International Journal of Molecular Sciences

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12 pages, 1241 KiB

Open AccessArticle

GATA3 as a Blood-Based RNA Biomarker for Idiopathic Parkinson’s Disease

by Shubhra Acharya, Andrew I. Lumley, Lu Zhang, Mélanie Vausort, Yvan Devaux and on behalf of the NCER-PD Consortium

Int. J. Mol. Sci. 2023, 24(12), 10040; https://doi.org/10.3390/ijms241210040 - 12 Jun 2023

Cited by 3 | Viewed by 1703

Abstract

Finding novel biomarkers for Parkinson’s disease (PD) is crucial for early disease diagnosis, severity assessment and identifying novel disease-modifying drug targets. Our study aimed at investigating the GATA3 mRNA levels in whole blood samples of idiopathic PD (iPD) patients with different disease severities [...] Read more.

Finding novel biomarkers for Parkinson’s disease (PD) is crucial for early disease diagnosis, severity assessment and identifying novel disease-modifying drug targets. Our study aimed at investigating the GATA3 mRNA levels in whole blood samples of idiopathic PD (iPD) patients with different disease severities as a biomarker for iPD. The present study is a cross-sectional, case-control study, with samples obtained from the Luxembourg Parkinson’s cohort (LuxPARK). iPD (N = 319) patients, along with age-matched controls without PD (non-PD; N = 319) were included in this study. Blood GATA3 mRNA expression was measured using quantitative reverse transcription PCR (RT-qPCR) assays. The capacity of GATA3 expression levels to establish the diagnosis of iPD (primary end-point) and assess disease severity (secondary end-point) was determined. The blood levels of GATA3 were significantly lower in iPD patients, compared to non-PD controls (p ≤ 0.001). Logistic regression models showed a significant association of GATA3 expression with iPD diagnosis after adjustment for the confounders (p = 0.005). Moreover, the addition of GATA3 expression to a baseline clinical model improved its iPD diagnosis capacity (p = 0.005). There was a significant association of GATA3 expression levels with the overall disease severity (p = 0.002), non-motor experiences of daily living (nm-EDL; p = 0.003) and sleep disturbances (p = 0.01). Our results suggest that GATA3 expression measured in blood may serve as a novel biomarker and may help in the diagnosis of iPD and assessment of disease severity. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 3.0)

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13 pages, 301 KiB

Open AccessArticle

Developing Biomarkers for the Skin: Biomarkers for the Diagnosis and Prediction of Treatment Outcomes of Alzheimer’s Disease

by Ching-Ying Wu, Chih-Yi Ho and Yuan-Han Yang

Int. J. Mol. Sci. 2023, 24(10), 8478; https://doi.org/10.3390/ijms24108478 - 9 May 2023

Cited by 6 | Viewed by 2167

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory decline and cognitive impairment. Research on biomarkers can aid in early diagnosis, monitoring disease progression, evaluating treatment efficacy, and advancing fundamental research. We conducted a cross-sectional longitudinal study to see if there is [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory decline and cognitive impairment. Research on biomarkers can aid in early diagnosis, monitoring disease progression, evaluating treatment efficacy, and advancing fundamental research. We conducted a cross-sectional longitudinal study to see if there is an association between AD patients and age-matched healthy controls for their physiologic skin characteristics, such as pH, hydration, transepidermal water loss (TEWL), elasticity, microcirculation, and ApoE genotyping. The study used the Mini-Mental State Examination (MMSE) and Clinical Dementia Rating-Sum of the Boxes (CDR-SB) scales as references to quantify the presence of disease, if any. Our findings demonstrate that AD patients have a dominantly neutral pH, greater skin hydration, and less elasticity compared to the control subjects. At baseline, the tortuous capillary percentage negatively correlated with MMSE scores in AD patients. However, AD patients who carry the ApoE E4 allele and exhibit a high percentage of tortuous capillaries and capillary tortuous numbers have shown better treatment outcomes at six months. Therefore, we believe that physiologic skin testing is a rapid and effective way to screen, monitor progression, and ultimately guide the most appropriate treatment for AD patients. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 3.0)

17 pages, 3468 KiB

Open AccessArticle

Blood-Based Proteomic Profiling Identifies Potential Biomarker Candidates and Pathogenic Pathways in Dementia

by Hanan Ehtewish, Areej Mesleh, Georgios Ponirakis, Alberto De la Fuente, Aijaz Parray, Ilham Bensmail, Houari Abdesselem, Marwan Ramadan, Shafi Khan, Mani Chandran, Raheem Ayadathil, Ahmed Elsotouhy, Ahmed Own, Hanadi Al Hamad, Essam M. Abdelalim, Julie Decock, Nehad M. Alajez, Omar Albagha, Paul J. Thornalley, Abdelilah Arredouani, Rayaz A. Malik and Omar M. A. El-Agnaf Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(9), 8117; https://doi.org/10.3390/ijms24098117 - 1 May 2023

Cited by 7 | Viewed by 3767

Abstract

Dementia is a progressive and debilitating neurological disease that affects millions of people worldwide. Identifying the minimally invasive biomarkers associated with dementia that could provide insights into the disease pathogenesis, improve early diagnosis, and facilitate the development of effective treatments is pressing. Proteomic [...] Read more.

Dementia is a progressive and debilitating neurological disease that affects millions of people worldwide. Identifying the minimally invasive biomarkers associated with dementia that could provide insights into the disease pathogenesis, improve early diagnosis, and facilitate the development of effective treatments is pressing. Proteomic studies have emerged as a promising approach for identifying the protein biomarkers associated with dementia. This pilot study aimed to investigate the plasma proteome profile and identify a panel of various protein biomarkers for dementia. We used a high-throughput proximity extension immunoassay to quantify 1090 proteins in 122 participants (22 with dementia, 64 with mild cognitive impairment (MCI), and 36 controls with normal cognitive function). Limma-based differential expression analysis reported the dysregulation of 61 proteins in the plasma of those with dementia compared with controls, and machine learning algorithms identified 17 stable diagnostic biomarkers that differentiated individuals with AUC = 0.98 ± 0.02. There was also the dysregulation of 153 plasma proteins in individuals with dementia compared with those with MCI, and machine learning algorithms identified 8 biomarkers that classified dementia from MCI with an AUC of 0.87 ± 0.07. Moreover, multiple proteins selected in both diagnostic panels such as NEFL, IL17D, WNT9A, and PGF were negatively correlated with cognitive performance, with a correlation coefficient (r²) ≤ −0.47. Gene Ontology (GO) and pathway analysis of dementia-associated proteins implicated immune response, vascular injury, and extracellular matrix organization pathways in dementia pathogenesis. In conclusion, the combination of high-throughput proteomics and machine learning enabled us to identify a blood-based protein signature capable of potentially differentiating dementia from MCI and cognitively normal controls. Further research is required to validate these biomarkers and investigate the potential underlying mechanisms for the development of dementia. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 3.0)

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16 pages, 4318 KiB

Open AccessArticle

Identification of Key Ferroptosis-Related Genes in the Peripheral Blood of Patients with Relapsing-Remitting Multiple Sclerosis and Its Diagnostic Value

by Xi Song, Zixuan Wang, Zixin Tian, Meihuan Wu, Yitao Zhou and Jun Zhang

Int. J. Mol. Sci. 2023, 24(7), 6399; https://doi.org/10.3390/ijms24076399 - 29 Mar 2023

Cited by 4 | Viewed by 2304

Abstract

Multiple sclerosis (MS) is a neurodegenerative disease with a complex pathogenesis. Re-lapsing-remitting multiple sclerosis (RRMS) is the most common subset of MS, accounting for approximately 85% of cases. Recent studies have shown that ferroptosis may contribute to the progression of RRMS, but the [...] Read more.

Multiple sclerosis (MS) is a neurodegenerative disease with a complex pathogenesis. Re-lapsing-remitting multiple sclerosis (RRMS) is the most common subset of MS, accounting for approximately 85% of cases. Recent studies have shown that ferroptosis may contribute to the progression of RRMS, but the underlying mechanism remains to be elucidated. Herein, this study intended to explore the molecular network of ferroptosis associated with RRMS and establish a predictive model for efficacy diagnosis. Firstly, RRMS-related module genes were identified using weighted gene co-expression network analysis (WGCNA). Secondly, the optimal machine learning model was selected from four options: the generalized linear model (GLM), random forest model (RF), support vector machine model (SVM), and extreme gradient boosting model (XGB). Subsequently, the predictive efficacy of the diagnostic model was evaluated using receiver operator characteristic (ROC) analysis. Finally, a SVM diagnostic model based on five genes (JUN, TXNIP, NCOA4, EIF2AK4, PIK3CA) was established, and it demonstrated good predictive performance in the validation dataset. In summary, our study provides a systematic exploration of the complex relationship between ferroptosis and RRMS, which may contribute to a better understanding of the role of ferroptosis in the pathogenesis of RRMS and provide promising diagnostic strategies for RRMS patients. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 3.0)

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16 pages, 1055 KiB

Open AccessArticle

Assessment of Plasma and Cerebrospinal Fluid Biomarkers in Different Stages of Alzheimer’s Disease and Frontotemporal Dementia

by Lourdes Álvarez-Sánchez, Carmen Peña-Bautista, Laura Ferré-González, Angel Balaguer, Miguel Baquero, Bonaventura Casanova-Estruch and Consuelo Cháfer-Pericás

Int. J. Mol. Sci. 2023, 24(2), 1226; https://doi.org/10.3390/ijms24021226 - 8 Jan 2023

Cited by 13 | Viewed by 2713

Abstract

Alzheimer’s disease (AD) is the primary type of dementia, followed by frontotemporal lobar degeneration (FTLD). They share some clinical characteristics, mainly at the early stages. So, the identification of early, specific, and minimally invasive biomarkers is required. In this study, some plasma biomarkers [...] Read more.

Alzheimer’s disease (AD) is the primary type of dementia, followed by frontotemporal lobar degeneration (FTLD). They share some clinical characteristics, mainly at the early stages. So, the identification of early, specific, and minimally invasive biomarkers is required. In this study, some plasma biomarkers (Amyloid β42, p-Tau181, t-Tau, neurofilament light (NfL), TAR DNA-binding protein 43 (TDP-43)) were determined by single molecule array technology (SIMOA^®) in control subjects (n = 22), mild cognitive impairment due to AD (MCI-AD, n = 33), mild dementia due to AD (n = 12), and FTLD (n = 11) patients. The correlations between plasma and cerebrospinal fluid (CSF) levels and the accuracy of plasma biomarkers for AD early diagnosis and discriminating from FTLD were analyzed. As result, plasma p-Tau181 and NfL levels correlated with the corresponding CSF levels. Additionally, plasma p-Tau181 showed good accuracy for distinguishing between the controls and AD, as well as discriminating between AD and FTLD. Moreover, plasma NfL could discriminate dementia-AD vs. controls, FTLD vs. controls, and MCI-AD vs. dementia-AD. Therefore, the determination of these biomarkers in plasma is potentially helpful in AD spectrum diagnosis, but also discriminating from FTLD. In addition, the accessibility of these potential early and specific biomarkers may be useful for AD screening protocols in the future. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 3.0)

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22 pages, 2107 KiB

Open AccessArticle

Exosomal Aβ-Binding Proteins Identified by “In Silico” Analysis Represent Putative Blood-Derived Biomarker Candidates for Alzheimer´s Disease

by Tânia Soares Martins, Rui Marçalo, Maria Ferreira, Margarida Vaz, Raquel M. Silva, Ilka Martins Rosa, Jonathan Vogelgsang, Jens Wiltfang, Odete A. B. da Cruz e Silva and Ana Gabriela Henriques

Int. J. Mol. Sci. 2021, 22(8), 3933; https://doi.org/10.3390/ijms22083933 - 11 Apr 2021

Cited by 15 | Viewed by 6968

Abstract

The potential of exosomes as biomarker resources for diagnostics and even for therapeutics has intensified research in the field, including in the context of Alzheimer´s disease (AD). The search for disease biomarkers in peripheral biofluids is advancing mainly due to the easy access [...] Read more.

The potential of exosomes as biomarker resources for diagnostics and even for therapeutics has intensified research in the field, including in the context of Alzheimer´s disease (AD). The search for disease biomarkers in peripheral biofluids is advancing mainly due to the easy access it offers. In the study presented here, emphasis was given to the bioinformatic identification of putative exosomal candidates for AD. The exosomal proteomes of cerebrospinal fluid (CSF), serum and plasma, were obtained from three databases (ExoCarta, EVpedia and Vesiclepedia), and complemented with additional exosomal proteins already associated with AD but not found in the databases. The final biofluids’ proteomes were submitted to gene ontology (GO) enrichment analysis and the exosomal Aβ-binding proteins that can constitute putative candidates were identified. Among these candidates, gelsolin, a protein known to be involved in inhibiting Abeta fibril formation, was identified, and it was tested in human samples. The levels of this Aβ-binding protein, with anti-amyloidogenic properties, were assessed in serum-derived exosomes isolated from controls and individuals with dementia, including AD cases, and revealed altered expression patterns. Identification of potential peripheral biomarker candidates for AD may be useful, not only for early disease diagnosis but also in drug trials and to monitor disease progression, allowing for a timely therapeutic intervention, which will positively impact the patient’s quality of life. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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28 pages, 7509 KiB

Open AccessArticle

Utilizing an Animal Model to Identify Brain Neurodegeneration-Related Biomarkers in Aging

by Ming-Hui Yang, Yi-Ming Arthur Chen, Shan-Chen Tu, Pei-Ling Chi, Kuo-Pin Chuang, Chin-Chuan Chang, Chiang-Hsuan Lee, Yi-Ling Chen, Che-Hsin Lee, Cheng-Hui Yuan and Yu-Chang Tyan

Int. J. Mol. Sci. 2021, 22(6), 3278; https://doi.org/10.3390/ijms22063278 - 23 Mar 2021

Cited by 3 | Viewed by 3963

Abstract

Glycine N-methyltransferase (GNMT) regulates S-adenosylmethionine (SAMe), a methyl donor in methylation. Over-expressed SAMe may cause neurogenic capacity reduction and memory impairment. GNMT knockout mice (GNMT-KO) was applied as an experimental model to evaluate its effect on neurons. In this study, proteins from brain [...] Read more.

Glycine N-methyltransferase (GNMT) regulates S-adenosylmethionine (SAMe), a methyl donor in methylation. Over-expressed SAMe may cause neurogenic capacity reduction and memory impairment. GNMT knockout mice (GNMT-KO) was applied as an experimental model to evaluate its effect on neurons. In this study, proteins from brain tissues were studied using proteomic approaches, Haemotoxylin and Eosin staining, immunohistochemistry, Western blotting, and ingenuity pathway analysis. The expression of Receptor-interacting protein 1(RIPK1) and Caspase 3 were up-regulated and activity-dependent neuroprotective protein (ADNP) was down-regulated in GNMT-KO mice regardless of the age. Besides, proteins related to neuropathology, such as excitatory amino acid transporter 2, calcium/calmodulin-dependent protein kinase type II subunit alpha, and Cu-Zn superoxide dismutase were found only in the group of aged wild-type mice; 4-aminobutyrate amino transferase, limbic system-associated membrane protein, sodium- and chloride-dependent GABA transporter 3 and ProSAAS were found only in the group of young GNMT-KO mice and are related to function of neurons; serum albumin and Rho GDP dissociation inhibitor 1 were found only in the group of aged GNMT-KO mice and are connected to neurodegenerative disorders. With proteomic analyses, a pathway involving Gonadotropin-releasing hormone (GnRH) signal was found to be associated with aging. The GnRH pathway could provide additional information on the mechanism of aging and non-aging related neurodegeneration, and these protein markers may be served in developing future therapeutic treatments to ameliorate aging and prevent diseases. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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16 pages, 3797 KiB

Open AccessArticle

Different miRNA Profiles in Plasma Derived Small and Large Extracellular Vesicles from Patients with Neurodegenerative Diseases

by Daisy Sproviero, Stella Gagliardi, Susanna Zucca, Maddalena Arigoni, Marta Giannini, Maria Garofalo, Martina Olivero, Michela Dell’Orco, Orietta Pansarasa, Stefano Bernuzzi, Micol Avenali, Matteo Cotta Ramusino, Luca Diamanti, Brigida Minafra, Giulia Perini, Roberta Zangaglia, Alfredo Costa, Mauro Ceroni, Nora I. Perrone-Bizzozero, Raffaele A. Calogero and Cristina Cereda Show full author list Hide full author list

Int. J. Mol. Sci. 2021, 22(5), 2737; https://doi.org/10.3390/ijms22052737 - 8 Mar 2021

Cited by 45 | Viewed by 5142

Abstract

Identifying biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our [...] Read more.

Identifying biomarkers is essential for early diagnosis of neurodegenerative diseases (NDs). Large (LEVs) and small extracellular vesicles (SEVs) are extracellular vesicles (EVs) of different sizes and biological functions transported in blood and they may be valid biomarkers for NDs. The aim of our study was to investigate common and different miRNA signatures in plasma derived LEVs and SEVs of Alzheimer’s disease (AD), Parkinson’s disease (PD), Amyotrophic Lateral Sclerosis (ALS) and Fronto-Temporal Dementia (FTD) patients. LEVs and SEVs were isolated from plasma of patients and healthy volunteers (CTR) by filtration and differential centrifugation and RNA was extracted. Small RNAs libraries were carried out by Next Generation Sequencing (NGS). MiRNAs discriminate all NDs diseases from CTRs and they can provide a signature for each NDs. Common enriched pathways for SEVs were instead linked to ubiquitin mediated proteolysis and Toll-like receptor signaling pathways and for LEVs to neurotrophin signaling and Glycosphingolipid biosynthesis pathway. LEVs and SEVs are involved in different pathways and this might give a specificity to their role in the spreading of the disease. The study of common and different miRNAs transported by LEVs and SEVs can be of great interest for biomarker discovery and for pathogenesis studies in neurodegeneration. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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15 pages, 1485 KiB

Open AccessArticle

Inflammasome in ALS Skeletal Muscle: NLRP3 as a Potential Biomarker

by Leticia Moreno-García, Francisco J. Miana-Mena, Laura Moreno-Martínez, Miriam de la Torre, Christian Lunetta, Claudia Tarlarini, Pilar Zaragoza, Ana Cristina Calvo and Rosario Osta

Int. J. Mol. Sci. 2021, 22(5), 2523; https://doi.org/10.3390/ijms22052523 - 3 Mar 2021

Cited by 24 | Viewed by 3930

Abstract

Since NLRP3 inflammasome plays a pivotal role in several neurodegenerative disorders, we hypothesized that levels of inflammasome components could help in diagnosis or prognosis of amyotrophic lateral sclerosis (ALS). Gene and protein expression was assayed by RT-PCR and Western blot. Spearman’s correlation coefficient [...] Read more.

Since NLRP3 inflammasome plays a pivotal role in several neurodegenerative disorders, we hypothesized that levels of inflammasome components could help in diagnosis or prognosis of amyotrophic lateral sclerosis (ALS). Gene and protein expression was assayed by RT-PCR and Western blot. Spearman’s correlation coefficient was used to determine the linear correlation of transcriptional expression levels with longevity throughout disease progression in mice models. Kaplan-Meier analysis was performed to evaluate MCC950 effects (NLRP3 inhibitor) on lifespan of SOD1G93A mice. The results showed significant alterations in NLRP3 inflammasome gene and protein levels in the skeletal muscle of SOD1G93A mice. Spearman’s correlation coefficient revealed a positive association between Nlrp3 transcriptional levels in skeletal muscle and longevity of SOD1G93A mice (r = 0.506; p = 0.027). Accordingly, NLRP3 inactivation with MCC950 decreased the lifespan of mice. Furthermore, NLRP3 mRNA levels were significantly elevated in the blood of ALS patients compared to healthy controls (p = 0.03). In conclusion, NLRP3 could be involved in skeletal muscle pathogenesis of ALS, either through inflammasome or independently, and may play a dual role during disease progression. NLRP3 gene expression levels could be used as a biomarker to improve diagnosis and prognosis in skeletal muscle from animal models and also to support diagnosis in clinical practice with the blood of ALS patients. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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14 pages, 289 KiB

Open AccessArticle

Early CSF Biomarkers and Late Functional Outcomes in Spinal Cord Injury. A Pilot Study

by Rita Capirossi, Beatrice Piunti, Mercedes Fernández, Elisa Maietti, Paola Rucci, Stefano Negrini, Tiziana Giovannini, Carlotte Kiekens and Laura Calzà

Int. J. Mol. Sci. 2020, 21(23), 9037; https://doi.org/10.3390/ijms21239037 - 27 Nov 2020

Cited by 12 | Viewed by 2508

Abstract

Although, biomarkers are regarded as an important tool for monitoring injury severity and treatment efficacy, and for predicting clinical evolution in many neurological diseases and disorders including spinal cord injury, there is still a lack of reliable biomarkers for the assessment of clinical [...] Read more.

Although, biomarkers are regarded as an important tool for monitoring injury severity and treatment efficacy, and for predicting clinical evolution in many neurological diseases and disorders including spinal cord injury, there is still a lack of reliable biomarkers for the assessment of clinical course and patient outcome. In this study, a biological dataset of 60 cytokines/chemokines, growth factorsm and intracellular and extracellular matrix proteins, analyzed in CSF within 24 h of injury, was used for correlation analysis with the clinical dataset of the same patients. A heat map was generated of positive and negative correlations between biomarkers and clinical rating scale scores at discharge, and between biomarkers and changes in clinical scores during the observation period. Using very stringent statistical criteria, we found 10 molecules which correlated with clinical scores at discharge, and five molecules, which correlated with changes in clinical scores. The proposed methodology may be useful for generating hypotheses regarding “predictive” and “treatment effectiveness” biomarkers, thereby suggesting potential candidates for disease-modifying therapies using a “bed-to-bench” approach. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

12 pages, 1027 KiB

Open AccessArticle

CSF Biomarkers Reflecting Protein Pathology and Axonal Degeneration Are Associated with Memory, Attentional, and Executive Functioning in Early-Stage Parkinson′s Disease

by Linda P. Oosterveld, Tessa I. Kuiper, Nour K. Majbour, Inge M. W. Verberk, Karin D. van Dijk, Jos W. R. Twisk, Omar M. El-Agnaf, Charlotte E. Teunissen, Henry C. Weinstein, Martin Klein, Henk W. Berendse and Wilma D. J. van de Berg

Int. J. Mol. Sci. 2020, 21(22), 8519; https://doi.org/10.3390/ijms21228519 - 12 Nov 2020

Cited by 7 | Viewed by 2385

Abstract

In early-stage Parkinson′s disease (PD), cognitive impairment is common, and a variety of cognitive domains including memory, attention, and executive functioning may be affected. Cerebrospinal fluid (CSF) biomarkers are potential markers of cognitive functioning. We aimed to explore whether CSF α-synuclein species, neurofilament [...] Read more.

In early-stage Parkinson′s disease (PD), cognitive impairment is common, and a variety of cognitive domains including memory, attention, and executive functioning may be affected. Cerebrospinal fluid (CSF) biomarkers are potential markers of cognitive functioning. We aimed to explore whether CSF α-synuclein species, neurofilament light chain, amyloid-β₄₂, and tau are associated with cognitive performance in early-stage PD patients. CSF levels of total-α-synuclein and phosphorylated-α-synuclein, neurofilament light chain, amyloid-β₄₂, and total-tau and phosphorylated-tau were measured in 26 PD patients (disease duration ≤5 years and Hoehn and Yahr stage 1–2.5). Multivariable linear regression models, adjusted for age, gender, and educational level, were used to assess the relationship between CSF biomarker levels and memory, attention, executive and visuospatial function, and language performance scores. In 26 early-stage PD patients, attention and memory were the most commonly affected domains. A higher CSF phosphorylated-α-synuclein/total-α-synuclein ratio was associated with better executive functioning (sβ = 0.40). Higher CSF neurofilament light was associated with worse memory (sβ = −0.59), attentional (sβ = −0.32), and executive functioning (sβ = −0.35). Reduced CSF amyloid-β₄₂ levels were associated with poorer attentional functioning (sβ = 0.35). Higher CSF phosphorylated-tau was associated with worse language functioning (sβ = −0.33). Thus, CSF biomarker levels, in particular neurofilament light, were related to the most commonly affected cognitive domains in early-stage PD. This indicates that CSF biomarker levels may identify early-stage PD patients who are at an increased risk of developing cognitive impairment. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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15 pages, 2539 KiB

Open AccessArticle

Structural and Functional Brain Abnormalities in Mouse Models of Lafora Disease

by Daniel F. Burgos, Lorena Cussó, Gentzane Sánchez-Elexpuru, Daniel Calle, Max Bautista Perpinyà, Manuel Desco, José M. Serratosa and Marina P. Sánchez

Int. J. Mol. Sci. 2020, 21(20), 7771; https://doi.org/10.3390/ijms21207771 - 20 Oct 2020

Cited by 5 | Viewed by 3003

Abstract

Mutations in the EPM2A and EPM2B genes, encoding laforin and malin proteins respectively, are responsible for Lafora disease, a fatal form of progressive myoclonus epilepsy with autosomal recessive inheritance. Neuroimaging studies of patients with Lafora disease have shown different degrees of brain atrophy, [...] Read more.

Mutations in the EPM2A and EPM2B genes, encoding laforin and malin proteins respectively, are responsible for Lafora disease, a fatal form of progressive myoclonus epilepsy with autosomal recessive inheritance. Neuroimaging studies of patients with Lafora disease have shown different degrees of brain atrophy, decreased glucose brain uptake and alterations on different brain metabolites mainly in the frontal cortex, basal ganglia and cerebellum. Mice deficient for laforin and malin present many features similar to those observed in patients, including cognitive, motor, histological and epileptic hallmarks. We describe the neuroimaging features found in two mouse models of Lafora disease. We found altered volumetric values in the cerebral cortex, hippocampus, basal ganglia and cerebellum using magnetic resonance imaging (MRI). Positron emission tomography (PET) of the cerebral cortex, hippocampus and cerebellum of Epm2a^−/− mice revealed abnormal glucose uptake, although no alterations in Epm2b^−/− mice were observed. Magnetic resonance spectroscopy (MRS) revealed significant changes in the concentration of several brain metabolites, including N-acetylaspartate (NAA), in agreement with previously described findings in patients. These data may provide new insights into disease mechanisms that may be of value for developing new biomarkers for diagnosis, prevention and treatment of Lafora disease using animal models. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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15 pages, 4312 KiB

Open AccessArticle

Classifications of Neurodegenerative Disorders Using a Multiplex Blood Biomarkers-Based Machine Learning Model

by Chin-Hsien Lin, Shu-I Chiu, Ta-Fu Chen, Jyh-Shing Roger Jang and Ming-Jang Chiu

Int. J. Mol. Sci. 2020, 21(18), 6914; https://doi.org/10.3390/ijms21186914 - 21 Sep 2020

Cited by 34 | Viewed by 5344

Abstract

Easily accessible biomarkers for Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), and related neurodegenerative disorders are urgently needed in an aging society to assist early-stage diagnoses. In this study, we aimed to develop machine learning algorithms using the multiplex blood-based biomarkers [...] Read more.

Easily accessible biomarkers for Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal dementia (FTD), and related neurodegenerative disorders are urgently needed in an aging society to assist early-stage diagnoses. In this study, we aimed to develop machine learning algorithms using the multiplex blood-based biomarkers to identify patients with different neurodegenerative diseases. Plasma samples (n = 377) were obtained from healthy controls, patients with AD spectrum (including mild cognitive impairment (MCI)), PD spectrum with variable cognitive severity (including PD with dementia (PDD)), and FTD. We measured plasma levels of amyloid-beta 42 (Aβ42), Aβ40, total Tau, p-Tau181, and α-synuclein using an immunomagnetic reduction-based immunoassay. We observed increased levels of all biomarkers except Aβ40 in the AD group when compared to the MCI and controls. The plasma α-synuclein levels increased in PDD when compared to PD with normal cognition. We applied machine learning-based frameworks, including a linear discriminant analysis (LDA), for feature extraction and several classifiers, using features from these blood-based biomarkers to classify these neurodegenerative disorders. We found that the random forest (RF) was the best classifier to separate different dementia syndromes. Using RF, the established LDA model had an average accuracy of 76% when classifying AD, PD spectrum, and FTD. Moreover, we found 83% and 63% accuracies when differentiating the individual disease severity of subgroups in the AD and PD spectrum, respectively. The developed LDA model with the RF classifier can assist clinicians in distinguishing variable neurodegenerative disorders. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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20 pages, 3892 KiB

Open AccessArticle

Serum Tau Proteins as Potential Biomarkers for the Assessment of Alzheimer’s Disease Progression

by Eunjoo Nam, Yeong-Bae Lee, Cheil Moon and Keun-A Chang

Int. J. Mol. Sci. 2020, 21(14), 5007; https://doi.org/10.3390/ijms21145007 - 15 Jul 2020

Cited by 55 | Viewed by 5708

Abstract

Total tau (t-tau) and phosphorylated tau (p-tau) protein elevations in cerebrospinal fluid (CFS) are well-established hallmarks of Alzheimer’s disease (AD), while the associations of serum t-tau and p-tau levels with AD have been inconsistent across studies. To identify more accessible non-invasive AD biomarkers, [...] Read more.

Total tau (t-tau) and phosphorylated tau (p-tau) protein elevations in cerebrospinal fluid (CFS) are well-established hallmarks of Alzheimer’s disease (AD), while the associations of serum t-tau and p-tau levels with AD have been inconsistent across studies. To identify more accessible non-invasive AD biomarkers, we measured serum tau proteins and associations with cognitive function in age-matched controls (AMC, n = 26), mild cognitive impairment group (MCI, n = 30), and mild-AD group (n = 20) according to the Mini-mental State Examination (MMSE), Clinical Dementia Rating (CDR), and Global Deterioration Scale (GDS) scores. Serum t-tau, but not p-tau, was significantly higher in the mild-AD group than AMC subjects (p < 0.05), and there were significant correlations of serum t-tau with MMSE and GDS scores. Receiver operating characteristic (ROC) analysis distinguished mild-AD from AMC subjects with moderate sensitivity and specificity (AUC = 0.675). We speculated that tau proteins in neuronal cell-derived exosomes (NEX) isolated from serum would be more strongly associated with brain tau levels and disease characteristics, as these exosomes can penetrate the blood-brain barrier. Indeed, ELISA and Western blotting indicated that both NEX t-tau and p-tau (S202) were significantly higher in the mild-AD group compared to AMC (p < 0.05) and MCI groups (p < 0.01). In contrast, serum amyloid β (Aβ_1–42) was lower in the mild-AD group compared to MCI groups (p < 0.001). During the 4-year follow-up, NEX t-tau and p-tau (S202) levels were correlated with the changes in GDS and MMSE scores. In JNPL3 transgenic (Tg) mice expressing a human tau mutation, t-tau and p-tau expression levels in NEX increased with neuropathological progression, and NEX tau was correlated with tau in brain tissue exosomes (tEX), suggesting that tau proteins reach the circulation via exosomes. Taken together, our data suggest that serum tau proteins, especially NEX tau proteins, are useful biomarkers for monitoring AD progression. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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22 pages, 1950 KiB

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The Inflammasome Adaptor Protein ASC in Mild Cognitive Impairment and Alzheimer’s Disease

by Xavier O. Scott, Marisa E. Stephens, Marie C. Desir, W. Dalton Dietrich, Robert W. Keane and Juan Pablo de Rivero Vaccari

Int. J. Mol. Sci. 2020, 21(13), 4674; https://doi.org/10.3390/ijms21134674 - 30 Jun 2020

Cited by 46 | Viewed by 4575

Abstract

Mild cognitive impairment (MCI) is characterized by memory loss in the absence of dementia and is considered the translational stage between normal aging and early Alzheimer’s disease (AD). Patients with MCI have a greater risk of advancing to AD. Thus, identifying early markers [...] Read more.

Mild cognitive impairment (MCI) is characterized by memory loss in the absence of dementia and is considered the translational stage between normal aging and early Alzheimer’s disease (AD). Patients with MCI have a greater risk of advancing to AD. Thus, identifying early markers of MCI has the potential to increase the therapeutic window to treat and manage the disease. Protein levels of the inflammasome signaling proteins apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and interleukin (IL)-18 were analyzed in the serum of patients with MCI, AD and healthy age-matched donors as possible biomarkers, as well as levels of soluble amyloid precursor proteins α/β (sAPP α/β) and neurofilament light (NfL). Cut-off points and positive and negative predictive values, as well as receiver operator characteristic (ROC) curves, likelihood ratios and accuracy were determined for these proteins. Although the levels of ASC were higher in MCI and AD than in age-matched controls, protein levels of ASC were higher in MCI than in AD cases. For control vs. MCI, the area under the curve (AUC) for ASC was 0.974, with a cut-off point of 264.9 pg/mL. These data were comparable to the AUC for sAPP α and β of 0.9687 and 0.9068, respectively, as well as 0.7734 for NfL. Moreover, similar results were obtained for control vs. AD and MCI vs. AD. These results indicate that ASC is a promising biomarker of MCI and AD. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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9 pages, 954 KiB

Open AccessArticle

Aβ1-42 and Tau as Potential Biomarkers for Diagnosis and Prognosis of Amyotrophic Lateral Sclerosis

by Débora Lanznaster, Rudolf C. Hergesheimer, Salah Eddine Bakkouche, Stephane Beltran, Patrick Vourc’h, Christian R. Andres, Diane Dufour-Rainfray, Philippe Corcia and Hélène Blasco

Int. J. Mol. Sci. 2020, 21(8), 2911; https://doi.org/10.3390/ijms21082911 - 21 Apr 2020

Cited by 21 | Viewed by 2937

Abstract

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, but its definitive diagnosis delays around 12 months. Although the research is highly active in the biomarker field, the absence of specific biomarkers for diagnosis contributes to this long delay. Another strategy [...] Read more.

Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease, but its definitive diagnosis delays around 12 months. Although the research is highly active in the biomarker field, the absence of specific biomarkers for diagnosis contributes to this long delay. Another strategy of biomarker identification based on less specific but sensitive molecules may be of interest in clinical practice. For example, markers related to other neurodegenerative diseases such as Alzheimer’s disease (AD) could be fully explored. Here, we compared baseline levels of amyloidβ1-42 (Aβ1-42), total Tau, and phosphorylated-Tau (phospho-Tau) protein in the cerebrospinal fluid (CSF) of ALS patients to controls and correlated it with clinical parameters of ALS progression collected over 12 months. We observed increased levels of Aβ1-42 (controls: 992.9 ± 358.3 ng/L; ALS: 1277.0 ± 296.6 ng/L; p < 0.0001) and increased Aβ1-42/phospho-Tau ratio and Innotest Amyloid Tau Index (IATI) (both p < 0.0001). IATI and the phospho-Tau/total Tau ratio correlated positively with ALSFRS-R and weight at baseline. Multivariate analysis revealed that baseline ALSFRS-R was associated with Aβ1-42 and phospho-Tau/total Tau ratio (p = 0.0109 and p = 0.0013, respectively). Total Tau and phospho-Tau levels correlated negatively with ALSFRS-R variation at months 6 and 9, respectively (p = 0.02 and p = 0.04, respectively). Phospho-Tau/total Tau ratio correlated positively with ALSFRS-R variation at month 9 (p = 0.04). CSF levels of Aβ1-42 could be used as a complementary tool to ALS diagnosis, and total Tau and phospho-Tau levels may help establishing the prognosis of ALS. Further studies merit exploring the pathophysiological mechanisms associated with these markers. Despite their lack of specificity, phospho-Tau/total Tau and Aβ1-42 should be combined to other biological and clinical markers in order to improve ALS management. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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13 pages, 1685 KiB

Open AccessArticle

Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis

by Cecilia Rajda, Zsolt Galla, Helga Polyák, Zoltán Maróti, Kristóf Babarczy, Dániel Pukoli and László Vécsei

Int. J. Mol. Sci. 2020, 21(8), 2665; https://doi.org/10.3390/ijms21082665 - 11 Apr 2020

Cited by 27 | Viewed by 3618

Abstract

Neurofilament light (NFL) has proved to be a good prognostic factor in multiple sclerosis (MS), as its level is proportionally elevated with extended neuraxonal damage. The involvement of the kynurenine pathway in neuroinflammation has been proved. The precursor of this pathway is the [...] Read more.

Neurofilament light (NFL) has proved to be a good prognostic factor in multiple sclerosis (MS), as its level is proportionally elevated with extended neuraxonal damage. The involvement of the kynurenine pathway in neuroinflammation has been proved. The precursor of this pathway is the essential amino acid tryptophan, which is catabolized 95% towards kynurenine metabolites. Quinolinic acid (QUIN) within the brain is only produced in activated microglia and macrophages, leading to axonal degeneration via the activation of N-Methyl-D-aspartate receptors. Neopterin is a biomarker for inflammation produced by macrophages. The association of these biomarkers has not previously been investigated. Our aim was to assess whether there is an association of the neurodegenerative biomarker NFL with the markers of neuroinflammation, e.g., kynurenine metabolites and neopterin, in the cerebrospinal fluid (CSF). CSF samples of patients with MS (pwMS; n = 37) and age-matched controls (n = 22) were compared for NFL levels by ELISA, while the kynurenine pathway metabolites tryptophan and neopterin were detected with mass spectrometry. Spearman’s correlation showed that NFL is an independent predictor of neurological disability in the MS group. Significant correlations were found between NFL, neopterin, and QUIN, and between kynurenine and neopterin. Receiver operating characteristic (ROC) curve analysis was used to plot the top three best predictors of MS-related disability that yielded the best specificity and sensitivity. Normalized NFL (AUC: 0.923), QUIN (AUC: 0.803), and neopterin (AUC: 0.843) were the best independent predictors of neurological disability in pwMS. The CSF NFL and CSF QUIN, together with neopterin, were elevated in the CSF of pwMS compared to controls. The combination of the neurodegenerative biomarkers together with biomarkers of neuroinflammation could provide additional information on the underlying pathomechanism of disease activity, which is essential for the identification of patients at risk of developing cumulative disabilities. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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14 pages, 954 KiB

Open AccessArticle

Differential Expression of SMAD Genes and S1PR1 on Circulating CD4+ T Cells in Multiple Sclerosis and Crohn’s Disease

by Judith Abarca-Zabalía, Ma Isabel García, Alberto Lozano Ros, Ignacio Marín-Jiménez, Maria L. Martínez-Ginés, Beatriz López-Cauce, María L. Martín-Barbero, Sara Salvador-Martín, María Sanjurjo-Saez, Jose M. García-Domínguez and Luis A. López Fernández

Int. J. Mol. Sci. 2020, 21(2), 676; https://doi.org/10.3390/ijms21020676 - 20 Jan 2020

Cited by 17 | Viewed by 4060

Abstract

The Th17 immune response plays a key role in autoimmune diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Expression of Th17-related genes in inflamed tissues has been reported in autoimmune diseases. However, values are frequently obtained using invasive methods. We [...] Read more.

The Th17 immune response plays a key role in autoimmune diseases such as multiple sclerosis (MS) and inflammatory bowel disease (IBD). Expression of Th17-related genes in inflamed tissues has been reported in autoimmune diseases. However, values are frequently obtained using invasive methods. We aimed to identify biomarkers of MS in an accessible sample, such as blood, by quantifying the relative expression of 91 Th17-related genes in CD4+ T lymphocytes from patients with MS during a relapse or during a remitting phase. We also compared our findings with those of healthy controls. After confirmation in a validation cohort, expression of SMAD7 and S1PR1 mRNAs was decreased in remitting disease (–2.3-fold and –1.3-fold, respectively) and relapsing disease (–2.2-fold and –1.3-fold, respectively). No differential expression was observed for other SMAD7-related genes, namely, SMAD2, SMAD3, and SMAD4. Under-regulation of SMAD7 and S1PR1 was also observed in another autoimmune disease, Crohn’s disease (CD) (−4.6-fold, -1.6-fold, respectively), suggesting the presence of common markers for autoimmune diseases. In addition, expression of TNF, SMAD2, SMAD3, and SMAD4 were also decreased in CD (–2.2-fold, –1.4-fold, –1.6-fold, and –1.6-fold, respectively). Our study suggests that expression of SMAD7 and S1PR1 mRNA in blood samples are markers for MS and CD, and TNF, SMAD2, SMAD3, and SMAD4 for CD. These genes could prove useful as markers of autoimmune diseases, thus obviating the need for invasive methods. Full article

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

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13 pages, 1324 KiB

Open AccessArticle

Oxidative Damage of DNA as Early Marker of Alzheimer’s Disease

by Carmen Peña-Bautista, Tania Tirle, Marina López-Nogueroles, Máximo Vento, Miguel Baquero and Consuelo Cháfer-Pericás

Int. J. Mol. Sci. 2019, 20(24), 6136; https://doi.org/10.3390/ijms20246136 - 5 Dec 2019

Cited by 49 | Viewed by 4863

Abstract

Alzheimer’s Disease (AD) is the most common cause of dementia, and its characteristic histopathological hallmarks are neurofibrillary tangles and senile plaques. Among involved mechanisms, oxidative stress plays an important role in damaging cell components (e.g., proteins, nucleic acids). In this study, different oxidized [...] Read more.

Alzheimer’s Disease (AD) is the most common cause of dementia, and its characteristic histopathological hallmarks are neurofibrillary tangles and senile plaques. Among involved mechanisms, oxidative stress plays an important role in damaging cell components (e.g., proteins, nucleic acids). In this study, different oxidized products of proteins and DNA were determined in the urine samples from mild cognitive impairment due to AD patients (n = 53) and healthy controls (n = 27) by means of ultra-performance liquid chromatography-tandem mass spectrometry analysis. A multivariate model developed by partial least squares generated a diagnostic model for AD with an AUC-ROC (area under the curve-receiver operating characteristic) of 0.843. From the studied analytes, 8-OHdG (8-hydroxy-2’-deoxyguanosine) and the ratio 8-OHdG/2dG (2’-deoxyguanosine) were able to distinguish between AD and healthy participants, showing statistically significant differences between groups, postulating DNA oxidation as a molecular pathway involved in early AD. Full article

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

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23 pages, 1667 KiB

Open AccessArticle

Meta-Analysis of Gene Expression Changes in the Blood of Patients with Mild Cognitive Impairment and Alzheimer’s Disease Dementia

by Virginie Bottero and Judith A. Potashkin

Int. J. Mol. Sci. 2019, 20(21), 5403; https://doi.org/10.3390/ijms20215403 - 30 Oct 2019

Cited by 31 | Viewed by 5869

Abstract

Background: Dementia is a major public health concern affecting approximately 47 million people worldwide. Mild cognitive impairment (MCI) is one form of dementia that affects an individual’s memory with or without affecting their daily life. Alzheimer’s disease dementia (ADD) is a more severe [...] Read more.

Background: Dementia is a major public health concern affecting approximately 47 million people worldwide. Mild cognitive impairment (MCI) is one form of dementia that affects an individual’s memory with or without affecting their daily life. Alzheimer’s disease dementia (ADD) is a more severe form of dementia that usually affects elderly individuals. It remains unclear whether MCI is a distinct disorder from or an early stage of ADD. Methods: Gene expression data from blood were analyzed to identify potential biomarkers that may be useful for distinguishing between these two forms of dementia. Results: A meta-analysis revealed 91 genes dysregulated in individuals with MCI and 387 genes dysregulated in ADD. Pathway analysis identified seven pathways shared between MCI and ADD and nine ADD-specific pathways. Fifteen transcription factors were associated with MCI and ADD, whereas seven transcription factors were specific for ADD. Mir-335-5p was specific for ADD, suggesting that it may be useful as a biomarker. Diseases that are associated with MCI and ADD included developmental delays, cognition impairment, and movement disorders. Conclusion: These results provide a better molecular understanding of peripheral changes that occur in MCI and ADD patients and may be useful in the identification of diagnostic and prognostic biomarkers. Full article

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

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14 pages, 758 KiB

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VGF Peptides in Cerebrospinal Fluid of Patients with Dementia with Lewy Bodies

by Inger van Steenoven, Barbara Noli, Cristina Cocco, Gian-Luca Ferri, Patrick Oeckl, Markus Otto, Marleen J. A. Koel-Simmelink, Claire Bridel, Wiesje M. van der Flier, Afina W. Lemstra and Charlotte E. Teunissen

Int. J. Mol. Sci. 2019, 20(19), 4674; https://doi.org/10.3390/ijms20194674 - 20 Sep 2019

Cited by 26 | Viewed by 4165

Abstract

In a previous proteomic study, we identified the neurosecretory protein VGF (VGF) as a potential biomarker for dementia with Lewy bodies (DLB). Here, we extended the study of VGF by comparing levels in cerebrospinal fluid (CSF) from 44 DLB patients, 20 Alzheimer’s disease [...] Read more.

In a previous proteomic study, we identified the neurosecretory protein VGF (VGF) as a potential biomarker for dementia with Lewy bodies (DLB). Here, we extended the study of VGF by comparing levels in cerebrospinal fluid (CSF) from 44 DLB patients, 20 Alzheimer’s disease (AD) patients, and 22 cognitively normal controls selected from the Amsterdam Dementia Cohort. CSF was analyzed using two orthogonal analytical methods: (1) In-house-developed quantitative ELISA and (2) selected reaction monitoring (SRM). We further addressed associations of VGF with other CSF biomarkers and cognition. VGF levels were lower in CSF from patients with DLB compared to either AD patients or controls. VGF was positively correlated with CSF tau and α-synuclein (0.55 < r < 0.75), but not with Aβ1-42. In DLB patients, low VGF levels were related to a more advanced cognitive decline at time of first presentation, whereas high levels of VGF were associated with steeper subsequent longitudinal cognitive decline. Hence, CSF VGF levels were lower in DLB compared to both AD and controls across different analytical methods. The strong associations with cognitive decline further points out VGF as a possible disease stage or prognostic marker for DLB. Full article

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

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12 pages, 532 KiB

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Plasma Metabolites Associated with Brain MRI Measures of Neurodegeneration in Older Adults in the Atherosclerosis Risk in Communities–Neurocognitive Study (ARIC-NCS)

by Danni Li, Jeffrey R. Misialek, Clifford R. Jack, Michelle M. Mielke, David Knopman, Rebecca Gottesman, Tom Mosley and Alvaro Alonso

Int. J. Mol. Sci. 2019, 20(7), 1744; https://doi.org/10.3390/ijms20071744 - 9 Apr 2019

Cited by 7 | Viewed by 3586

Abstract

Background: Plasma metabolites are associated with cognitive and physical function in the elderly. Because cerebral small vessel disease (SVD) and neurodegeneration are common causes of cognitive and physical function decline, the primary objective of this study was to investigate the associations of six [...] Read more.

Background: Plasma metabolites are associated with cognitive and physical function in the elderly. Because cerebral small vessel disease (SVD) and neurodegeneration are common causes of cognitive and physical function decline, the primary objective of this study was to investigate the associations of six plasma metabolites (two plasma phosphatidylcholines [PCs]: PC aa C36:5 and PC aa 36:6 and four sphingomyelins [SMs]: SM C26:0, SM [OH] C22:1, SM [OH] C22:2, SM [OH] C24:1) with magnetic resonance imaging (MRI) features of cerebral SVD and neurodegeneration in older adults. Methods: This study included 238 older adults in the Atherosclerosis Risk in Communities study at the fifth exam. Multiple linear regression was used to assess the association of each metabolite (log-transformed) in separate models with MRI measures except lacunar infarcts, for which binary logistic regression was used. Results: Higher concentrations of plasma PC aa C36:5 had adverse associations with MRI features of cerebral SVD (odds ratio of 1.69 [95% confidence interval: 1.01, 2.83] with lacunar infarct, and beta of 0.16 log [cm3] [0.02, 0.30] with log [White Matter Hyperintensities (WMH) volume]) while higher concentrations of 3 plasma SM (OH)s were associated with higher total brain volume (beta of 12.0 cm3 [5.5, 18.6], 11.8 cm3 [5.0, 18.6], and 7.3 cm3 [1.2, 13.5] for SM [OH] C22:1, SM [OH] C22:2, and SM [OH] C24:1, respectively). Conclusions: This study identified associations between certain plasma metabolites and brain MRI measures of SVD and neurodegeneration in older adults, particularly higher SM (OH) concentrations with higher total brain volume. Full article

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

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16 pages, 2109 KiB

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Integrated Lipidomics and Metabolomics Analysis of Tears in Multiple Sclerosis: An Insight into Diagnostic Potential of Lacrimal Fluid

by Ilaria Cicalini, Claudia Rossi, Damiana Pieragostino, Luca Agnifili, Leonardo Mastropasqua, Maria di Ioia, Giovanna De Luca, Marco Onofrj, Luca Federici and Piero Del Boccio

Int. J. Mol. Sci. 2019, 20(6), 1265; https://doi.org/10.3390/ijms20061265 - 13 Mar 2019

Cited by 55 | Viewed by 5453

Abstract

Metabolomics based on mass spectrometry represents an innovative approach to characterize multifactorial diseases, such as multiple sclerosis (MuS). To date, the most important biomarker source for MuS diagnosis is the cerebrospinal fluid. However, an important goal for research is to identify new molecules [...] Read more.

Metabolomics based on mass spectrometry represents an innovative approach to characterize multifactorial diseases, such as multiple sclerosis (MuS). To date, the most important biomarker source for MuS diagnosis is the cerebrospinal fluid. However, an important goal for research is to identify new molecules in more easily accessible biological fluids. A very interesting biofluid in MuS is represented by tears, considered as an intermediate fluid between the cerebrospinal fluid and serum. In this work, we developed a merged strategy for the analysis of lipids containing choline by Liquid Chromatography coupled to Tandem Mass Spectrometry (LC-MS/MS), as well as for the targeted analysis of free carnitine, acylcarnitines and aminoacids by direct infusion mass spectrometry. Samples for both metabolomics and lipidomics approaches were obtained in a single extraction procedure from tears of patients affected by MuS and healthy controls. Tear lipidomics showed 30 phospholipids significantly modulated and, notably, many sphingomyelins resulted lower in MuS. Moreover, the metabolomics approach carried out both on tears and serum highlighted the diagnostic potential of specific aminoacids and acylcarnitines. In conclusion, the metabolic profiling of tears appears to reflect the pathological conditions of the central nervous system, suggesting that the molecular repository of tears can be considered as a source of potential biomarkers for MuS. Full article

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

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17 pages, 2525 KiB

Open AccessReview

Mitochondrial Dynamics in Neurodegenerative Diseases: Unraveling the Role of Fusion and Fission Processes

by Hubert Grel, Damian Woznica, Katarzyna Ratajczak, Ewelina Kalwarczyk, Julia Anchimowicz, Weronika Switlik, Piotr Olejnik, Piotr Zielonka, Magdalena Stobiecka and Slawomir Jakiela

Int. J. Mol. Sci. 2023, 24(17), 13033; https://doi.org/10.3390/ijms241713033 - 22 Aug 2023

Cited by 22 | Viewed by 4228

Abstract

Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration and death of neurons, leading to a range of neurological symptoms. Despite the heterogeneity of these conditions, a common denominator is the implication of mitochondrial dysfunction in their pathogenesis. [...] Read more.

Neurodegenerative diseases (NDs) are a diverse group of disorders characterized by the progressive degeneration and death of neurons, leading to a range of neurological symptoms. Despite the heterogeneity of these conditions, a common denominator is the implication of mitochondrial dysfunction in their pathogenesis. Mitochondria play a crucial role in creating biomolecules, providing energy through adenosine triphosphate (ATP) generated by oxidative phosphorylation (OXPHOS), and producing reactive oxygen species (ROS). When they’re not functioning correctly, becoming fragmented and losing their membrane potential, they contribute to these diseases. In this review, we explore how mitochondria fuse and undergo fission, especially in the context of NDs. We discuss the genetic and protein mutations linked to these diseases and how they impact mitochondrial dynamics. We also look at the key regulatory proteins in fusion (MFN1, MFN2, and OPA1) and fission (DRP1 and FIS1), including their post-translational modifications. Furthermore, we highlight potential drugs that can influence mitochondrial dynamics. By unpacking these complex processes, we aim to direct research towards treatments that can improve life quality for people with these challenging conditions. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 3.0)

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13 pages, 950 KiB

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Brain-Biomarker Changes in Body Fluids of Patients with Parkinson’s Disease

by Cristina Cocco, Antonio Luigi Manai, Elias Manca and Barbara Noli

Int. J. Mol. Sci. 2023, 24(13), 10932; https://doi.org/10.3390/ijms241310932 - 30 Jun 2023

Cited by 6 | Viewed by 2173

Abstract

Parkinson’s disease (PD) is an incurable neurodegenerative disease that is rarely diagnosed at an early stage. Although the understanding of PD-related mechanisms has greatly improved over the last decade, the diagnosis of PD is still based on neurological examination through the identification of [...] Read more.

Parkinson’s disease (PD) is an incurable neurodegenerative disease that is rarely diagnosed at an early stage. Although the understanding of PD-related mechanisms has greatly improved over the last decade, the diagnosis of PD is still based on neurological examination through the identification of motor symptoms, including bradykinesia, rigidity, postural instability, and resting tremor. The early phase of PD is characterized by subtle symptoms with a misdiagnosis rate of approximately 16–20%. The difficulty in recognizing early PD has implications for the potential use of novel therapeutic approaches. For this reason, it is important to discover PD brain biomarkers that can indicate early dopaminergic dysfunction through their changes in body fluids, such as saliva, urine, blood, or cerebrospinal fluid (CSF). For the CFS-based test, the invasiveness of sampling is a major limitation, whereas the other body fluids are easier to obtain and could also allow population screening. Following the identification of the crucial role of alpha-synuclein (α-syn) in the pathology of PD, a very large number of studies have summarized its changes in body fluids. However, methodological problems have led to the poor diagnostic/prognostic value of this protein and alternative biomarkers are currently being investigated. The aim of this paper is therefore to summarize studies on protein biomarkers that are alternatives to α-syn, particularly those that change in nigrostriatal areas and in biofluids, with a focus on blood, and, eventually, saliva and urine. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 3.0)

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18 pages, 2664 KiB

Open AccessReview

The Potential Connection between Molecular Changes and Biomarkers Related to ALS and the Development and Regeneration of CNS

by Damjan Glavač, Miranda Mladinić, Jelena Ban, Graciela L. Mazzone, Cynthia Sámano, Ivana Tomljanović, Gregor Jezernik and Metka Ravnik-Glavač

Int. J. Mol. Sci. 2022, 23(19), 11360; https://doi.org/10.3390/ijms231911360 - 26 Sep 2022

Cited by 4 | Viewed by 2492

Abstract

Neurodegenerative diseases are one of the greatest medical burdens of the modern age, being mostly incurable and with limited prognostic and diagnostic tools. Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the loss of motoneurons, with a complex etiology, [...] Read more.

Neurodegenerative diseases are one of the greatest medical burdens of the modern age, being mostly incurable and with limited prognostic and diagnostic tools. Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the loss of motoneurons, with a complex etiology, combining genetic, epigenetic, and environmental causes. The neuroprotective therapeutic approaches are very limited, while the diagnostics rely on clinical examination and the exclusion of other diseases. The recent advancement in the discovery of molecular pathways and gene mutations involved in ALS has deepened the understanding of the disease pathology and opened the possibility for new treatments and diagnostic procedures. Recently, 15 risk loci with distinct genetic architectures and neuron-specific biology were identified as linked to ALS through common and rare variant association analyses. Interestingly, the quantity of related proteins to these genes has been found to change during early postnatal development in mammalian spinal cord tissue (opossum Monodelphis domestica) at the particular time when neuroregeneration stops being possible. Here, we discuss the possibility that the ALS-related genes/proteins could be connected to neuroregeneration and development. Moreover, since the regulation of gene expression in developmental checkpoints is frequently regulated by non-coding RNAs, we propose that studying the changes in the composition and quantity of non-coding RNA molecules, both in ALS patients and in the developing central nervous (CNS) system of the opossum at the time when neuroregeneration ceases, could reveal potential biomarkers useful in ALS prognosis and diagnosis. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 3.0)

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22 pages, 367 KiB

Open AccessReview

Electroencephalography as a Non-Invasive Biomarker of Alzheimer’s Disease: A Forgotten Candidate to Substitute CSF Molecules?

by Paloma Monllor, Ana Cervera-Ferri, Maria-Angeles Lloret, Daniel Esteve, Begoña Lopez, Jose-Luis Leon and Ana Lloret

Int. J. Mol. Sci. 2021, 22(19), 10889; https://doi.org/10.3390/ijms221910889 - 8 Oct 2021

Cited by 20 | Viewed by 3520

Abstract

Biomarkers for disease diagnosis and prognosis are crucial in clinical practice. They should be objective and quantifiable and respond to specific therapeutic interventions. Optimal biomarkers should reflect the underlying process (pathological or not), be reproducible, widely available, and allow measurements repeatedly over time. [...] Read more.

Biomarkers for disease diagnosis and prognosis are crucial in clinical practice. They should be objective and quantifiable and respond to specific therapeutic interventions. Optimal biomarkers should reflect the underlying process (pathological or not), be reproducible, widely available, and allow measurements repeatedly over time. Ideally, biomarkers should also be non-invasive and cost-effective. This review aims to focus on the usefulness and limitations of electroencephalography (EEG) in the search for Alzheimer’s disease (AD) biomarkers. The main aim of this article is to review the evolution of the most used biomarkers in AD and the need for new peripheral and, ideally, non-invasive biomarkers. The characteristics of the EEG as a possible source for biomarkers will be revised, highlighting its advantages compared to the molecular markers available so far. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

15 pages, 324 KiB

Open AccessReview

A Sex Perspective in Neurodegenerative Diseases: microRNAs as Possible Peripheral Biomarkers

by Paola Piscopo, Maria Bellenghi, Valeria Manzini, Alessio Crestini, Giada Pontecorvi, Massimo Corbo, Elena Ortona, Alessandra Carè and Annamaria Confaloni

Int. J. Mol. Sci. 2021, 22(9), 4423; https://doi.org/10.3390/ijms22094423 - 23 Apr 2021

Cited by 36 | Viewed by 3747

Abstract

Sex is a significant variable in the prevalence and incidence of neurological disorders. Sex differences exist in neurodegenerative disorders (NDs), where sex dimorphisms play important roles in the development and progression of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the last [...] Read more.

Sex is a significant variable in the prevalence and incidence of neurological disorders. Sex differences exist in neurodegenerative disorders (NDs), where sex dimorphisms play important roles in the development and progression of Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. In the last few years, some sex specific biomarkers for the identification of NDs have been described and recent studies have suggested that microRNA (miRNA) could be included among these, as influenced by the hormonal and genetic background. Failing to consider the possible differences between males and females in miRNA evaluation could introduce a sex bias in studies by not considering some of these sex-related biomarkers. In this review, we recapitulate what is known about the sex-specific differences in peripheral miRNA levels in neurodegenerative diseases. Several studies have reported sex-linked disparities, and from the literature analysis miR-206 particularly has been shown to have a sex-specific involvement. Hopefully, in the near future, patient stratification will provide important additional clues in diagnosis, prognosis, and tailoring of the best therapeutic approaches for each patient. Sex-specific biomarkers, such as miRNAs, could represent a useful tool for characterizing subgroups of patients. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

33 pages, 1135 KiB

Open AccessReview

Targeting for Success: Demonstrating Proof-of-Concept with Mechanistic Early Phase Clinical Pharmacology Studies for Disease-Modification in Neurodegenerative Disorders

by Maurits F. J. M. Vissers, Jules A. A. C. Heuberger and Geert Jan Groeneveld

Int. J. Mol. Sci. 2021, 22(4), 1615; https://doi.org/10.3390/ijms22041615 - 5 Feb 2021

Cited by 7 | Viewed by 4586

Abstract

The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we [...] Read more.

The clinical failure rate for disease-modifying treatments (DMTs) that slow or stop disease progression has been nearly 100% for the major neurodegenerative disorders (NDDs), with many compounds failing in expensive and time-consuming phase 2 and 3 trials for lack of efficacy. Here, we critically review the use of pharmacological and mechanistic biomarkers in early phase clinical trials of DMTs in NDDs, and propose a roadmap for providing early proof-of-concept to increase R&D productivity in this field of high unmet medical need. A literature search was performed on published early phase clinical trials aimed at the evaluation of NDD DMT compounds using MESH terms in PubMed. Publications were selected that reported an early phase clinical trial with NDD DMT compounds between 2010 and November 2020. Attention was given to the reported use of pharmacodynamic (mechanistic and physiological response) biomarkers. A total of 121 early phase clinical trials were identified, of which 89 trials (74%) incorporated one or multiple pharmacodynamic biomarkers. However, only 65 trials (54%) used mechanistic (target occupancy or activation) biomarkers to demonstrate target engagement in humans. The most important categories of early phase mechanistic and response biomarkers are discussed and a roadmap for incorporation of a robust biomarker strategy for early phase NDD DMT clinical trials is proposed. As our understanding of NDDs is improving, there is a rise in potentially disease-modifying treatments being brought to the clinic. Further increasing the rational use of mechanistic biomarkers in early phase trials for these (targeted) therapies can increase R&D productivity with a quick win/fast fail approach in an area that has seen a nearly 100% failure rate to date. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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21 pages, 687 KiB

Open AccessReview

What, When and How to Measure—Peripheral Biomarkers in Therapy of Huntington’s Disease

by Lukasz Przybyl, Magdalena Wozna-Wysocka, Emilia Kozlowska and Agnieszka Fiszer

Int. J. Mol. Sci. 2021, 22(4), 1561; https://doi.org/10.3390/ijms22041561 - 4 Feb 2021

Cited by 23 | Viewed by 5593

Abstract

Among the main challenges in further advancing therapeutic strategies for Huntington’s disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the [...] Read more.

Among the main challenges in further advancing therapeutic strategies for Huntington’s disease (HD) is the development of biomarkers which must be applied to assess the efficiency of the treatment. HD is a dreadful neurodegenerative disorder which has its source of pathogenesis in the central nervous system (CNS) but is reflected by symptoms in the periphery. Visible symptoms include motor deficits and slight changes in peripheral tissues, which can be used as hallmarks for prognosis of the course of HD, e.g., the onset of the disease symptoms. Knowing how the pathology develops in the context of whole organisms is crucial for the development of therapy which would be the most beneficial for patients, as well as for proposing appropriate biomarkers to monitor disease progression and/or efficiency of treatment. We focus here on molecular peripheral biomarkers which could be used as a measurable outcome of potential therapy. We present and discuss a list of wet biomarkers which have been proposed in recent years to measure pre- and postsymptomatic HD. Interestingly, investigation of peripheral biomarkers in HD can unravel new aspects of the disease pathogenesis. This especially refers to inflammatory proteins or specific immune cells which attract scientific attention in neurodegenerative disorders. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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42 pages, 1919 KiB

Open AccessReview

Competing Endogenous RNA Networks as Biomarkers in Neurodegenerative Diseases

by Leticia Moreno-García, Tresa López-Royo, Ana Cristina Calvo, Janne Markus Toivonen, Miriam de la Torre, Laura Moreno-Martínez, Nora Molina, Paula Aparicio, Pilar Zaragoza, Raquel Manzano and Rosario Osta

Int. J. Mol. Sci. 2020, 21(24), 9582; https://doi.org/10.3390/ijms21249582 - 16 Dec 2020

Cited by 74 | Viewed by 7900

Abstract

Protein aggregation is classically considered the main cause of neuronal death in neurodegenerative diseases (NDDs). However, increasing evidence suggests that alteration of RNA metabolism is a key factor in the etiopathogenesis of these complex disorders. Non-coding RNAs are the major contributor to the [...] Read more.

Protein aggregation is classically considered the main cause of neuronal death in neurodegenerative diseases (NDDs). However, increasing evidence suggests that alteration of RNA metabolism is a key factor in the etiopathogenesis of these complex disorders. Non-coding RNAs are the major contributor to the human transcriptome and are particularly abundant in the central nervous system, where they have been proposed to be involved in the onset and development of NDDs. Interestingly, some ncRNAs (such as lncRNAs, circRNAs and pseudogenes) share a common functionality in their ability to regulate gene expression by modulating miRNAs in a phenomenon known as the competing endogenous RNA mechanism. Moreover, ncRNAs are found in body fluids where their presence and concentration could serve as potential non-invasive biomarkers of NDDs. In this review, we summarize the ceRNA networks described in Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis and spinocerebellar ataxia type 7, and discuss their potential as biomarkers of these NDDs. Although numerous studies have been carried out, further research is needed to validate these complex interactions between RNAs and the alterations in RNA editing that could provide specific ceRNET profiles for neurodegenerative disorders, paving the way to a better understanding of these diseases. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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24 pages, 1415 KiB

Open AccessReview

Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway

by Nóra Török, Masaru Tanaka and László Vécsei

Int. J. Mol. Sci. 2020, 21(24), 9338; https://doi.org/10.3390/ijms21249338 - 8 Dec 2020

Cited by 97 | Viewed by 9202

Abstract

Neurodegenerative diseases are multifactorial, initiated by a series of the causative complex which develops into a certain clinical picture. The pathogenesis and disease course vary from patient to patient. Thus, it should be likewise to the treatment. Peripheral biomarkers are to play a [...] Read more.

Neurodegenerative diseases are multifactorial, initiated by a series of the causative complex which develops into a certain clinical picture. The pathogenesis and disease course vary from patient to patient. Thus, it should be likewise to the treatment. Peripheral biomarkers are to play a central role for tailoring a personalized therapeutic plan for patients who suffered from neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis, among others. Nevertheless, the use of biomarkers in clinical practice is still underappreciated and data presented in biomarker research for clinical use is still uncompelling, compared to the abundant data available for drug research and development. So is the case with kynurenines (KYNs) and the kynurenine pathway (KP) enzymes, which have been associated with a wide range of diseases including cancer, autoimmune diseases, inflammatory diseases, neurologic diseases, and psychiatric disorders. This review article discusses current knowledge of KP alterations observed in the central nervous system as well as the periphery, its involvement in pathogenesis and disease progression, and emerging evidence of roles of microbiota in the gut-brain axis, searching for practical peripheral biomarkers which ensure personalized treatment plans for neurodegenerative diseases. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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19 pages, 1298 KiB

Open AccessReview

Peripheral Glycolysis in Neurodegenerative Diseases

by Simon M. Bell, Toby Burgess, James Lee, Daniel J. Blackburn, Scott P. Allen and Heather Mortiboys

Int. J. Mol. Sci. 2020, 21(23), 8924; https://doi.org/10.3390/ijms21238924 - 24 Nov 2020

Cited by 43 | Viewed by 7207

Abstract

Neurodegenerative diseases are a group of nervous system conditions characterised pathologically by the abnormal deposition of protein throughout the brain and spinal cord. One common pathophysiological change seen in all neurodegenerative disease is a change to the metabolic function of nervous system and [...] Read more.

Neurodegenerative diseases are a group of nervous system conditions characterised pathologically by the abnormal deposition of protein throughout the brain and spinal cord. One common pathophysiological change seen in all neurodegenerative disease is a change to the metabolic function of nervous system and peripheral cells. Glycolysis is the conversion of glucose to pyruvate or lactate which results in the generation of ATP and has been shown to be abnormal in peripheral cells in Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. Changes to the glycolytic pathway are seen early in neurodegenerative disease and highlight how in multiple neurodegenerative conditions pathology is not always confined to the nervous system. In this paper, we review the abnormalities described in glycolysis in the three most common neurodegenerative diseases. We show that in all three diseases glycolytic changes are seen in fibroblasts, and red blood cells, and that liver, kidney, muscle and white blood cells have abnormal glycolysis in certain diseases. We highlight there is potential for peripheral glycolysis to be developed into multiple types of disease biomarker, but large-scale bio sampling and deciphering how glycolysis is inherently altered in neurodegenerative disease in multiple patients’ needs to be accomplished first to meet this aim. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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21 pages, 2168 KiB

Open AccessReview

Alpha-Synuclein in the Gastrointestinal Tract as a Potential Biomarker for Early Detection of Parkinson’s Disease

by Dominika Fricova, Jana Harsanyiova and Alzbeta Kralova Trancikova

Int. J. Mol. Sci. 2020, 21(22), 8666; https://doi.org/10.3390/ijms21228666 - 17 Nov 2020

Cited by 14 | Viewed by 6810

Abstract

The primary pathogenesis associated with Parkinson’s disease (PD) occurs in peripheral tissues several years before the onset of typical motor symptoms. Early and reliable diagnosis of PD could provide new treatment options for PD patients and improve their quality of life. At present, [...] Read more.

The primary pathogenesis associated with Parkinson’s disease (PD) occurs in peripheral tissues several years before the onset of typical motor symptoms. Early and reliable diagnosis of PD could provide new treatment options for PD patients and improve their quality of life. At present, however, diagnosis relies mainly on clinical symptoms, and definitive diagnosis is still based on postmortem pathological confirmation of dopaminergic neuronal degeneration. In addition, the similarity of the clinical, cognitive, and neuropathological features of PD with other neurodegenerative diseases calls for new biomarkers, suitable for differential diagnosis. Alpha-synuclein (α-Syn) is a potential PD biomarker, due to its close connection with the pathogenesis of the disease. Here we summarize the currently available information on the possible use of α-Syn as a biomarker of early stages of PD in gastrointestinal (GI) tissues, highlight its potential to distinguish PD and other neurodegenerative diseases, and suggest alternative methods (primarily developed for other tissue analysis) that could improve α-Syn detection procedures or diagnostic methods in general. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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27 pages, 2009 KiB

Open AccessReview

Utility of Animal Models to Understand Human Alzheimer’s Disease, Using the Mastermind Research Approach to Avoid Unnecessary Further Sacrifices of Animals

by Tian Qin, Samantha Prins, Geert Jan Groeneveld, Gerard Van Westen, Helga E. de Vries, Yin Cheong Wong, Luc J.M. Bischoff and Elizabeth C.M. de Lange

Int. J. Mol. Sci. 2020, 21(9), 3158; https://doi.org/10.3390/ijms21093158 - 30 Apr 2020

Cited by 14 | Viewed by 6478

Abstract

To diagnose and treat early-stage (preclinical) Alzheimer’s disease (AD) patients, we need body-fluid-based biomarkers that reflect the processes that occur in this stage, but current knowledge on associated processes is lacking. As human studies on (possible) onset and early-stage AD would be extremely [...] Read more.

To diagnose and treat early-stage (preclinical) Alzheimer’s disease (AD) patients, we need body-fluid-based biomarkers that reflect the processes that occur in this stage, but current knowledge on associated processes is lacking. As human studies on (possible) onset and early-stage AD would be extremely expensive and time-consuming, we investigate the potential value of animal AD models to help to fill this knowledge gap. We provide a comprehensive overview of processes associated with AD pathogenesis and biomarkers, current knowledge on AD-related biomarkers derived from on human and animal brains and body fluids, comparisons of biomarkers obtained in human AD and frequently used animal AD models, and emerging body-fluid-based biomarkers. In human studies, amyloid beta (Aβ), hyperphosphorylated tau (P-tau), total tau (T-tau), neurogranin, SNAP-25, glial fibrillary acidic protein (GFAP), YKL-40, and especially neurofilament light (NfL) are frequently measured. In animal studies, the emphasis has been mostly on Aβ. Although a direct comparison between human (familial and sporadic) AD and (mostly genetic) animal AD models cannot be made, still, in brain, cerebrospinal fluid (CSF), and blood, a majority of similar trends are observed for human AD stage and animal AD model life stage. This indicates the potential value of animal AD models in understanding of the onset and early stage of AD. Moreover, animal studies can be smartly designed to provide mechanistic information on the interrelationships between the different AD processes in a longitudinal fashion and may also include the combinations of different conditions that may reflect comorbidities in human AD, according to the Mastermind Research approach. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 2.0)

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21 pages, 672 KiB

Open AccessReview

Circulating RNAs as Potential Biomarkers in Amyotrophic Lateral Sclerosis

by Metka Ravnik-Glavač and Damjan Glavač

Int. J. Mol. Sci. 2020, 21(5), 1714; https://doi.org/10.3390/ijms21051714 - 3 Mar 2020

Cited by 44 | Viewed by 5433

Abstract

Amyotrophic lateral sclerosis (ALS) is a complex multi-system neurodegenerative disorder with currently limited diagnostic and no therapeutic options. Despite the intense efforts no clinically applicable biomarkers for ALS are yet established. Most current research is thus focused, in particular, in identifying potential non-invasive [...] Read more.

Amyotrophic lateral sclerosis (ALS) is a complex multi-system neurodegenerative disorder with currently limited diagnostic and no therapeutic options. Despite the intense efforts no clinically applicable biomarkers for ALS are yet established. Most current research is thus focused, in particular, in identifying potential non-invasive circulating biomarkers for more rapid and accurate diagnosis and monitoring of the disease. In this review, we have focused on messenger RNA (mRNA), non-coding RNAs (lncRNAs), micro RNAs (miRNAs) and circular RNA (circRNAs) as potential biomarkers for ALS in peripheral blood serum, plasma and cells. The most promising miRNAs include miR-206, miR-133b, miR-27a, mi-338-3p, miR-183, miR-451, let-7 and miR-125b. To test clinical potential of this miRNA panel, a useful approach may be to perform such analysis on larger multi-center scale using similar experimental design. However, other types of RNAs (lncRNAs, circRNAs and mRNAs) that, together with miRNAs, represent RNA networks, have not been yet extensively studied in blood samples of patients with ALS. Additional research has to be done in order to find robust circulating biomarkers and therapeutic targets that will distinguish key RNA interactions in specific ALS-types to facilitate diagnosis, predict progression and design therapy. Full article

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

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19 pages, 1944 KiB

Open AccessReview

Is Sleep Disruption a Cause or Consequence of Alzheimer’s Disease? Reviewing Its Possible Role as a Biomarker

by Maria-Angeles Lloret, Ana Cervera-Ferri, Mariana Nepomuceno, Paloma Monllor, Daniel Esteve and Ana Lloret

Int. J. Mol. Sci. 2020, 21(3), 1168; https://doi.org/10.3390/ijms21031168 - 10 Feb 2020

Cited by 39 | Viewed by 7785

Abstract

In recent years, the idea that sleep is critical for cognitive processing has gained strength. Alzheimer’s disease (AD) is the most common form of dementia worldwide and presents a high prevalence of sleep disturbances. However, it is difficult to establish causal relations, since [...] Read more.

In recent years, the idea that sleep is critical for cognitive processing has gained strength. Alzheimer’s disease (AD) is the most common form of dementia worldwide and presents a high prevalence of sleep disturbances. However, it is difficult to establish causal relations, since a vicious circle emerges between different aspects of the disease. Nowadays, we know that sleep is crucial to consolidate memory and to remove the excess of beta-amyloid and hyperphosphorilated tau accumulated in AD patients’ brains. In this review, we discuss how sleep disturbances often precede in years some pathological traits, as well as cognitive decline, in AD. We describe the relevance of sleep to memory consolidation, focusing on changes in sleep patterns in AD in contrast to normal aging. We also analyze whether sleep alterations could be useful biomarkers to predict the risk of developing AD and we compile some sleep-related proposed biomarkers. The relevance of the analysis of the sleep microstructure is highlighted to detect specific oscillatory patterns that could be useful as AD biomarkers. Full article

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

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16 pages, 932 KiB

Open AccessReview

The NRF2 Signaling Network Defines Clinical Biomarkers and Therapeutic Opportunity in Friedreich’s Ataxia

by Piergiorgio La Rosa, Enrico Silvio Bertini and Fiorella Piemonte

Int. J. Mol. Sci. 2020, 21(3), 916; https://doi.org/10.3390/ijms21030916 - 30 Jan 2020

Cited by 32 | Viewed by 9097

Abstract

Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction [...] Read more.

Friedreich’s ataxia (FA) is a trinucleotide repeats expansion neurodegenerative disorder, for which no cure or approved therapies are present. In most cases, GAA trinucleotide repetitions in the first intron of the FXN gene are the genetic trigger of FA, determining a strong reduction of frataxin, a mitochondrial protein involved in iron homeostasis. Frataxin depletion impairs iron–sulfur cluster biosynthesis and determines iron accumulation in the mitochondria. Mounting evidence suggests that these defects increase oxidative stress susceptibility and reactive oxygen species production in FA, where the pathologic picture is worsened by a defective regulation of the expression and signaling pathway modulation of the transcription factor NF-E2 p45-related factor 2 (NRF2), one of the fundamental mediators of the cellular antioxidant response. NRF2 protein downregulation and impairment of its nuclear translocation can compromise the adequate cellular response to the frataxin depletion-dependent redox imbalance. As NRF2 stability, expression, and activation can be modulated by diverse natural and synthetic compounds, efforts have been made in recent years to understand if regulating NRF2 signaling might ameliorate the pathologic defects in FA. Here we provide an analysis of the pharmaceutical interventions aimed at restoring the NRF2 signaling network in FA, elucidating specific biomarkers useful for monitoring therapeutic effectiveness, and developing new therapeutic tools. Full article

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

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15 pages, 1024 KiB

Open AccessReview

When Does Alzheimer′s Disease Really Start? The Role of Biomarkers

by Ana Lloret, Daniel Esteve, Maria-Angeles Lloret, Ana Cervera-Ferri, Begoña Lopez, Mariana Nepomuceno and Paloma Monllor

Int. J. Mol. Sci. 2019, 20(22), 5536; https://doi.org/10.3390/ijms20225536 - 6 Nov 2019

Cited by 70 | Viewed by 12271

Abstract

While Alzheimer’s disease (AD) classical diagnostic criteria rely on clinical data from a stablished symptomatic disease, newer criteria aim to identify the disease in its earlier stages. For that, they incorporated the use of AD’s specific biomarkers to reach a diagnosis, including the [...] Read more.

While Alzheimer’s disease (AD) classical diagnostic criteria rely on clinical data from a stablished symptomatic disease, newer criteria aim to identify the disease in its earlier stages. For that, they incorporated the use of AD’s specific biomarkers to reach a diagnosis, including the identification of Aβ and tau depositions, glucose hypometabolism, and cerebral atrophy. These biomarkers created a new concept of the disease, in which AD’s main pathological processes have already taken place decades before we can clinically diagnose the first symptoms. Therefore, AD is now considered a dynamic disease with a gradual progression, and dementia is its final stage. With that in mind, new models were proposed, considering the orderly increment of biomarkers and the disease as a continuum, or the variable time needed for the disease’s progression. In 2011, the National Institute on Aging and the Alzheimer’s Association (NIA-AA) created separate diagnostic recommendations for each stage of the disease continuum—preclinical, mild cognitive impairment, and dementia. However, new scientific advances have led them to create a unifying research framework in 2018 that, although not intended for clinical use as of yet, is a step toward shifting the focus from the clinical symptoms to the biological alterations and toward changing the future diagnostic and treatment possibilities. This review aims to discuss the role of biomarkers in the onset of AD. Full article

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

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7 pages, 581 KiB

Open AccessCommentary

Exploring the Skin Brain Link: Biomarkers in the Skin with Implications for Aging Research and Alzheimer’s Disease Diagnostics

by Stefanie Klostermeier, Annie Li, Helen X. Hou, Ula Green and Jochen K. Lennerz

Int. J. Mol. Sci. 2023, 24(17), 13309; https://doi.org/10.3390/ijms241713309 - 28 Aug 2023

Cited by 1 | Viewed by 2773

Abstract

Neurodegenerative diseases, including Alzheimer’s disease (AD), are challenging to diagnose. Currently the field must rely on imperfect diagnostic modalities. A recent study identified differences in several key bio-mechano-physiological parameters of the skin between AD patients and healthy controls. Here, we visually align these [...] Read more.

Neurodegenerative diseases, including Alzheimer’s disease (AD), are challenging to diagnose. Currently the field must rely on imperfect diagnostic modalities. A recent study identified differences in several key bio-mechano-physiological parameters of the skin between AD patients and healthy controls. Here, we visually align these differences with the relevant histological, aging, and embryological paradigms to raise awareness for these potential biomarkers. In a study conducted by Wu et al., a series of n = 41 patients (n = 29 with AD and n = 12 healthy controls) were evaluated, demonstrating that AD patients exhibit a less acidic skin pH, increased skin hydration, and reduced skin elasticity compared to healthy controls. We constructed a visual overview and explored the relevant paradigms. We present a visual comparison of these factors, highlighting four paradigms: (1) the findings emphasize a shared ectodermal origin of the brain and the skin; (2) functional systems such as micro-vascularization, innervation, eccrine excretory functions, and the extracellular matrix undergo distinct changes in patients with AD; (3) the human skin mirrors the alterations in brain stiffness observed in aging studies; (4) assessment of physiological features of the skin is cost-effective, accessible, and easily amenable for monitoring and integration with cognitive assessment studies. Understanding the relationship between aging skin and aging brain is an exciting frontier, holding great promise for improved diagnostics. Further prospective and larger-scale investigations are needed to solidify the brain-skin link and determine the extent to which this relationship can be leveraged for diagnostic applications. Full article

(This article belongs to the Special Issue Peripheral Biomarkers in Neurodegenerative Diseases 3.0)

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