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Peripheral Biomarkers in Neurodegenerative Diseases

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

Deadline for manuscript submissions: closed (31 December 2019) | Viewed by 55178

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Dr. Ana Lloret

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Facultad de Medicina y Odontologia, Universitat de Valencia, 46010 Valencia, Spain
Interests: Alzheimer's disease; oxidative stress; glutamate excitotoxicity in AD
Special Issues, Collections and Topics in MDPI journals

Dr. Ana Cervera

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Neuronal Circuits Lab, Department of Human Anatomy and Embryology, Faculty of Medicine and Odontology, Universitat de València, Av. Blasco Ibáñez 15, 46010 València, Spain
Interests: systems neuroscience; brain oscillations; hippocampus; memory processing; attention
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Special Issue Information

Dear colleagues,

The knowledge of neurodegenerative diseases has been circumscribed for many years to its clinical aspects and, in some cases, to different therapeutic attempts. Close to twenty years ago, little was known about the causes of these diseases and of their production mechanisms. The progress made in recent years has been very positive, and new avenues of investigation are being opened. Today we know that neurodegenerative diseases are mainly the consequence of abnormalities in the process of certain proteins, which gives rise to their accumulation in neurons or in their vicinity, diminishing or canceling their functions. The discovery of these proteins has allowed their use as molecular or imaging markers of these diseases, such as beta-amyloid in the case of Alzheimer's. Therefore, the use of biomarkers in the diagnosis of neurodegenerative diseases has increased in recent years. Biomarkers are events found in the human body that are used to identify a biological state. Clinically they are very useful to determine the risk, presence, and severity of a disease. Cerebrospinal fluid (CSF) is the most common source of molecular biomarkers in neurodegeneration. On the other hand, neuroimaging also provides important information about the affected brain areas. Among these biomarkers, those which are involved with neuroimaging are usually expensive and their affordability is frequently limited. CSF biomarkers are sensitive and specific, but their use is limited because a lumbar puncture is required and thus they can cause side effects.

Given the impact of dementia on the global population, the scientific community has driven itself into the quest of finding new biomarkers whose availability is easier for both patients and clinicians. Therefore, the option was to search for new blood-borne biomarkers. Moreover, due to the lower price and reduced invasiveness, a peripheral biomarker can also provide the chance to serve as a screening test to help the diagnosis of neurodegeneration and to monitor progression and response to a hypothetical treatment.

The purpose of this Special Issue is to collect recent information about peripheral biomarkers in neurodegenerative diseases such as Parkinson's, Alzheimer's, Lewy bodies dementia, multiple sclerosis, frontal dementia, Huntington disease, and others. Papers about molecules useful for diagnosis, evolution, prevention, and risk factors are welcome. We invite authors to contribute original research articles as well as review articles exploring peripheral biomarkers in neurodegeneration. Potential topics include but are not limited to the following:

- microRNAs, proteins, and lipids as peripheral biomarkers of Alzheimer’s, Parkinson’s, Huntington, etc.

- Oxidized or inflammation-related molecules as markers of any neurodegenerative disease.

- New CSF molecules as biomarkers of neurodegenerative diseases.

- Neuroimaging and neuronal activity as biomarkers of neurodegenerative diseases.

Dr. Ana Lloret
Dr. Ana Cervera
Guest Editors

Manuscript Submission Information

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Keywords

Alzheimer’s disease
Parkinson disease
Huntington disease
amyotrophic lateral sclerosis
Friedreich’s ataxia
Lewy bodies dementia
spinal muscular atrophy

Related Special Issues

Peripheral Biomarkers in Neurodegenerative Diseases 2.0 in International Journal of Molecular Sciences (21 articles)
Peripheral Biomarkers in Neurodegenerative Diseases 3.0 in International Journal of Molecular Sciences (40 articles)

Published Papers (10 papers)

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Research

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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 16 | Viewed by 3452

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 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 - 05 Dec 2019

Cited by 45 | Viewed by 4322

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 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 29 | Viewed by 5193

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 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

Open AccessArticle

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 25 | Viewed by 3595

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 (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

Open AccessArticle

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 - 09 Apr 2019

Cited by 7 | Viewed by 3160

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 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

Open AccessArticle

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 48 | Viewed by 4846

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 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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Review

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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 - 03 Mar 2020

Cited by 39 | Viewed by 4700

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 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 35 | Viewed by 6728

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 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 27 | Viewed by 7879

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 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 - 06 Nov 2019

Cited by 57 | Viewed by 10554

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 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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