Special Issue "Novel Biomarkers for Alzheimer’s Disease and other Neurodegenerative Diseases"

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: 30 June 2021.

Special Issue Editors

Dr. Dimitrios Kapogiannis
Website
Guest Editor
Laboratory of Clinical Investigation, National Institute on Aging/National Institutes of Health (NIA/NIH), Baltimore, MD 21224, USA; Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
Interests: exosomes; extracellular vesicles; biomarkers; Tau; insulin resistance; complement
Dr. Erden Eren

Guest Editor
Laboratory of Clinical Investigation, National Institute on Aging/National Institutes of Health (NIA/NIH), Baltimore, MD 21224, USA
Interests: exosomes; extracellular vesicles; biomarkers; Tau; insulin resistance; complement

Special Issue Information

Dear Colleagues,

The importance of biomarkers for clinical and preclinical diagnosis of Alzheimer’s disease and other neurodegenerative disorders is increasingly being recognized as an essential aspect of the worldwide effort to improve clinical outcomes and as a stepstone for therapeutic discovery. Traditional cerebrospinal fluid, peripheral blood, and neuroimaging biomarkers have made valuable contributions to our understanding of the evolution of these diseases but may have reached a plateau of potential impact. Novel approaches to biomarker discovery and validation are required for further progress to be made. This Special Issue aims to showcase novel candidate biomarkers and innovative approaches to biomarker discovery, with an emphasis on scientific rigor and reproducibility. Extracellular vesicle-based biomarkers and multi-omic approaches will be featured as particularly promising examples, but methodological challenges will be readily acknowledged and addressed.

Dr. Dimitrios Kapogiannis
Dr. Erden Eren
Guest Editors

Manuscript Submission Information

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Keywords

  • Alzheimer’s Disease
  • neurodegenerative diseases
  • biomarkers
  • neuroinflammation
  • Tau
  • exosomes
  • extracellular vesicles

Published Papers (8 papers)

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Research

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Open AccessArticle
Characterization and Biomarker Analyses of Post-COVID-19 Complications and Neurological Manifestations
Cells 2021, 10(2), 386; https://doi.org/10.3390/cells10020386 - 13 Feb 2021
Abstract
As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected [...] Read more.
As the SARS-CoV-2 pandemic continues, reports have demonstrated neurologic sequelae following COVID-19 recovery. Mechanisms to explain long-term neurological sequelae are unknown and need to be identified. Plasma from 24 individuals recovering from COVID-19 at 1 to 3 months after initial infection were collected for cytokine and antibody levels and neuronal-enriched extracellular vesicle (nEV) protein cargo analyses. Plasma cytokine IL-4 was increased in all COVID-19 participants. Volunteers with self-reported neurological problems (nCoV, n = 8) had a positive correlation of IL6 with age or severity of the sequalae, at least one co-morbidity and increased SARS-CoV-2 antibody compared to those COVID-19 individuals without neurological issues (CoV, n = 16). Protein markers of neuronal dysfunction including amyloid beta, neurofilament light, neurogranin, total tau, and p-T181-tau were all significantly increased in the nEVs of all participants recovering from COVID-19 compared to historic controls. This study suggests ongoing peripheral and neuroinflammation after COVID-19 infection that may influence neurological sequelae by altering nEV proteins. Individuals recovering from COVID-19 may have occult neural damage while those with demonstrative neurological symptoms additionally had more severe infection. Longitudinal studies to monitor plasma biomarkers and nEV cargo are warranted to assess persistent neurodegeneration and systemic effects. Full article
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Open AccessArticle
Pathologically Decreased CSF Levels of Synaptic Marker NPTX2 in DLB Are Correlated with Levels of Alpha-Synuclein and VGF
Cells 2021, 10(1), 38; https://doi.org/10.3390/cells10010038 - 29 Dec 2020
Abstract
Background: Dementia with Lewy bodies (DLB) is a neurodegenerative disease where synaptic loss and reduced synaptic integrity are important neuropathological substrates. Neuronal Pentraxin 2(NPTX2) is a synaptic protein that drives the GABAergic inhibitory circuit. Our aim was to examine if NPTX2 cerebral spinal [...] Read more.
Background: Dementia with Lewy bodies (DLB) is a neurodegenerative disease where synaptic loss and reduced synaptic integrity are important neuropathological substrates. Neuronal Pentraxin 2(NPTX2) is a synaptic protein that drives the GABAergic inhibitory circuit. Our aim was to examine if NPTX2 cerebral spinal fluid (CSF) levels in DLB patients were altered and how these levels related to other synaptic protein levels and to cognitive function and decline. Methods: NPTX2, VGF, and α-synuclein levels were determined in CSF of cognitive healthy (n = 27), DLB (n = 48), and AD (n = 20) subjects. Multiple cognitive domains were tested, and data were compared using linear models. Results: Decreased NPTX2 levels were observed in DLB (median = 474) and AD (median = 453) compared to cognitive healthy subjects (median = 773). Strong correlations between NPTX2, VGF, and α-synuclein were observed dependent on diagnosis. Combined, these markers had a high differentiating power between DLB and cognitive healthy subjects (AUC = 0.944). Clinically, NPTX2 levels related to global cognitive function and cognitive decline in the visual spatial domain. Conclusion: NPTX2 CSF levels were reduced in DLB and closely correlated to decreased VGF and α-synuclein CSF levels. CSF NPTX2 levels in DLB related to decreased functioning in the visual spatial domain. Full article
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Open AccessArticle
Hearing Loss in Alzheimer’s Disease Is Associated with Altered Serum Lipidomic Biomarker Profiles
Cells 2020, 9(12), 2556; https://doi.org/10.3390/cells9122556 - 28 Nov 2020
Cited by 1
Abstract
Recent data have found that aging-related hearing loss (ARHL) is associated with the development of Alzheimer’s Disease (AD). However, the nature of the relationship between these two disorders is not clear. There are multiple potential factors that link ARHL and AD, and previous [...] Read more.
Recent data have found that aging-related hearing loss (ARHL) is associated with the development of Alzheimer’s Disease (AD). However, the nature of the relationship between these two disorders is not clear. There are multiple potential factors that link ARHL and AD, and previous investigators have speculated that shared metabolic dysregulation may underlie the propensity to develop both disorders. Here, we investigate the distribution of serum lipidomic biomarkers in AD subjects with or without hearing loss in a publicly available dataset. Serum levels of 349 known lipids from 16 lipid classes were measured in 185 AD patients. Using previously defined co-regulated sets of lipids, both age- and sex-adjusted, we found that lipid sets enriched in phosphatidylcholine and phosphatidylethanolamine showed a strong inverse association with hearing loss. Examination of biochemical classes confirmed these relationships and revealed that serum phosphatidylcholine levels were significantly lower in AD subjects with hearing loss. A similar relationship was not found in normal subjects. These data suggest that a synergistic relationship may exist between AD, hearing loss and metabolic biomarkers, such that in the context of a pathological state such as AD, alterations in serum metabolic profiles are associated with hearing loss. These data also point to a potential role for phosphatidylcholine, a molecule with antioxidant properties, in the underlying pathophysiology of ARHL in the context of AD, which has implications for our understanding and potential treatment of both disorders. Full article
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Open AccessArticle
Proteomic Profiling of Extracellular Vesicles Derived from Cerebrospinal Fluid of Alzheimer’s Disease Patients: A Pilot Study
Cells 2020, 9(9), 1959; https://doi.org/10.3390/cells9091959 - 25 Aug 2020
Cited by 6
Abstract
Pathological hallmarks of Alzheimer’s disease (AD) are deposits of amyloid beta (Aβ) and hyper-phosphorylated tau aggregates in brain plaques. Recent studies have highlighted the importance of Aβ and tau-containing extracellular vesicles (EVs) in AD. We therefore examined EVs separated from cerebrospinal fluid (CSF) [...] Read more.
Pathological hallmarks of Alzheimer’s disease (AD) are deposits of amyloid beta (Aβ) and hyper-phosphorylated tau aggregates in brain plaques. Recent studies have highlighted the importance of Aβ and tau-containing extracellular vesicles (EVs) in AD. We therefore examined EVs separated from cerebrospinal fluid (CSF) of AD, mild cognitive impairment (MCI), and control (CTRL) patient samples to profile the protein composition of CSF EV. EV fractions were separated from AD (n = 13), MCI (n = 10), and CTRL (n = 10) CSF samples using MagCapture Exosome Isolation kit. The CSF-derived EV proteins were identified and quantified by label-free and tandem mass tag (TMT)-labeled mass spectrometry. Label-free proteomics analysis identified 2546 proteins that were significantly enriched for extracellular exosome ontology by Gene Ontology analysis. Canonical Pathway Analysis revealed glia-related signaling. Quantitative proteomics analysis, moreover, showed that EVs expressed 1284 unique proteins in AD, MCI and CTRL groups. Statistical analysis identified three proteins—HSPA1A, NPEPPS, and PTGFRN—involved in AD progression. In addition, the PTGFRN showed a moderate correlation with amyloid plaque (rho = 0.404, p = 0.027) and tangle scores (rho = 0.500, p = 0.005) in AD, MCI and CTRL. Based on the CSF EV proteomics, these data indicate that three proteins, HSPA1A, NPEPPS and PTGFRN, may be used to monitor the progression of MCI to AD. Full article
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Open AccessArticle
Revealing the Proteome of Motor Cortex Derived Extracellular Vesicles Isolated from Amyotrophic Lateral Sclerosis Human Postmortem Tissues
Cells 2020, 9(7), 1709; https://doi.org/10.3390/cells9071709 - 16 Jul 2020
Cited by 2
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the deposition of misfolded proteins in the motor cortex and motor neurons. Although a multitude of ALS-associated mutated proteins have been identified, several have been linked to small extracellular vesicles such as exosomes [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by the deposition of misfolded proteins in the motor cortex and motor neurons. Although a multitude of ALS-associated mutated proteins have been identified, several have been linked to small extracellular vesicles such as exosomes involved in cell−cell communication. This study aims to determine the proteome of extracellular vesicles isolated from the motor cortex of ALS subjects and to identify novel ALS-associated deregulated proteins. Motor cortex extracellular vesicles (MCEVs) were isolated from human postmortem ALS (n = 10) and neurological control (NC, n = 5) motor cortex brain tissues and the MCEVs protein content subsequently underwent mass spectrometry analysis, allowing for a panel of ALS-associated proteins to be identified. This panel consists of 16 statistically significant differentially packaged proteins identified in the ALS MCEVs. This includes several upregulated RNA-binding proteins which were determined through pathway analysis to be associated with stress granule dynamics. The identification of these RNA-binding proteins in the ALS MCEVs suggests there may be a relationship between ALS-associated stress granules and ALS MCEV packaging, highlighting a potential role for small extracellular vesicles such as exosomes in the pathogenesis of ALS and as potential peripheral biomarkers for ALS. Full article
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Open AccessFeature PaperArticle
Astrocyte- and Neuron-Derived Extracellular Vesicles from Alzheimer’s Disease Patients Effect Complement-Mediated Neurotoxicity
Cells 2020, 9(7), 1618; https://doi.org/10.3390/cells9071618 - 04 Jul 2020
Cited by 4
Abstract
We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurotoxicity involving Membrane Attack Complex (MAC) formation, we assessed the effects [...] Read more.
We have previously shown that blood astrocytic-origin extracellular vesicles (AEVs) from Alzheimer’s disease (AD) patients contain high complement levels. To test the hypothesis that circulating EVs from AD patients can induce complement-mediated neurotoxicity involving Membrane Attack Complex (MAC) formation, we assessed the effects of immunocaptured AEVs (using anti-GLAST antibody), in comparison with neuronal-origin (N)EVs (using anti-L1CAM antibody), and nonspecific CD81+ EVs (using anti-CD81 antibody), from the plasma of AD, frontotemporal lobar degeneration (FTLD), and control participants. AEVs (and, less effectively, NEVs) of AD participants induced Membrane Attack Complex (MAC) expression on recipient neurons (by immunohistochemistry), membrane disruption (by EthD-1 assay), reduced neurite density (by Tuj-1 immunohistochemistry), and decreased cell viability (by MTT assay) in rat cortical neurons and human iPSC-derived neurons. Demonstration of decreased cell viability was replicated in a separate cohort of autopsy-confirmed AD patients. These effects were not produced by CD81+ EVs from AD participants or AEVs/NEVs from FTLD or control participants, and were suppressed by the MAC inhibitor CD59 and other complement inhibitors. Our results support the stated hypothesis and should motivate future studies on the roles of neuronal MAC deposition and AEV/NEV uptake, as effectors of neurodegeneration in AD. Full article
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Review

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Open AccessReview
Novel PET Biomarkers to Disentangle Molecular Pathways across Age-Related Neurodegenerative Diseases
Cells 2020, 9(12), 2581; https://doi.org/10.3390/cells9122581 - 02 Dec 2020
Abstract
There is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could [...] Read more.
There is a need to disentangle the etiological puzzle of age-related neurodegenerative diseases, whose clinical phenotypes arise from known, and as yet unknown, pathways that can act distinctly or in concert. Enhanced sub-phenotyping and the identification of in vivo biomarker-driven signature profiles could improve the stratification of patients into clinical trials and, potentially, help to drive the treatment landscape towards the precision medicine paradigm. The rapidly growing field of neuroimaging offers valuable tools to investigate disease pathophysiology and molecular pathways in humans, with the potential to capture the whole disease course starting from preclinical stages. Positron emission tomography (PET) combines the advantages of a versatile imaging technique with the ability to quantify, to nanomolar sensitivity, molecular targets in vivo. This review will discuss current research and available imaging biomarkers evaluating dysregulation of the main molecular pathways across age-related neurodegenerative diseases. The molecular pathways focused on in this review involve mitochondrial dysfunction and energy dysregulation; neuroinflammation; protein misfolding; aggregation and the concepts of pathobiology, synaptic dysfunction, neurotransmitter dysregulation and dysfunction of the glymphatic system. The use of PET imaging to dissect these molecular pathways and the potential to aid sub-phenotyping will be discussed, with a focus on novel PET biomarkers. Full article
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Open AccessReview
Extracellular Vesicles in Alzheimer’s and Parkinson’s Disease: Small Entities with Large Consequences
Cells 2020, 9(11), 2485; https://doi.org/10.3390/cells9112485 - 15 Nov 2020
Cited by 2
Abstract
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are incurable, devastating neurodegenerative disorders characterized by the formation and spreading of protein aggregates throughout the brain. Although the exact spreading mechanism is not completely understood, extracellular vesicles (EVs) have been proposed as potential contributors. Indeed, [...] Read more.
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are incurable, devastating neurodegenerative disorders characterized by the formation and spreading of protein aggregates throughout the brain. Although the exact spreading mechanism is not completely understood, extracellular vesicles (EVs) have been proposed as potential contributors. Indeed, EVs have emerged as potential carriers of disease-associated proteins and are therefore thought to play an important role in disease progression, although some beneficial functions have also been attributed to them. EVs can be isolated from a variety of sources, including biofluids, and the analysis of their content can provide a snapshot of ongoing pathological changes in the brain. This underlines their potential as biomarker candidates which is of specific relevance in AD and PD where symptoms only arise after considerable and irreversible neuronal damage has already occurred. In this review, we discuss the known beneficial and detrimental functions of EVs in AD and PD and we highlight their promising potential to be used as biomarkers in both diseases. Full article
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