 - 05 Jan 2024

Cited by 1 | Viewed by 1777

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative movement disorder worldwide, which is primarily characterized by motor impairments. Even though multiple hypotheses have been proposed over the decades that explain the pathogenesis of PD, presently, there are no cures or promising preventive therapies for PD. This could be attributed to the intricate pathophysiology of PD and the poorly understood molecular mechanism. To address these challenges comprehensively, a thorough disease model is imperative for a nuanced understanding of PD’s underlying pathogenic mechanisms. This review offers a detailed analysis of the current state of knowledge regarding the molecular mechanisms underlying the pathogenesis of PD, with a particular emphasis on the roles played by gene-based factors in the disease’s development and progression. This study includes an extensive discussion of the proteins and mutations of primary genes that are linked to PD, including α-synuclein, GBA1, LRRK2, VPS35, PINK1, DJ-1, and Parkin. Further, this review explores plausible mechanisms for DAergic neural loss, non-motor and non-dopaminergic pathologies, and the risk factors associated with PD. The present study will encourage the related research fields to understand better and analyze the current status of the biochemical mechanisms of PD, which might contribute to the design and development of efficacious and safe treatment strategies for PD in future endeavors. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

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19 pages, 2058 KiB

Open AccessReview

Role of Sirtuin 3 in Degenerative Diseases of the Central Nervous System

by Haofuzi Zhang, Shuhui Dai, Yuefan Yang, Jialiang Wei, Xin Li, Peng Luo and Xiaofan Jiang

Biomolecules 2023, 13(5), 735; https://doi.org/10.3390/biom13050735 - 24 Apr 2023

Cited by 7 | Viewed by 2038

Abstract

An NAD⁺-dependent deacetylase called Sirtuin 3 (Sirt3) is involved in the metabolic processes of the mitochondria, including energy generation, the tricarboxylic acid cycle, and oxidative stress. Sirt3 activation can slow down or prevent mitochondrial dysfunction in response to neurodegenerative disorders, demonstrating a strong neuroprotective impact. The mechanism of Sirt3 in neurodegenerative illnesses has been elucidated over time; it is essential for neuron, astrocyte, and microglial function, and its primary regulatory factors include antiapoptosis, oxidative stress, and the maintenance of metabolic homeostasis. Neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS), may benefit from a thorough and in-depth investigation of Sirt3. In this review, we primarily cover Sirt3’s role and its regulation in the nerve cells and the connection between Sirt3 and neurodegenerative disorders. Full article

(This article belongs to the Special Issue Advances in Biomarkers for Neurodegenerative Diseases)

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