AUTHOR	TITLE	JOURNAL	LANGUANGE	DOCTYPE	KEYWORDS	ABSTRACT	AFFILIATION	EMAIL 	DOI	PUBYEAR	PUBVOL	PUBISSUE	FPAGE	LPAGE	ARTNUMBER	PAGENUM
Cybulska, Klaudia; Perk, Lars; Booij, Jan; Laverman, Peter; Rijpkema, Mark	Huntington’s Disease: A Review of the Known PET Imaging Biomarkers and Targeting Radiotracers	Molecules	EN	Review	Huntington’s disease; mutant huntingtin; Positron Emission Tomography; radiochemistry; fluorine-18; carbon-11; radiopharmaceuticals; [11C]raclopride; [18F]MNI-659	Huntington’s disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the huntingtin gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomography (PET) studies relating to HD was performed, including clinical and preclinical data. PET is a powerful tool for visualisation of the HD pathology by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed molecular snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognise particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochemical picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.	Department of Radiology and Nuclear Medicine, Radboud University Medical Center, Geert Grooteplein-Zuid 10, 6525 EZ Nijmegen, The Netherlands	klaudia.cybulska@radboudumc.nl; lars.perk@radboudumc.nl; jan.booij@radboudumc.nl; peter.laverman@radboudumc.nl; mark.rijpkema@radboudumc.nl	10.3390/molecules25030482	2020	25	3	-	-	482	-
Pelucchi, Silvia; Stringhi, Ramona; Marcello, Elena	Dendritic Spines in Alzheimer’s Disease: How the Actin Cytoskeleton Contributes to Synaptic Failure	International Journal of Molecular Sciences	EN	Review	synaptopathy; actin cytoskeleton; actin-binding proteins; amyloid; synaptic plasticity	Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by Aβ-driven synaptic dysfunction in the early phases of pathogenesis. In the synaptic context, the actin cytoskeleton is a crucial element to maintain the dendritic spine architecture and to orchestrate the spine’s morphology remodeling driven by synaptic activity. Indeed, spine shape and synaptic strength are strictly correlated and precisely governed during plasticity phenomena in order to convert short-term alterations of synaptic strength into long-lasting changes that are embedded in stable structural modification. These functional and structural modifications are considered the biological basis of learning and memory processes. In this review we discussed the existing evidence regarding the role of the spine actin cytoskeleton in AD synaptic failure. We revised the physiological function of the actin cytoskeleton in the spine shaping and the contribution of actin dynamics in the endocytosis mechanism. The internalization process is implicated in different aspects of AD since it controls both glutamate receptor membrane levels and amyloid generation. The detailed understanding of the mechanisms controlling the actin cytoskeleton in a unique biological context as the dendritic spine could pave the way to the development of innovative synapse-tailored therapeutic interventions and to the identification of novel biomarkers to monitor synaptic loss in AD.	Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milan, Italy	silvia.pelucchi@unimi.it; stringhi.ramona@gmail.com; elena.marcello@unimi.it	10.3390/ijms21030908	2020	21	3	-	-	908	-
Barkovits, Katalin; Kruse, Niels; Linden, Andreas; Tönges, Lars; Pfeiffer, Kathy; Mollenhauer, Brit; Marcus, Katrin	Blood Contamination in CSF and Its Impact on Quantitative Analysis of Alpha-Synuclein	Cells	EN	Article	cerebrospinal fluid; blood contamination; mass spectrometry; ELISA; urine strip; alpha-synuclein; quantification	Analysis of cerebrospinal fluid (CSF) is important for diagnosis of neurological diseases. Especially for neurodegenerative diseases, abnormal protein abundance in CSF is an important biomarker. However, the quality of CSF is a key factor for the analytic outcome. Any external contamination has tremendous impact on the analysis and the reliability of the results. In this study, we evaluated the effect of blood contamination in CSF with respect to protein biomarker identification. We compared three distinct measures: Combur10-Test® strips, a specific hemoglobin ELISA, and bottom-up mass spectrometry (MS)-based proteomics for the determination of the general blood contamination level. In parallel, we studied the impact of blood contamination on the detectability of alpha-synuclein (aSyn), a highly abundant protein in blood/erythrocytes and a potential biomarker for Parkinson’s disease. Comparable results were achieved, with all three approaches enabling detection of blood levels in CSF down to 0.001%. We found higher aSyn levels with increasing blood contamination, highlighting the difficulty of authentic quantification of this protein in CSF. Based on our results, we identified other markers for blood contamination beyond hemoglobin and defined a grading system for blood levels in CSF samples, including a lower limit of tolerable blood contamination for MS-based biomarker studies.	Ruhr-University, Faculty of Medicine, Medizinisches Proteom-Center, 44801 Bochum, Germany	katalin.barkovits@rub.de; n.kruse@med.uni-goettingen.de; andreas.linden@mpibpc.mpg.de; lars.toenges@rub.de; kathy.pfeiffer@rub.de; brit.mollenhauer@paracelsus-kliniken.de; katrin.marcus@rub.de	10.3390/cells9020370	2020	9	2	-	-	370	-
Tschuschke, Max; Kocherova, Ievgeniia; Bryja, Artur; Mozdziak, Paul; Angelova Volponi, Ana; Janowicz, Krzysztof; Sibiak, Rafał; Piotrowska-Kempisty, Hanna; Iżycki, Dariusz; Bukowska, Dorota; Antosik, Paweł; Shibli, Jamil; Dyszkiewicz-Konwińska, Marta; Kempisty, Bartosz	Inclusion Biogenesis, Methods of Isolation and Clinical Application of Human Cellular Exosomes	Journal of Clinical Medicine	EN	Review	exosome; neurodegenerative disease; cancer; biomarker; clinical application	Exosomes are a heterogenous subpopulation of extracellular vesicles 30–150 nm in range and of endosome-derived origin. We explored the exosome formation through different systems, including the endosomal sorting complex required for transport (ESCRT) and ESCRT-independent system, looking at the mechanisms of release. Different isolation techniques and specificities of exosomes from different tissues and cells are also discussed. Despite more than 30 years of research that followed their definition and indicated their important role in cellular physiology, the exosome biology is still in its infancy with rapidly growing interest. The reasons for the rapid increase in interest with respect to exosome biology is because they provide means of intercellular communication and transmission of macromolecules between cells, with a potential role in the development of diseases. Moreover, they have been investigated as prognostic biomarkers, with a potential for further development as diagnostic tools for neurodegenerative diseases and cancer. The interest grows further with the fact that exosomes were reported as useful vectors for drugs.	Department of Anatomy, Poznan University of Medical Sciences, 60-781 Poznań, Poland	maxtsch@wp.pl; ikocherova@ump.edu.pl; abryja@ump.edu.pl; pemozdzi@ncsu.edu; ana.angelova@kcl.ac.uk; krzysztof.janowicz.16@abdn.ac.uk; 75094@student.ump.edu.pl; hpiotrow@ump.edu.pl; dmizy@ump.edu.pl; dbukowska@umk.pl; pantosik@umk.pl; jashibli@yahoo.com; m.dyszkiewicz@ump.edu.pl; bkempisty@ump.edu.pl	10.3390/jcm9020436	2020	9	2	-	-	436	-
Maciejczyk, Mateusz; Zalewska, Anna; Gerreth, Karolina	Salivary Redox Biomarkers in Selected Neurodegenerative Diseases	Journal of Clinical Medicine	EN	Review	neurodegenerative diseases (NDDs); saliva; oxidative stress; salivary biomarkers	Neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, are disorders, which cause irreversible and progressive deterioration of the central nervous system. The pathophysiology of NDDs is still not fully explained; nevertheless, oxidative stress is considered as a critical mediator of cerebral degeneration, brain inflammation, as well as neuronal apoptosis. Therefore, it is not surprising that redox biomarkers are increasingly used in the diagnosis of neurodegenerative diseases. As saliva is a very easy to obtain bioliquid, it seems promising to use this biomaterial in the diagnosis of NDDs. Saliva collection is easy, cheap, stress-free, and non-infectious, and it does not require the help of a specialised medical personnel. Additionally, the concentrations of many salivary redox biomarkers correlate with their content in blood serum as well as the degree of disease progression, which makes them non-invasive indicators of NDDs. This paper reviews the latest knowledge concerning the use of salivary redox biomarkers in the diagnosis and prognosis of selected neurodegenerative diseases.	Department of Hygiene, Epidemiology and Ergonomics, Medical University of Bialystok, 2C Adama Mickiewicza Street, 15-022 Bialystok, Poland	mat.maciejczyk@gmail.com; azalewska426@gmail.com; karolinagerreth@poczta.onet.pl	10.3390/jcm9020497	2020	9	2	-	-	497	-
Mansuriya, Bhargav; Altintas, Zeynep	Applications of Graphene Quantum Dots in Biomedical Sensors	Sensors	EN	Review	graphene quantum dots (GQDs); nanomaterials; biosensors; optical sensors; electrochemical sensors; photoelectrochemical sensors; biomedical applications	Due to the proliferative cancer rates, cardiovascular diseases, neurodegenerative disorders, autoimmune diseases and a plethora of infections across the globe, it is essential to introduce strategies that can rapidly and specifically detect the ultralow concentrations of relevant biomarkers, pathogens, toxins and pharmaceuticals in biological matrices. Considering these pathophysiologies, various research works have become necessary to fabricate biosensors for their early diagnosis and treatment, using nanomaterials like quantum dots (QDs). These nanomaterials effectively ameliorate the sensor performance with respect to their reproducibility, selectivity as well as sensitivity. In particular, graphene quantum dots (GQDs), which are ideally graphene fragments of nanometer size, constitute discrete features such as acting as attractive fluorophores and excellent electro-catalysts owing to their photo-stability, water-solubility, biocompatibility, non-toxicity and lucrativeness that make them favorable candidates for a wide range of novel biomedical applications. Herein, we reviewed about 300 biomedical studies reported over the last five years which entail the state of art as well as some pioneering ideas with respect to the prominent role of GQDs, especially in the development of optical, electrochemical and photoelectrochemical biosensors. Additionally, we outline the ideal properties of GQDs, their eclectic methods of synthesis, and the general principle behind several biosensing techniques.	Technical University of Berlin, Straße des 17. Juni 124, 10623 Berlin, Germany	b.mansuriya@campus.tu-berlin.de; zeynep.altintas@tu-berlin.de	10.3390/s20041072	2020	20	4	-	-	1072	-
Perez, Barbara; Shutterly, Alison; Chan, Ying; Byrne, Barry; Corti, Manuela	Management of Neuroinflammatory Responses to AAV-Mediated Gene Therapies for Neurodegenerative Diseases	Brain Sciences	EN	Review	AAV; gene therapy; neurodegeneration; neuroinflammation; immunosuppression	Recently, adeno-associated virus (AAV)-mediated gene therapies have attracted clinical interest for treating neurodegenerative diseases including spinal muscular atrophy (SMA), Canavan disease (CD), Parkinson’s disease (PD), and Friedreich’s ataxia (FA). The influx of clinical findings led to the first approved gene therapy for neurodegenerative disorders in 2019 and highlighted new safety concerns for patients. Large doses of systemically administered AAV stimulate host immune responses, resulting in anti-capsid and anti-transgene immunity with implications for transgene expression, treatment longevity, and patient safety. Delivering lower doses directly to the central nervous system (CNS) is a promising alternative, resulting in higher transgene expression with decreased immune responses. However, neuroinflammatory responses after CNS-targeted delivery of AAV are a critical concern. Reported signs of AAV-associated neuroinflammation in preclinical studies include dorsal root ganglion (DRG) and spinal cord pathology with mononuclear cell infiltration. In this review, we discuss ways to manage neuroinflammation, including choice of AAV capsid serotypes, CNS-targeting routes of delivery, genetic modifications to the vector and/or transgene, and adding immunosuppressive strategies to clinical protocols. As additional gene therapies for neurodegenerative diseases enter clinics, tracking biomarkers of neuroinflammation will be important for understanding the impact immune reactions can have on treatment safety and efficacy.	Department of Pediatrics and Powell Gene Therapy Center, University of Florida, Gainesville, FL 32610, USA	barbara.perez@ufl.edu; alison.shutterly@aavantibio.com; yingkai_chan@hms.harvard.edu; barry.byrne@ufl.edu; m.corti@ufl.edu	10.3390/brainsci10020119	2020	10	2	-	-	119	-
Kao, Yu-Chia; Ho, Pei-Chuan; Tu, Yuan-Kun; Jou, I-Ming; Tsai, Kuen-Jer	Lipids and Alzheimer’s Disease	International Journal of Molecular Sciences	EN	Review	Alzheimer disease; lipids; fats; fatty acids; cholesterols; lipidomics	Lipids, as the basic component of cell membranes, play an important role in human health as well as brain function. The brain is highly enriched in lipids, and disruption of lipid homeostasis is related to neurologic disorders as well as neurodegenerative diseases such as Alzheimer’s disease (AD). Aging is associated with changes in lipid composition. Alterations of fatty acids at the level of lipid rafts and cerebral lipid peroxidation were found in the early stage of AD. Genetic and environmental factors such as apolipoprotein and lipid transporter carrying status and dietary lipid content are associated with AD. Insight into the connection between lipids and AD is crucial to unraveling the metabolic aspects of this puzzling disease. Recent advances in lipid analytical methodology have led us to gain an in-depth understanding on lipids. As a result, lipidomics have becoming a hot topic of investigation in AD, in order to find biomarkers for disease prediction, diagnosis, and prevention, with the ultimate goal of discovering novel therapeutics.	Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan	yukanomail2006@yahoo.com.tw; peggy821124@gmail.com; ed100917@edah.org.tw; jming@mail.ncku.edu.tw; kjtsai@mail.ncku.edu.tw	10.3390/ijms21041505	2020	21	4	-	-	1505	-
Lin, Xiaozeng; Kapoor, Anil; Gu, Yan; Chow, Mathilda; Peng, Jingyi; Zhao, Kuncheng; Tang, Damu	Contributions of DNA Damage to Alzheimer’s Disease	International Journal of Molecular Sciences	EN	Review	Alzheimer’s disease pathogenesis; diagnostic biomarkers for Alzheimer disease; DNA damage response; DNA damage repair	Alzheimer’s disease (AD) is the most common type of neurodegenerative disease. Its typical pathology consists of extracellular amyloid-β (Aβ) plaques and intracellular tau neurofibrillary tangles. Mutations in the APP, PSEN1, and PSEN2 genes increase Aβ production and aggregation, and thus cause early onset or familial AD. Even with this strong genetic evidence, recent studies support AD to result from complex etiological alterations. Among them, aging is the strongest risk factor for the vast majority of AD cases: Sporadic late onset AD (LOAD). Accumulation of DNA damage is a well-established aging factor. In this regard, a large amount of evidence reveals DNA damage as a critical pathological cause of AD. Clinically, DNA damage is accumulated in brains of AD patients. Genetically, defects in DNA damage repair resulted from mutations in the BRAC1 and other DNA damage repair genes occur in AD brain and facilitate the pathogenesis. Abnormalities in DNA damage repair can be used as diagnostic biomarkers for AD. In this review, we discuss the association, the causative potential, and the biomarker values of DNA damage in AD pathogenesis.	Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada	linx36@mcmaster.ca; akapoor@mcmaster.ca; yangu0220@gmail.com; mathildachow1994@gmail.com; pengj31@mcmaster.ca; kunchengzhao@icloud.com; damut@mcmaster.ca	10.3390/ijms21051666	2020	21	5	-	-	1666	-
Hara, Akira; Niwa, Masayuki; Noguchi, Kei; Kanayama, Tomohiro; Niwa, Ayumi; Matsuo, Mikiko; Hatano, Yuichiro; Tomita, Hiroyuki	Galectin-3 as a Next-Generation Biomarker for Detecting Early Stage of Various Diseases	Biomolecules	EN	Review	galectin-3; biomarker; diagnostic; prognostic; early stage; tumor; animal model	Galectin-3 is a β-galactoside-binding lectin which is important in numerous biological activities in various organs, including cell proliferation, apoptotic regulation, inflammation, fibrosis, and host defense. Galectin-3 is predominantly located in the cytoplasm and expressed on the cell surface, and then often secreted into biological fluids, like serum and urine. It is also released from injured cells and inflammatory cells under various pathological conditions. Many studies have revealed that galectin-3 plays an important role as a diagnostic or prognostic biomarker for certain types of heart disease, kidney disease, viral infection, autoimmune disease, neurodegenerative disorders, and tumor formation. In particular, it has been recognized that galectin-3 is extremely useful for detecting many of these diseases in their early stages. The purpose of this article is to review and summarize the recent literature focusing on the biomarker characteristics and long-term outcome predictions of galectin-3, in not only patients with various types of diseases, but associated animal models.	Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan	ahara@gifu-u.ac.jp; mniwa@gifu-u.ac.jp; v2111027@edu.gifu-u.ac.jp; t_knym@gifu-u.ac.jp; mulmirry@yahoo.co.jp; kyokui100202@gmail.com; yuha@gifu-u.ac.jp; h_tomita@gifu-u.ac.jp	10.3390/biom10030389	2020	10	3	-	-	389	-
Nambo-Venegas, Rafael; Valdez-Vargas, Claudia; Cisneros, Bulmaro; Palacios-González, Berenice; Vela-Amieva, Marcela; Ibarra-González, Isabel; Cerecedo-Zapata, César; Martínez-Cruz, Emilio; Cortés, Hernán; Reyes-Grajeda, Juan; Magaña, Jonathan	Altered Plasma Acylcarnitines and Amino Acids Profile in Spinocerebellar Ataxia Type 7	Biomolecules	EN	Article	spinocerebellar ataxia 7; CAG repeats; polyglutamine disease; metabolomics; biomarkers; mitochondrial disease; metabolic pathways	Spinocerebellar ataxia type 7 (SCA7), a neurodegenerative disease characterized by cerebellar ataxia and retinal degeneration, is caused by an abnormal CAG repeat expansion in the ATXN7 gene coding region. The onset and severity of SCA7 are highly variable between patients, thus identification of sensitive biomarkers that accurately diagnose the disease and monitoring its progression are needed. With the aim of identified SCA7-specific metabolites with clinical relevance, we report for the first time, to the best of our knowledge, a metabolomics profiling of circulating acylcarnitines and amino acids in SCA7 patients. We identified 21 metabolites with altered levels in SCA7 patients and determined two different sets of metabolites with diagnostic power. The first signature of metabolites (Valine, Leucine, and Tyrosine) has the ability to discriminate between SCA7 patients and healthy controls, while the second one (Methionine, 3-hydroxytetradecanoyl-carnitine, and 3-hydroxyoctadecanoyl-carnitine) possess the capability to differentiate between early-onset and adult-onset patients, as shown by the multivariate model and ROC analyses. Furthermore, enrichment analyses of metabolic pathways suggest alterations in mitochondrial function, energy metabolism, and fatty acid beta-oxidation in SCA7 patients. In summary, circulating SCA7-specific metabolites identified in this study could serve as effective predictors of SCA7 progression in the clinics, as they are sampled in accessible biofluid and assessed by a relatively simple biochemical assay.	Laboratory of Chronic Diseases Biochemistry, National Genomics Medicine Institute (INMEGEN), Mexico City 14610, Mexico	rafaelnambo@yahoo.com.mx; cvaldezqbp@outlook.com; bcisnero@cinvestav.mx; bpalacios@inmegen.gob.mx; dravelaamieva@yahoo.com; icig@servidor.unam.mx; misael_207@hotmail.com; crisver.gob@gmail.com; hcortes@inr.gob.mx; jreyes@inmegen.gob.mx; jmagana@inr.gob.mx	10.3390/biom10030390	2020	10	3	-	-	390	-
Ravnik-Glavač, Metka; Glavač, Damjan	Circulating RNAs as Potential Biomarkers in Amyotrophic Lateral Sclerosis	International Journal of Molecular Sciences	EN	Review	amyotrophic lateral sclerosis; ALS; circulating biomarkers; circulating RNAs; blood; miRNA; lncRNA; circRNA; mRNA; ceRNET	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.	Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia	metka.ravnik-glavac@mf.uni-lj.si; damjan.glavac@mf.uni-lj.si	10.3390/ijms21051714	2020	21	5	-	-	1714	-
Cavalli, Eugenio; Battaglia, Giuseppe; Basile, Maria; Bruno, Valeria; Petralia, Maria; Lombardo, Salvo; Pennisi, Manuela; Kalfin, Reni; Tancheva, Lyubka; Fagone, Paolo; Nicoletti, Ferdinando; Mangano, Katia	Exploratory Analysis of iPSCS-Derived Neuronal Cells as Predictors of Diagnosis and Treatment of Alzheimer Disease	Brain Sciences	EN	Article	Alzheimer disease; Induced pluripotent stem cells-derived neuronal cells; drug repurposing; biomarkers	Alzheimer’s disease (AD) represents the most common neurodegenerative disorder, with 47 million affected people worldwide. Current treatment strategies are aimed at reducing the symptoms and do slow down the progression of the disease, but inevitably fail in the long-term. Induced pluripotent stem cells (iPSCs)-derived neuronal cells from AD patients have proven to be a reliable model for AD pathogenesis. Here, we have conducted an in silico analysis aimed at identifying pathogenic gene-expression profiles and novel drug candidates. The GSE117589 microarray dataset was used for the identification of Differentially Expressed Genes (DEGs) between iPSC-derived neuronal progenitor (NP) cells and neurons from AD patients and healthy donors. The Discriminant Analysis Module (DAM) algorithm was used for the identification of biomarkers of disease. Drugs with anti-signature gene perturbation profiles were identified using the L1000FWD software. DAM analysis was used to identify a list of potential biomarkers among the DEGs, able to discriminate AD patients from healthy people. Finally, anti-signature perturbation analysis identified potential anti-AD drugs. This study set the basis for the investigation of potential novel pharmacological strategies for AD. Furthermore, a subset of genes for the early diagnosis of AD is proposed.	Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy	eugeniocavalli9@hotmail.it; giuseppe.battaglia@uniroma1.it; sofiabasile@hotmail.it; valeria.bruno@uniroma1.it; m.cristinapetralia@gmail.com; salvo.lombardo.sdl@gmail.com; manuela.pennisi@unict.it; reni_kalfin@abv.bg; lyubkatancheva@gmail.com; paolofagone@yahoo.it; ferdinic@unict.it; kmangano@unict.it	10.3390/brainsci10030166	2020	10	3	-	-	166	-
Rabbito, Alessandro; Dulewicz, Maciej; Kulczyńska-Przybik, Agnieszka; Mroczko, Barbara	Biochemical Markers in Alzheimer’s Disease	International Journal of Molecular Sciences	EN	Review	Alzheimer’s disease; biomarkers; diagnosis	Alzheimer’s disease (AD) is one of the most frequent neurodegenerative diseases affecting more than 35 million people in the world, and its incidence is estimated to triple by 2050. Alzheimer’s disease is an age-related disease characterized by the progressive loss of memory and cognitive function, caused by the unstoppable neurodegeneration and brain atrophy. Current AD treatments only relieve the symptoms. The first molecular signs of the disease identified decades ago and were related to the tau neurofibrillary tangles and the β amyloid plaques. Despite the considerable progress in the diagnostic field, there is no certain knowledge of the specific biomarkers reflecting molecular mechanisms that trigger the symptoms of the disease. Therefore, there is an enormous need to find biomarkers useful for early diagnosis, before the first symptoms appear, and develop new therapeutic targets, which would guarantee improving patients’ quality of life. Researchers from all around the world are looking for biomarkers that can be identified in different biological fluids such as plasma, serum, and cerebrospinal fluid, specific for Alzheimer’s disease. In this review, we would like to resume some of the most interesting discovery in pathological mechanisms underlying Alzheimer’s disease and promising biomarkers.	Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Białystok, Poland	alessandro.rabbito@umb.edu.pl; maciejdulewicz@gmail.com; kulczynska.agnieszka@gmail.com; mroczko@umb.edu.pl	10.3390/ijms21061989	2020	21	6	-	-	1989	-
Eraña, Hasier; Charco, Jorge; González-Miranda, Ezequiel; García-Martínez, Sandra; López-Moreno, Rafael; Pérez-Castro, Miguel; Díaz-Domínguez, Carlos; García-Salvador, Adrián; Castilla, Joaquín	Detection of Pathognomonic Biomarker PrPSc and the Contribution of Cell Free-Amplification Techniques to the Diagnosis of Prion Diseases	Biomolecules	EN	Review	transmissible spongiform encephalopathy; prion disease; PrPSc; diagnostic; PMCA; RT-QuIC	Transmissible spongiform encephalopathies or prion diseases are rapidly progressive neurodegenerative diseases, the clinical manifestation of which can resemble other promptly evolving neurological maladies. Therefore, the unequivocal ante-mortem diagnosis is highly challenging and was only possible by histopathological and immunohistochemical analysis of the brain at necropsy. Although surrogate biomarkers of neurological damage have become invaluable to complement clinical data and provide more accurate diagnostics at early stages, other neurodegenerative diseases show similar alterations hindering the differential diagnosis. To solve that, the detection of the pathognomonic biomarker of disease, PrPSc, the aberrantly folded isoform of the prion protein, could be used. However, the amounts in easily accessible tissues or body fluids at pre-clinical or early clinical stages are extremely low for the standard detection methods. The solution comes from the recent development of in vitro prion propagation techniques, such as Protein Misfolding Cyclic Amplification (PMCA) and Real Time-Quaking Induced Conversion (RT-QuIC), which have been already applied to detect minute amounts of PrPSc in different matrixes and make early diagnosis of prion diseases feasible in a near future. Herein, the most relevant tissues and body fluids in which PrPSc has been detected in animals and humans are being reviewed, especially those in which cell-free prion propagation systems have been used with diagnostic purposes.	Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain	herana.atlas@cicbiogune.es; jmoreno.atlas@cicbiogune.es; egmiranda@cicbiogune.es; sgarcia.atlas@cicbiogune.es; rlopez@cicbiogune.es; maperez@cicbiogune.es; cdiaz@cicbiogune.es; garciaad@gaiker.es; castilla@joaquincastilla.com	10.3390/biom10030469	2020	10	3	-	-	469	-
Pilozzi, Alexander; Huang, Xudong	Overcoming Alzheimer’s Disease Stigma by Leveraging Artificial Intelligence and Blockchain Technologies	Brain Sciences	EN	Review	Alzheimer’s disease; artificial intelligence; natural language processing; sentiment analysis; social media; blockchain; stigma	Alzheimer’s disease (AD) imposes a considerable burden on those diagnosed. Faced with a neurodegenerative decline for which there is no effective cure or prevention method, sufferers of the disease are subject to judgement, both self-imposed and otherwise, that can have a great deal of effect on their lives. The burden of this stigma is more than just psychological, as reluctance to face an AD diagnosis can lead people to avoid early diagnosis, treatment, and research opportunities that may be beneficial to them, and that may help progress towards fighting AD and its progression. In this review, we discuss how recent advents in information technology may be employed to help fight this stigma. Using artificial intelligence (AI) technologies, specifically natural language processing (NLP), to classify the sentiment and tone of texts, such as those of online posts on various social media sites, has proven to be an effective tool for assessing the opinions of the general public on certain topics. These tools can be used to analyze the public stigma surrounding AD. Additionally, there is much concern among individuals that an AD diagnosis, or evidence of pre-clinical AD such as a biomarker or imaging test results, may wind up unintentionally disclosed to an entity that may discriminate against them. The lackluster security record of many medical institutions justifies this fear to an extent. Adopting more secure and decentralized methods of data transfer and storage, and giving patients enhanced ability to control their own data, such as a blockchain-based method, may help to alleviate some of these fears.	Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA	apilozzi@mgh.harvard.edu; huang.xudong@mgh.harvard.edu	10.3390/brainsci10030183	2020	10	3	-	-	183	-
Martínez-Iglesias, Olaia; Carrera, Iván; Carril, Juan; Fernández-Novoa, Lucía; Cacabelos, Natalia; Cacabelos, Ramón	DNA Methylation in Neurodegenerative and Cerebrovascular Disorders	International Journal of Molecular Sciences	EN	Article	Alzheimer disease; Parkinson disease; DNA methylation; neurodegenerative diseases; cerebrovascular diseases; DNMTs; diagnostic biomarker	DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer’s, Parkinson’s or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer’s disease mouse model (3xTg-AD). Our results show that both global methylation (n = 141) and hydroxymethylation (n = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia (n = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD (n = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders.	Euroespes Biomedical Research Center, International Center of Neuroscience and Genomic Medicine, 15165 Corunna, Spain	epigenetica@euroespes.com; biotecnologiasalud@ebiotec.com; genomica@euroespes.com; genetica@ebiotec.com; serviciodocumentacion@euroespes.com; rcacabelos@euroespes.com	10.3390/ijms21062220	2020	21	6	-	-	2220	-
Abu-Rumeileh, Samir; Oeckl, Patrick; Baiardi, Simone; Halbgebauer, Steffen; Steinacker, Petra; Capellari, Sabina; Otto, Markus; Parchi, Piero	CSF Ubiquitin Levels Are Higher in Alzheimer’s Disease than in Frontotemporal Dementia and Reflect the Molecular Subtype in Prion Disease	Biomolecules	EN	Article	biomarkers; human prion disease; Creutzfeldt–Jakob disease; Alzheimer’s disease; frontotemporal dementia; neurofilament ligh chain; ubiquitin; mass spectrometry; chitinase-3-like protein 1	Disturbances in the ubiquitin-proteasome system seem to play a role in neurodegenerative dementias (NDs). Previous studies documented an increase of cerebrospinal fluid (CSF) free monoubiquitin in Alzheimer’s disease (AD) and Creutzfeldt–Jakob disease (CJD). However, to date, no study explored this biomarker across the heterogeneous spectrum of prion disease. Using a liquid chromatography−multiple reaction monitoring mass spectrometry, we investigated CSF free monoubiquitin in controls (n = 28) and in cases with prion disease (n = 84), AD (n = 38), and frontotemporal dementia (FTD) (n = 30). Furthermore, in CJD subtypes, we evaluated by immunohistochemistry (IHC) the relative extent of brain ubiquitin deposits. Prion disease and, to a lesser extent, AD subjects showed increased levels of CSF free monoubiquitin, whereas FTD cases had median protein values similar to controls. The biomarker showed a good to optimal accuracy in the differential diagnosis between NDs and, most interestingly, between AD and FTD. After stratification, according to molecular subtypes, sporadic CJD VV2 demonstrated significantly higher levels of CSF ubiquitin and more numerous brain ubiquitin deposits at IHC in comparison to the typical and most prevalent MM(V)1 subtype. Moreover, CSF ubiquitin correlated with biomarkers of neurodegeneration and astrogliosis in NDs, and was associated with disease stage but not with survival in prion disease. The differential increase of CSF free monoubiquitin in prion disease subtypes and AD may reflect common, though disease and time-specific, phenomena related to neurodegeneration, such as neuritic damage, dysfunctional proteostasis, and neuroinflammation.	Department of Biomedical and NeuroMotor Sciences (DIBINEM), University of Bologna, 40138 Bologna, Italy	samir.aburumeileh@gmail.com; patrick.oeckl@uni-ulm.de; simone.baiardi6@unibo.it; steffen.halbgebauer@uni-ulm.de; petra.steinacker@uni-ulm.de; sabina.capellari@unibo.it; markus.otto@uni-ulm.de; piero.parchi@unibo.it	10.3390/biom10040497	2020	10	4	-	-	497	-
Gayen, Manoshi; Bhomia, Manish; Balakathiresan, Nagaraja; Knollmann-Ritschel, Barbara	Exosomal MicroRNAs Released by Activated Astrocytes as Potential Neuroinflammatory Biomarkers	International Journal of Molecular Sciences	EN	Article	MicroRNA; Astrocytes; neuroinflammation; Biomarkers	Neuroinflammation is a hallmark of several neurodegenerative diseases and disorders, including traumatic brain injury (TBI). Neuroinflammation results in the activation of glial cells which exacerbates the neuroinflammatory process by secretion of pro-inflammatory cytokines and results in disruption of glial transmission networks. The glial cells, including astrocytes, play a critical role in the maintenance of homeostasis in the brain. Activated astrocytes release several factors as part of the inflammatory process including cytokines, proteins, and microRNAs (miRNAs). MiRNAs are noncoding RNA molecules involved in normal physiological processes and disease pathogenesis. MiRNAs have been implicated as important cell signaling molecules, and they are potential diagnostic biomarkers and therapeutic targets for various diseases, including neurological disorders. Exosomal miRNAs released by astrocytic response to neuroinflammation is not yet studied. In this study, primary human astrocytes were activated by IL-1β stimulation and we examined astrocytic exosomal miRNA cargo released in a neuroinflammatory stress model. Results indicate that acute neuroinflammation and oxidative stress induced by IL-1β generates the release of a specific subset of miRNAs via exosomes, which may have a potential role in regulating the inflammatory response. Additionally, these miRNAs may serve as potential biomarkers of neuroinflammation associated with neurological disorders and injuries.	Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030, USA	gayen@uchc.edu; manish.bhomia.ctr@usuhs.edu; nagaraja.balakathiresan.ctr@usuhs.edu; barbara.knollmann-ritschel@usuhs.edu	10.3390/ijms21072312	2020	21	7	-	-	2312	-
Tanaka, Masaru; Toldi, József; Vécsei, László	Exploring the Etiological Links behind Neurodegenerative Diseases: Inflammatory Cytokines and Bioactive Kynurenines	International Journal of Molecular Sciences	EN	Review	neurodegenerative diseases; Alzheimer’s disease; Parkinson’s disease; neuroinflammation; amyloid; tau; prion; cytokine; tryptophan; kynurenine; multifactorial causality	Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative diseases (NDs), presenting a broad range of symptoms from motor dysfunctions to psychobehavioral manifestations. A common clinical course is the proteinopathy-induced neural dysfunction leading to anatomically corresponding neuropathies. However, current diagnostic criteria based on pathology and symptomatology are of little value for the sake of disease prevention and drug development. Overviewing the pathomechanism of NDs, this review incorporates systematic reviews on inflammatory cytokines and tryptophan metabolites kynurenines (KYNs) of human samples, to present an inferential method to explore potential links behind NDs. The results revealed increases of pro-inflammatory cytokines and neurotoxic KYNs in NDs, increases of anti-inflammatory cytokines in AD, PD, Huntington’s disease (HD), Creutzfeldt–Jakob disease, and human immunodeficiency virus (HIV)-associated neurocognitive disorders, and decreases of neuromodulatory KYNs in AD, PD, and HD. The results reinforced a strong link between inflammation and neurotoxic KYNs, confirmed activation of adaptive immune response, and suggested a possible role in the decrease of neuromodulatory KYNs, all of which may contribute to the development of chronic low grade inflammation. Commonalities of multifactorial NDs were discussed to present a current limit of diagnostic criteria, a need for preclinical biomarkers, and an approach to search the initiation factors of NDs.	MTA-SZTE, Neuroscience Research Group, Semmelweis u. 6, H-6725 Szeged, Hungary	tanaka.masaru.1@med.u-szeged.hu; toldi@bio.u-szeged.hu; vecsei.laszlo@med.u-szeged.hu	10.3390/ijms21072431	2020	21	7	-	-	2431	-
Percival, Benita; Gibson, Miles; Wilson, Philippe; Platt, Frances; Grootveld, Martin	Metabolomic Studies of Lipid Storage Disorders, with Special Reference to Niemann-Pick Type C Disease: A Critical Review with Future Perspectives	International Journal of Molecular Sciences	EN	Review	metabolomics; lysosomal storage disorders; Niemann-Pick Type C Disease; lipidoses; nuclear magnetic resonance (NMR) analysis; liquid chromatography-mass spectrometric (LC-MS) analysis; multivariate power calculations; validation and cross-validation; biomarkers	Lysosomal storage disorders (LSDs) are predominantly very rare recessive autosomal neurodegenerative diseases.Sphingolipidoses, a sub-group of LSDs, result from defects in lysosomal enzymes involved in sphingolipid catabolism, and feature disrupted storage systems which trigger complex pathogenic cascades with other organelles collaterally affected. This process leads to cell dysfunction and death, particularly in the central nervous system. One valuable approach to gaining insights into the global impact of lysosomal dysfunction is through metabolomics, which represents a discovery tool for investigating disease-induced modifications in the patterns of large numbers of simultaneously-analysed metabolites, which also features the identification of biomarkers Here, the scope and applications of metabolomics strategies to the investigation of sphingolipidoses is explored in order to facilitate our understanding of the biomolecular basis of these conditions. This review therefore surveys the benefits of applying ’state-of-the-art’ metabolomics strategies, both univariate and multivariate, to sphingolipidoses, particularly Niemann-Pick type C disease. Relevant limitations of these techniques are also discussed, along with the latest advances and developments. We conclude that metabolomics strategies are highly valuable, distinctive bioanalytical techniques for probing LSDs, most especially for the detection and validation of potential biomarkers. They also show much promise for monitoring disease progression and the evaluation of therapeutic strategies and targets.	Leicester School of Pharmacy, De Montfort University, The Gateway, Leicester LE1 9BH, UK	benita.c.percival@dmu.ac.uk; miles.gibson@dmu.ac.uk; philippe.wilson@ntu.ac.uk; frances.platt@pharm.ox.ac.uk; mgrootveld@dmu.ac.uk	10.3390/ijms21072533	2020	21	7	-	-	2533	-
Wallace, David; Taalab, Yasmeen; Heinze, Sarah; Tariba Lovaković, Blanka; Pizent, Alica; Renieri, Elisavet; Tsatsakis, Aristidis; Farooqi, Ammad; Javorac, Dragana; Andjelkovic, Milena; Bulat, Zorica; Antonijević, Biljana; Buha Djordjevic, Aleksandra	Toxic-Metal-Induced Alteration in miRNA Expression Profile as a Proposed Mechanism for Disease Development	Cells	EN	Review	miRNA; gene expression; cadmium; lead; arsenic; mercury; manganese; cancer; neurodegenerative diseases (NDDs); epigenetic modification	Toxic metals are extensively found in the environment, households, and workplaces and contaminate food and drinking water. The crosstalk between environmental exposure to toxic metals and human diseases has been frequently described. The toxic mechanism of action was classically viewed as the ability to dysregulate the redox status, production of inflammatory mediators and alteration of mitochondrial function. Recently, growing evidence showed that heavy metals might exert their toxicity through microRNAs (miRNA)—short, single-stranded, noncoding molecules that function as positive/negative regulators of gene expression. Aberrant alteration of the endogenous miRNA has been directly implicated in various pathophysiological conditions and signaling pathways, consequently leading to different types of cancer and human diseases. Additionally, the gene-regulatory capacity of miRNAs is particularly valuable in the brain—a complex organ with neurons demonstrating a significant ability to adapt following environmental stimuli. Accordingly, dysregulated miRNAs identified in patients suffering from neurological diseases might serve as biomarkers for the earlier diagnosis and monitoring of disease progression. This review will greatly emphasize the effect of the toxic metals on human miRNA activities and how this contributes to progression of diseases such as cancer and neurodegenerative disorders (NDDs).	School of Biomedical Science, Oklahoma State University Center for Health Sciences, Tulsa, OK 74107, USA	david.wallace@okstate.edu; dryasmeen.taalab@mans.edu.eg; sarah.heinze@med.uni-heidelberg.de; btariba@imi.hr; apizent@imi.hr; e.renieri@med.uoc.gr; tsatsaka@uoc.gr; ammadfarooqi@rlmclahore.com; dragana.javorac@pharmacy.bg.ac.rs; millena.andjelkovic@gmail.com; zorica.bulat@pharmacy.bg.ac.rs; biljana.antonijevic@pharmacy.bg.ac.rs; aleksandra.buha@pharmacy.bg.ac.rs	10.3390/cells9040901	2020	9	4	-	-	901	-
Rajda, Cecilia; Galla, Zsolt; Polyák, Helga; Maróti, Zoltán; Babarczy, Kristóf; Pukoli, Dániel; Vécsei, László	Cerebrospinal Fluid Neurofilament Light Chain Is Associated with Kynurenine Pathway Metabolite Changes in Multiple Sclerosis	International Journal of Molecular Sciences	EN	Article	CSF; neurofilament light; multiple sclerosis; quinolinic acid	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.	Department of Neurology, Faculty of Medicine, University of Szeged, Semmelweis u. 6., H-6725 Szeged, Hungary	rajda.cecilia@med.u-szeged.hu; galla.zsolt@med.u-szeged.hu; polyak.helga@med.u-szeged.hu; maroti.zoltan@med.u-szeged.hu; babarczy.kristof@med.u-szeged.hu; pukoli.daniel@med.u-szeged.hu; vecsei.laszlo@med.u-szeged.hu	10.3390/ijms21082665	2020	21	8	-	-	2665	-
Kubis-Kubiak, Adriana; Dyba, Aleksandra; Piwowar, Agnieszka	The Interplay between Diabetes and Alzheimer’s Disease—In the Hunt for Biomarkers	International Journal of Molecular Sciences	EN	Review	diabetes mellitus; Alzheimer’s disease; biomarkers; S100 proteins	The brain is an organ in which energy metabolism occurs most intensively and glucose is an essential and dominant energy substrate. There have been many studies in recent years suggesting a close relationship between type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD) as they have many pathophysiological features in common. The condition of hyperglycemia exposes brain cells to the detrimental effects of glucose, increasing protein glycation and is the cause of different non-psychiatric complications. Numerous observational studies show that not only hyperglycemia but also blood glucose levels near lower fasting limits (72 to 99 mg/dL) increase the incidence of AD, regardless of whether T2DM will develop in the future. As the comorbidity of these diseases and earlier development of AD in T2DM sufferers exist, new AD biomarkers are being sought for etiopathogenetic changes associated with early neurodegenerative processes as a result of carbohydrate disorders. The S100B protein seem to be interesting in this respect as it may be a potential candidate, especially important in early diagnostics of these diseases, given that it plays a role in both carbohydrate metabolism disorders and neurodegenerative processes. It is therefore necessary to clarify the relationship between the concentration of the S100B protein and glucose and insulin levels. This paper draws attention to a valuable research objective that may in the future contribute to a better diagnosis of early neurodegenerative changes, in particular in subjects with T2DM and may be a good basis for planning experiments related to this issue as well as a more detailed explanation of the relationship between the neuropathological disturbances and changes of glucose and insulin concentrations in the brain.	Department of Toxicology, Faculty of Pharmacy, Wroclaw Medical University, 50367 Wroclaw, Poland	adriana.kubis-kubiak@umed.wroc.pl; aleksandra.dyba@student.umed.wroc.pl; agnieszka.piwowar@umed.wroc.pl	10.3390/ijms21082744	2020	21	8	-	-	2744	-
Sancandi, Marco; Uysal-Onganer, Pinar; Kraev, Igor; Mercer, Audrey; Lange, Sigrun	Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease	International Journal of Molecular Sciences	EN	Article	Peptidylarginine deiminases (PADs); protein deimination; extracellular vesicles (EVs); pre-motor Parkinson’s disease; microRNA (miR21, miR155, miR210)	The identification of biomarkers for early diagnosis of Parkinson’s disease (PD) is of pivotal importance for improving approaches for clinical intervention. The use of translatable animal models of pre-motor PD therefore offers optimal opportunities for novel biomarker discovery in vivo. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that contribute to protein misfolding through post-translational deimination of arginine to citrulline. Furthermore, PADs are an active regulator of extracellular vesicle (EV) release. Both protein deimination and extracellular vesicles (EVs) are gaining increased attention in relation to neurodegenerative diseases, including in PD, while roles in pre-motor PD have yet to be investigated. The current study aimed at identifying protein candidates of deimination in plasma and plasma-EVs in a rat model of pre-motor PD, to assess putative contributions of such post-translational changes in the early stages of disease. EV-cargo was further assessed for deiminated proteins as well as three key micro-RNAs known to contribute to inflammation and hypoxia (miR21, miR155, and miR210) and also associated with PD. Overall, there was a significant increase in circulating plasma EVs in the PD model compared with sham animals and inflammatory and hypoxia related microRNAs were significantly increased in plasma-EVs of the pre-motor PD model. A significantly higher number of protein candidates were deiminated in the pre-motor PD model plasma and plasma-EVs, compared with those in the sham animals. KEGG (Kyoto encyclopedia of genes and genomes) pathways identified for deiminated proteins in the pre-motor PD model were linked to “Alzheimer’s disease”, “PD”, “Huntington’s disease”, “prion diseases”, as well as for “oxidative phosphorylation”, “thermogenesis”, “metabolic pathways”, “Staphylococcus aureus infection”, gap junction, “platelet activation”, “apelin signalling”, “retrograde endocannabinoid signalling”, “systemic lupus erythematosus”, and “non-alcoholic fatty liver disease”. Furthermore, PD brains showed significantly increased staining for total deiminated proteins in the brain vasculature in cortex and hippocampus, as well as increased immunodetection of deiminated histone H3 in dentate gyrus and cortex. Our findings identify EVs and post-translational protein deimination as novel biomarkers in early pre-motor stages of PD.	Department of Pharmacology, UCL School of Pharmacy, London WC1N 1AX, UK	marco.sancandi.16@ucl.ac.uk; p.onganer@westminster.ac.uk; igor.kraev@open.ac.uk; a.mercer@ucl.ac.uk; s.lange@westminster.ac.uk	10.3390/ijms21082743	2020	21	8	-	-	2743	-
Schepici, Giovanni; Silvestro, Serena; Trubiani, Oriana; Bramanti, Placido; Mazzon, Emanuela	Salivary Biomarkers: Future Approaches for Early Diagnosis of Neurodegenerative Diseases	Brain Sciences	EN	Review	salivary biomarkers; Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; multiple sclerosis	Many neurological diseases are characterized by progressive neuronal degeneration. Early diagnosis and new markers are necessary for prompt therapeutic intervention. Several studies have aimed to identify biomarkers in different biological liquids. Furthermore, it is being considered whether saliva could be a potential biological sample for the investigation of neurodegenerative diseases. This work aims to provide an overview of the literature concerning biomarkers identified in saliva for the diagnosis of neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and multiple sclerosis (MS). Specifically, the studies have revealed that is possible to quantify beta-amyloid1–42 and TAU protein from the saliva of AD patients. Instead, alpha-synuclein and protein deglycase (DJ-1) have been identified as new potential salivary biomarkers for the diagnosis of PD. Nevertheless, future studies will be needed to validate these salivary biomarkers in the diagnosis of neurological diseases.	IRCCS Centro Neurolesi “Bonino-Pulejo”, Via Provinciale Palermo, Contrada Casazza, 98124 Messina, Italy	giovanni.schepici@irccsme.it; serena.silvestro@irccsme.it; trubiani@unich.it; placido.bramanti@irccsme.it; emanuela.mazzon@irccsme.it	10.3390/brainsci10040245	2020	10	4	-	-	245	-
Lanznaster, Débora; Hergesheimer, Rudolf; Bakkouche, Salah; Beltran, Stephane; Vourc’h, Patrick; Andres, Christian; Dufour-Rainfray, Diane; Corcia, Philippe; Blasco, Hélène	Aβ1-42 and Tau as Potential Biomarkers for Diagnosis and Prognosis of Amyotrophic Lateral Sclerosis	International Journal of Molecular Sciences	EN	Article	ALS; biomarker; Aβ1-42; total Tau; CSF	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.	UMR 1253, iBrain, University of Tours, Inserm, 37000 Tours, France	debora.lanznaster@univ-tours.fr; rchergesheimer@gmail.com; s.bakkouche@chu-tours.fr; s.beltran@chu-tours.fr; patrick.vourch@univ-tours.fr; christian.andres@univ-tours.fr; diane.dufour@univ-tours.fr; philippe.corcia@univ-tours.fr; helene.blasco@univ-tours.fr	10.3390/ijms21082911	2020	21	8	-	-	2911	-
Angelopoulou, Efthalia; Paudel, Yam; Villa, Chiara; Shaikh, Mohd.; Piperi, Christina	Lymphocyte-Activation Gene 3 (LAG3) Protein as a Possible Therapeutic Target for Parkinson’s Disease: Molecular Mechanisms Connecting Neuroinflammation to α-Synuclein Spreading Pathology	Biology	EN	Review	LAG3; Parkinson’s disease; α-synuclein; neuroinflammation; biomarker	Parkinson’s disease (PD) is the most common neurodegenerative movement disorder without any objective biomarker available to date. Increasing evidence highlights the critical role of neuroinflammation, including T cell responses, and spreading of aggregated α-synuclein in PD progression. Lymphocyte-activation gene 3 (LAG3) belongs to the immunoglobulin (Ig) superfamily expressed by peripheral immune cells, microglia and neurons and plays a key role in T cell regulation. The role of LAG3 has been extensively investigated in several human cancers, whereas until recently, the role of LAG3 in the central nervous system (CNS) has been largely unknown. Accumulating evidence highlights the potential role of LAG3 in PD pathogenesis, mainly by binding to α-synuclein fibrils and affecting its endocytosis and intercellular transmission, which sheds more light on the connection between immune dysregulation and α-synuclein spreading pathology. Serum and cerebrospinal fluid (CSF) soluble LAG3 (sLAG3) levels have been demonstrated to be potentially associated with PD development and clinical phenotype, suggesting that sLAG3 could represent an emerging PD biomarker. Specific single nucleotide polymorphisms (SNPs) of the LAG3 gene have been also related to PD occurrence especially in the female population, enlightening the pathophysiological background of gender-related PD clinical differences. Given also the ongoing clinical trials investigating various LAG3-targeting strategies in human diseases, new opportunities are being developed for PD treatment research. In this review, we discuss recent preclinical and clinical evidence on the role of LAG3 in PD pathogenesis and biomarker potential, aiming to elucidate its underlying molecular mechanisms.	Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece	angelthal@med.uoa.gr; yam.paudel@monash.edu; chiara.villa@unimib.it; farooq.shaikh@monash.edu; cpiperi@med.uoa.gr	10.3390/biology9040086	2020	9	4	-	-	86	-
Basile, Maria; Battaglia, Giuseppe; Bruno, Valeria; Mangano, Katia; Fagone, Paolo; Petralia, Maria; Nicoletti, Ferdinando; Cavalli, Eugenio	The Dichotomic Role of Macrophage Migration Inhibitory Factor in Neurodegeneration	International Journal of Molecular Sciences	EN	Review	macrophage migration inhibitory factor; neurodegeneration; amyotrophic lateral sclerosis; Parkinson disease; Huntington disease	Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine expressed by different cell types and exerting multiple biological functions. It has been shown that MIF may be involved in several disorders, including neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS), Parkinson disease (PD), and Huntington disease (HD), that represent an unmet medical need. Therefore, further studies are needed to identify novel pathogenetic mechanisms that may translate into tailored therapeutic approaches so to improve patients’ survival and quality of life. Here, we reviewed the preclinical and clinical studies investigating the role of MIF in ALS, PD, and HD. The emerging results suggest that MIF might play a dichotomic role in these disorders, exerting a protective action in ALS, a pathogenetic action in HD, and a yet undefined and debated role in PD. The better understanding of the role of MIF in these diseases could allow its use as a novel diagnostic and therapeutic tool for the monitoring and treatment of the patients and for eventual biomarker-driven therapeutic approaches.	Department of Biomedical and Biotechnological Sciences, University of Catania, Via S. Sofia 89, 95123 Catania, Italy	sofiabasile@hotmail.it; giuseppe.battaglia@uniroma1.it; valeria.bruno@uniroma1.it; kmangano@unict.it; paolofagone@yahoo.it; m.cristinapetralia@gmail.com; ferdinic@unict.it; eugeniocavalli9@hotmail.it	10.3390/ijms21083023	2020	21	8	-	-	3023	-
Markovic, Milica; Ben-Shabat, Shimon; Aponick, Aaron; Zimmermann, Ellen; Dahan, Arik	Lipids and Lipid-Processing Pathways in Drug Delivery and Therapeutics	International Journal of Molecular Sciences	EN	Concept Paper	lipid; fatty acid; glyceride; steroid; phospholipid; oral drug absorption; prodrug; phospholipase A2 (PLA2)	The aim of this work is to analyze relevant endogenous lipid processing pathways, in the context of the impact that lipids have on drug absorption, their therapeutic use, and utilization in drug delivery. Lipids may serve as biomarkers of some diseases, but they can also provide endogenous therapeutic effects for certain pathological conditions. Current uses and possible clinical benefits of various lipids (fatty acids, steroids, triglycerides, and phospholipids) in cancer, infectious, inflammatory, and neurodegenerative diseases are presented. Lipids can also be conjugated to a drug molecule, accomplishing numerous potential benefits, one being the improved treatment effect, due to joined influence of the lipid carrier and the drug moiety. In addition, such conjugates have increased lipophilicity relative to the parent drug. This leads to improved drug pharmacokinetics and bioavailability, the ability to join endogenous lipid pathways and achieve drug targeting to the lymphatics, inflamed tissues in certain autoimmune diseases, or enable overcoming different barriers in the body. Altogether, novel mechanisms of the lipid role in diseases are constantly discovered, and new ways to exploit these mechanisms for the optimal drug design that would advance different drug delivery/therapy aspects are continuously emerging.	Department of Clinical Pharmacology, School of Pharmacy, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel	milica@post.bgu.ac.il; sbs@bgu.ac.il; aponick@chem.ufl.edu; ellen.zimmermann@medicine.ufl.edu; arikd@bgu.ac.il	10.3390/ijms21093248	2020	21	9	-	-	3248	-
Coates, Lucy; Shi, Jian; Rochester, Lynn; Del Din, Silvia; Pantall, Annette	Entropy of Real-World Gait in Parkinson’s Disease Determined from Wearable Sensors as a Digital Marker of Altered Ambulatory Behavior	Sensors	EN	Article	wearable technology; gait; Parkinson’s disease; sample entropy; variability; real-world	Parkinson’s disease (PD) is a common age-related neurodegenerative disease. Gait impairment is frequent in the later stages of PD contributing to reduced mobility and quality of life. Digital biomarkers such as gait velocity and step length are predictors of motor and cognitive decline in PD. Additional gait parameters may describe different aspects of gait and motor control in PD. Sample entropy (SampEnt), a measure of signal predictability, is a nonlinear approach that quantifies regularity of a signal. This study investigated SampEnt as a potential biomarker for PD and disease duration. Real-world gait data over a seven-day period were collected using an accelerometer (Axivity AX3, York, UK) placed on the low back and gait metrics extracted. SampEnt was determined for the stride time, with vector length and threshold parameters optimized. People with PD had higher stride time SampEnt compared to older adults, indicating reduced gait regularity. The range of SampEnt increased over 36 months for the PD group, although the mean value did not change. SampEnt was associated with dopaminergic medication dose but not with clinical motor scores. In conclusion, this pilot study indicates that SampEnt from real-world data may be a useful parameter reflecting clinical status although further research is needed involving larger populations.	School of Mathematics, Statistics and Physics, Newcastle University, Newcastle upon Tyne NE1 7RU, UK	lucy.a.coates@hotmail.com; jian.shi@newcastle.ac.uk; lynn.rochester@newcastle.ac.uk; silvia.del-din@newcastle.ac.uk; annette.pantall@newcastle.ac.uk	10.3390/s20092631	2020	20	9	-	-	2631	-
Lim, Key-Hwan; Joo, Jae-Yeol	Predictive Potential of Circulating Ube2h mRNA as an E2 Ubiquitin-Conjugating Enzyme for Diagnosis or Treatment of Alzheimer’s Disease	International Journal of Molecular Sciences	EN	Article	Alzheimer’s disease; E2 ubiquitin conjugating enzyme; Ube2h; ubiquitin	Neurodegenerative disorders are caused by neuronal cell death, miscommunications between synapse, and abnormal accumulations of proteins in the brain. Alzheimer’s disease (AD) is one of the age-related disorders, which are the most common degenerative disorders today, and strongly affects memory consolidation and cognitive function in the brain. Amyloid-β and tau proteins are triggers for AD pathogenesis, and usually used as AD candidate biomarkers in the clinical research. Especially, clinical exam, brain imaging and molecular biological methods are being used to diagnosis for AD. Genome-wide association study (GWAS) is a new biomedical method, and its use contributes to understanding many human diseases, including brain diseases. Here, we identified ubiquitin conjugating enzyme E2 (Ube2) gene expression in neurons through GWAS. The subfamilies of Ube2’s genetic expression and inborn errors affect the ubiquitin proteasome system (UPS), leading to protein degradation in the brain. We found that only Ube2h mRNA transcription was significantly increased in the blood from AD, however we did not find any change of Ube2 subfamily genes’ expression in the blood and brain tissue. These data may provide information for diagnosis or clinical approach, and suggest that cell-free circulating Ube2h mRNA is a novel potential biomarker for AD.	Neurodegenerative Diseases Research Group, Korea Brain Research Institute, Daegu 41062, Korea	khlim@kbri.re.kr; joojy@kbri.re.kr	10.3390/ijms21093398	2020	21	9	-	-	3398	-
Picca, Anna; Guerra, Flora; Calvani, Riccardo; Coelho-Junior, Hélio; Bossola, Maurizio; Landi, Francesco; Bernabei, Roberto; Bucci, Cecilia; Marzetti, Emanuele	Generation and Release of Mitochondrial-Derived Vesicles in Health, Aging and Disease	Journal of Clinical Medicine	EN	Review	biomarkers; exosomes; extracellular vesicles; geroprotective interventions; mitophagy; mitochondrial damage; mitochondrial dynamics; mitochondrial-derived vesicles (MDVs); mitochondrial-lysosomal axis; neurodegeneration	Mitochondria are intracellular organelles involved in a myriad of activities. To safeguard their vital functions, mitochondrial quality control (MQC) systems are in place to support organelle plasticity as well as physical and functional connections with other cellular compartments. In particular, mitochondrial interactions with the endosomal compartment support the shuttle of ions and metabolites across organelles, while those with lysosomes ensure the recycling of obsolete materials. The extrusion of mitochondrial components via the generation and release of mitochondrial-derived vesicles (MDVs) has recently been described. MDV trafficking is now included among MQC pathways, possibly operating via mitochondrial–lysosomal contacts. Since mitochondrial dysfunction is acknowledged as a hallmark of aging and a major pathogenic factor of multiple age-associated conditions, the analysis of MDVs and, more generally, of extracellular vesicles (EVs) is recognized as a valuable research tool. The dissection of EV trafficking may help unravel new pathophysiological pathways of aging and diseases as well as novel biomarkers to be used in research and clinical settings. Here, we discuss (1) MQC pathways with a focus on mitophagy and MDV generation; (2) changes of MQC pathways during aging and their contribution to inflamm-aging and progeroid conditions; and (3) the relevance of MQC failure to several disorders, including neurodegenerative conditions (i.e., Parkinson’s disease, Alzheimer’s disease) and cardiovascular disease.	Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, 00168 Rome, Italy	anna.picca@guest.policlinicogemelli.it; guerraflora@gmail.com; riccardo.calvani@guest.policlinicogemelli.it; coelhojunior@hotmail.com.br; maurizio.bossola@unicatt.it; francesco.landi@unicatt.it; roberto.bernabei@unicatt.it; cecilia.bucci@unisalento.it; emanuele.marzetti@policlinicogemelli.it	10.3390/jcm9051440	2020	9	5	-	-	1440	-
Moss, Donald	Improving Anti-Neurodegenerative Benefits of Acetylcholinesterase Inhibitors in Alzheimer’s Disease: Are Irreversible Inhibitors the Future?	International Journal of Molecular Sciences	EN	Review	Alzheimer’s disease; acetylcholinesterase inhibitor; acetylcholinesterase; butyrylcholinesterase; atrophy; donepezil; rivastigmine; galantamine; metrifonate; methanesulfonyl fluoride	Decades of research have produced no effective method to prevent, delay the onset, or slow the progression of Alzheimer’s disease (AD). In contrast to these failures, acetylcholinesterase (AChE, EC 3.1.1.7) inhibitors slow the clinical progression of the disease and randomized, placebo-controlled trials in prodromal and mild to moderate AD patients have shown AChE inhibitor anti-neurodegenerative benefits in the cortex, hippocampus, and basal forebrain. CNS neurodegeneration and atrophy are now recognized as biomarkers of AD according to the National Institute on Aging-Alzheimer’s Association (NIA-AA) criteria and recent evidence shows that these markers are among the earliest signs of prodromal AD, before the appearance of amyloid. The current AChE inhibitors (donepezil, rivastigmine, and galantamine) have short-acting mechanisms of action that result in dose-limiting toxicity and inadequate efficacy. Irreversible AChE inhibitors, with a long-acting mechanism of action, are inherently CNS selective and can more than double CNS AChE inhibition possible with short-acting inhibitors. Irreversible AChE inhibitors open the door to high-level CNS AChE inhibition and improved anti-neurodegenerative benefits that may be an important part of future treatments to more effectively prevent, delay the onset, or slow the progression of AD.	Department of Psychology, University of Texas at El Paso, El Paso, TX 79968, USA	dmoss@utep.edu	10.3390/ijms21103438	2020	21	10	-	-	3438	-
Wang, Linlin; Zeng, Li; Jiang, Hailun; Li, Zhuorong; Liu, Rui	Microarray Profile of Long Noncoding RNA and Messenger RNA Expression in a Model of Alzheimer’s Disease	Life	EN	Article	Alzheimer’s disease; long noncoding RNA; messenger RNA; microRNA; gene network	Alzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by a deficiency in cognitive skills. Although long noncoding RNAs (lncRNAs) have been proposed as associated with AD, the aberrant lncRNAs expression and the co-expression of lncRNAs-mRNAs network in AD remains unclear. Therefore, in this study, lncRNA microarray was performed on the brain of APP/PS1 mice at different age, widely used as an AD mouse model, and on age-matched wide-type controls. Our results identified a total of 3306 lncRNAs and 2458 mRNAs as aberrantly expressed among AD mice at different age and their age-matched control. Gene Ontology and pathway analysis of the AD-related lncRNAs and mRNAs indicated that neuroinflammation-related and synaptic transmission signaling pathways represented the main enriched pathways. An lncRNA–mRNA–miRNA network between the differentially expressed transcripts was constructed. Moreover, an mRNA–miRNA network between both significantly dysregulated and highly conserved genes was also constructed, and among this network, the IGF1, P2RX7, TSPO, SERPINE1, EGFR, HMOX1, and NFE212 genes were predicted to play a role in the development of AD. In conclusion, this study illustrated the prognostic value of lncRNAs and mRNAs associated to AD pathology by microarray analysis and might provide potential novel biomarkers in the diagnosis and treatment of AD.	Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China	wanglinlin@wfmc.edu.cn; zengli@imb.pumc.edu.cn; jianghailun@bjtth.org; lizhuorong@imb.pumc.edu.cn; liurui@imb.pumc.edu.cn	10.3390/life10050064	2020	10	5	-	-	64	-
Lidón, Laia; Urrea, Laura; Llorens, Franc; Gil, Vanessa; Alvarez, Ignacio; Diez-Fairen, Monica; Aguilar, Miguel; Pastor, Pau; Zerr, Inga; Alcolea, Daniel; Lleó, Alberto; Vidal, Enric; Gavín, Rosalina; Ferrer, Isidre; Del Rio, Jose	Disease-Specific Changes in Reelin Protein and mRNA in Neurodegenerative Diseases	Cells	EN	Article	Reelin; Creutzfeldt-Jakob disease; Alzheimer’s disease; Parkinson’s disease dementia; a-synucleopathies; cerebrospinal fluid	Reelin is an extracellular glycoprotein that modulates neuronal function and synaptic plasticity in the adult brain. Decreased levels of Reelin activity have been postulated as a key factor during neurodegeneration in Alzheimer’s disease (AD) and in aging. Thus, changes in levels of full-length Reelin and Reelin fragments have been revealed in cerebrospinal fluid (CSF) and in post-mortem brains samples of AD patients with respect to non-AD patients. However, conflicting studies have reported decreased or unchanged levels of full-length Reelin in AD patients compared to control (nND) cases in post-mortem brains and CSF samples. In addition, a compelling analysis of Reelin levels in neurodegenerative diseases other than AD is missing. In this study, we analyzed brain levels of RELN mRNA and Reelin protein in post-mortem frontal cortex samples from different sporadic AD stages, Parkinson’s disease with dementia (PDD), and Creutzfeldt-Jakob disease (sCJD), obtained from five different Biobanks. In addition, we measured Reelin protein levels in CSF samples of patients with mild cognitive impairment (MCI), dementia, or sCJD diagnosis and a group of neurologically healthy cases. The results indicate an increase in RELN mRNA in the frontal cortex of advanced stages of AD and in sCJD(I) compared to controls. This was not observed in PDD and early AD stages. However, Reelin protein levels in frontal cortex samples were unchanged between nND and advanced AD stages and PDD. Nevertheless, they decreased in the CSF of patients with dementia in comparison to those not suffering with dementia and patients with MCI. With respect to sCJD, there was a tendency to increase in brain samples in comparison to nND and to decrease in the CSF with respect to nND. In conclusion, Reelin levels in CSF cannot be considered as a diagnostic biomarker for AD or PDD. However, we feel that the CSF Reelin changes observed between MCI, patients with dementia, and sCJD might be helpful in generating a biomarker signature in prodromal studies of unidentified dementia and sCJD.	Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia (IBEC), Barcelona Institute of Science and Technology (BIST), Science Park of Barcelona, 08028 Barcelona, Spain	llidon@ibecbarcelona.eu; lurrea@ibecbarcelona.eu; franc.llorens@gmail.com; vgil@ibecbarcelona.eu; ignacio.alvafer@gmail.com; monicadifa@gmail.com; miquelaguilar@gmail.com; pastorpau@gmail.com; ingazerr@med.uni-goettingen.de; dalcolea@santpau.cat; alleo@santpau.cat; enric.vidal@irta.cat; rgavin@ub.edu; 8082ifa@gmail.com; jadelrio@ibecbarcelona.eu	10.3390/cells9051252	2020	9	5	-	-	1252	-
Nguyen, Thuy; Ta, Qui; Nguyen, Thi; Nguyen, Thi; Vo, Van	Role of Body-Fluid Biomarkers in Alzheimer’s Disease Diagnosis	Diagnostics	EN	Review	Alzheimer’s disease; biomarkers; diagnostics; Aβ; CSF; tau	Alzheimer’s disease (AD) is a complex neurodegenerative disease that requires extremely specific biomarkers for its diagnosis. For current diagnostics capable of identifying AD, the development and validation of early stage biomarkers is a top research priority. Body-fluid biomarkers might closely reflect synaptic dysfunction in the brain and, thereby, could contribute to improving diagnostic accuracy and monitoring disease progression, and serve as markers for assessing the response to disease-modifying therapies at early onset. Here, we highlight current advances in the research on the capabilities of body-fluid biomarkers and their role in AD pathology. Then, we describe and discuss current applications of the potential biomarkers in clinical diagnostics in AD.	Faculty of Pharmacy, Ho Chi Minh City University of Technology (HUTECH), Ho Chi Minh City 700000, Vietnam	nt.trang85@hutech.edu.vn; tathoaiqui@duytan.edu.vn; oanhntk@hufi.edu.vn; dungntt@ntt.edu.vn; giauvvo@gmail.com	10.3390/diagnostics10050326	2020	10	5	-	-	326	-
Kloska, Anna; Malinowska, Marcelina; Gabig-Cimińska, Magdalena; Jakóbkiewicz-Banecka, Joanna	Lipids and Lipid Mediators Associated with the Risk and Pathology of Ischemic Stroke	International Journal of Molecular Sciences	EN	Review	eicosanoids; cholesterol; ischemic stroke; ischemia; lipoproteins; polyunsaturated fatty acids	Stroke is a severe neurological disorder in humans that results from an interruption of the blood supply to the brain. Worldwide, stoke affects over 100 million people each year and is the second largest contributor to disability. Dyslipidemia is a modifiable risk factor for stroke that is associated with an increased risk of the disease. Traditional and non-traditional lipid measures are proposed as biomarkers for the better detection of subclinical disease. In the central nervous system, lipids and lipid mediators are essential to sustain the normal brain tissue structure and function. Pathways leading to post-stroke brain deterioration include the metabolism of polyunsaturated fatty acids. A variety of lipid mediators are generated from fatty acids and these molecules may have either neuroprotective or neurodegenerative effects on the post-stroke brain tissue; therefore, they largely contribute to the outcome and recovery from stroke. In this review, we provide an overview of serum lipids associated with the risk of ischemic stroke. We also discuss the role of lipid mediators, with particular emphasis on eicosanoids, in the pathology of ischemic stroke. Finally, we summarize the latest research on potential targets in lipid metabolic pathways for ischemic stroke treatment and on the development of new stroke risk biomarkers for use in clinical practice.	Department of Medical Biology and Genetics, Faculty of Biology, University of Gdańsk, Wita Stwosza 59, 80-308 Gdańsk, Poland	anna.kloska@ug.edu.pl; marcelina.malinowska@ug.edu.pl; magdalena.gabig-ciminska@ug.edu.pl; joanna.jakobkiewicz-banecka@biol.ug.edu.pl	10.3390/ijms21103618	2020	21	10	-	-	3618	-
Cordaro, Annalaura; Neri, Giulia; Sciortino, Maria; Scala, Angela; Piperno, Anna	Graphene-Based Strategies in Liquid Biopsy and in Viral Diseases Diagnosis	Nanomaterials	EN	Review	graphene; SERS; liquid biopsy; circulating tumor cells; exosomes; circulating nucleic acids; COVID-19	Graphene-based materials are intriguing nanomaterials with applications ranging from nanotechnology-related devices to drug delivery systems and biosensing. Multifunctional graphene platforms were proposed for the detection of several typical biomarkers (i.e., circulating tumor cells, exosomes, circulating nucleic acids, etc.) in liquid biopsy, and numerous methods, including optical, electrochemical, surface-enhanced Raman scattering (SERS), etc., have been developed for their detection. Due to the massive advancements in biology, material chemistry, and analytical technology, it is necessary to review the progress in this field from both medical and chemical sides. Liquid biopsy is considered a revolutionary technique that is opening unexpected perspectives in the early diagnosis and, in therapy monitoring, severe diseases, including cancer, metabolic syndrome, autoimmune, and neurodegenerative disorders. Although nanotechnology based on graphene has been poorly applied for the rapid diagnosis of viral diseases, the extraordinary properties of graphene (i.e., high electronic conductivity, large specific area, and surface functionalization) can be also exploited for the diagnosis of emerging viral diseases, such as the coronavirus disease 2019 (COVID-19). This review aimed to provide a comprehensive and in-depth summarization of the contribution of graphene-based nanomaterials in liquid biopsy, discussing the remaining challenges and the future trend; moreover, the paper gave the first look at the potentiality of graphene in COVID-19 diagnosis.	Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, 98166 Messina, Italy	acordaro@unime.it; nerig@unime.it; mtsciortino@unime.it; ascala@unime.it; apiperno@unime.it	10.3390/nano10061014	2020	10	6	-	-	1014	-
Pellegrini, Marco; Vagge, Aldo; Ferro Desideri, Lorenzo; Bernabei, Federico; Triolo, Giacinto; Mastropasqua, Rodolfo; Del Noce, Chiara; Borrelli, Enrico; Sacconi, Riccardo; Iovino, Claudio; Di Zazzo, Antonio; Forlini, Matteo; Giannaccare, Giuseppe	Optical Coherence Tomography Angiography in Neurodegenerative Disorders	Journal of Clinical Medicine	EN	Review	optical coherence tomography angiography; neurodegenerative disorders; Alzheimer’s disease; Parkinson’s disease; multiple sclerosis; glaucoma	Retinal microcirculation shares similar features with cerebral small blood vessels. Thus, the retina may be considered an accessible ‘window’ to detect the microvascular damage occurring in the setting of neurodegenerative disorders. Optical coherence tomography angiography (OCT-A) is a non-invasive imaging modality providing depth resolved images of blood flow in the retina, choroid, and optic nerve. In this review, we summarize the current literature on the application of OCT-A in glaucoma and central nervous system conditions such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Future directions aiming at evaluating whether OCT-A can be an additional biomarker for the early diagnosis and monitoring of neurodegenerative disorders are also discussed.	Ophthalmology Unit, S. Orsola-Malpighi University Hospital, University of Bologna, 40138 Bologna, Italy	marco.pellegrini@hotmail.it; aldo.vagge@gmail.com; lorenzoferrodes@gmail.com; federico.bernabei89@gmail.com; giacinto.triolo@gmail.com; rodolfo.mastropasqua@gmail.com; delnocechiara@gmail.com; borrelli.enrico@yahoo.com; ric.sacconi@gmail.com; claudioiovino88@gmail.com; antoniodizazzo@gmail.com; matteoforlini@gmail.com; giuseppe.giannaccare@gmail.com	10.3390/jcm9061706	2020	9	6	-	-	1706	-
Mauriz, Elba	Low-Fouling Substrates for Plasmonic Sensing of Circulating Biomarkers in Biological Fluids	Biosensors	EN	Review	nanoplasmonics; low-fouling; circulating biomarkers; biological fluids; SPR; LSPR; SERS	The monitoring of biomarkers in body fluids provides valuable prognostic information regarding disease onset and progression. Most biosensing approaches use noninvasive screening tools and are conducted in order to improve early clinical diagnosis. However, biofouling of the sensing surface may disturb the quantification of circulating biomarkers in complex biological fluids. Thus, there is a great need for antifouling interfaces to be designed in order to reduce nonspecific adsorption and prevent inactivation of biological receptors and loss of sensitivity. To address these limitations and enable their application in clinical practice, a variety of plasmonic platforms have been recently developed for biomarker analysis in easily accessible biological fluids. This review presents an overview of the latest advances in the design of antifouling strategies for the detection of clinically relevant biomarkers on the basis of the characteristics of biological samples. The impact of nanoplasmonic biosensors as point-of-care devices has been examined for a wide range of biomarkers associated with cancer, inflammatory, infectious and neurodegenerative diseases. Clinical applications in readily obtainable biofluids such as blood, saliva, urine, tears and cerebrospinal and synovial fluids, covering almost the whole range of plasmonic applications, from surface plasmon resonance (SPR) to surface-enhanced Raman scattering (SERS), are also discussed.	Department of Nursing and Physiotherapy, Universidad de León, Campus de Vegazana, s/n, 24071 León, Spain	elba.mauriz@unileon.es	10.3390/bios10060063	2020	10	6	-	-	63	-
Margină, Denisa; Ungurianu, Anca; Purdel, Carmen; Tsoukalas, Dimitris; Sarandi, Evangelia; Thanasoula, Maria; Tekos, Fotios; Mesnage, Robin; Kouretas, Demetrios; Tsatsakis, Aristidis	Chronic Inflammation in the Context of Everyday Life: Dietary Changes as Mitigating Factors	International Journal of Environmental Research and Public Health	EN	Review	diet; polyphenols; inflammation; real-life risk simulation; fasting; COVID-19	The lifestyle adopted by most people in Western societies has an important impact on the propensity to metabolic disorders (e.g., diabetes, cancer, cardiovascular disease, neurodegenerative diseases). This is often accompanied by chronic low-grade inflammation, driven by the activation of various molecular pathways such as STAT3 (signal transducer and activator of transcription 3), IKK (IκB kinase), MMP9 (matrix metallopeptidase 9), MAPK (mitogen-activated protein kinases), COX2 (cyclooxigenase 2), and NF-Kβ (nuclear factor kappa-light-chain-enhancer of activated B cells). Multiple intervention studies have demonstrated that lifestyle changes can lead to reduced inflammation and improved health. This can be linked to the concept of real-life risk simulation, since humans are continuously exposed to dietary factors in small doses and complex combinations (e.g., polyphenols, fibers, polyunsaturated fatty acids, etc.). Inflammation biomarkers improve in patients who consume a certain amount of fiber per day; some even losing weight. Fasting in combination with calorie restriction modulates molecular mechanisms such as m-TOR, FOXO, NRF2, AMPK, and sirtuins, ultimately leads to significantly reduced inflammatory marker levels, as well as improved metabolic markers. Moving toward healthier dietary habits at the individual level and in publicly-funded institutions, such as schools or hospitals, could help improving public health, reducing healthcare costs and improving community resilience to epidemics (such as COVID-19), which predominantly affects individuals with metabolic diseases.	Department of Biochemistry, Faculty of Pharmacy, “Carol Davila” University of Medicine and Pharmacy, Traian Vuia 6, 020956 Bucharest, Romania	denisa.margina@umfcd.ro; anca.ungurianu@umfcd.ro; carmen.purdel@umfcd.ro; dr.tsoukalas@gmail.com; esarandi6@hotmail.com; mariathanasoula84@gmail.com; fotis.tek@gmail.com; robin.mesnage@kcl.ac.uk; dkouret@gmail.com; tsatsaka@uoc.gr	10.3390/ijerph17114135	2020	17	11	-	-	4135	-
Hassan, Qusai; Ahmadi, Soha; Kerman, Kagan	Recent Advances in Monitoring Cell Behavior Using Cell-Based Impedance Spectroscopy	Micromachines	EN	Review	cell-based impedance; cell culture; electrochemical impedance spectroscopy; high-throughput screening	Cell-based impedance spectroscopy (CBI) is a powerful tool that uses the principles of electrochemical impedance spectroscopy (EIS) by measuring changes in electrical impedance relative to a voltage applied to a cell layer. CBI provides a promising platform for the detection of several properties of cells including the adhesion, motility, proliferation, viability and metabolism of a cell culture. This review gives a brief overview of the theory, instrumentation, and detection principles of CBI. The recent applications of the technique are given in detail for research into cancer, neurodegenerative diseases, toxicology as well as its application to 2D and 3D in vitro cell cultures. CBI has been established as a biophysical marker to provide quantitative cellular information, which can readily be adapted for single-cell analysis to complement the existing biomarkers for clinical research on disease progression.	Department of Physical and Environmental Sciences, University of Toronto Scarborough, 1265 Military Trail, Toronto, ON M1C 1A4, Canada	qusai.hassan@mail.utoronto.ca; soha.ahmadi@mail.utoronto.ca; kagan.kerman@utoronto.ca	10.3390/mi11060590	2020	11	6	-	-	590	-
Toivonen, Janne; Sanz-Rubio, David; López-Pérez, Óscar; Marín-Moreno, Alba; Bolea, Rosa; Osta, Rosario; Badiola, Juan; Zaragoza, Pilar; Espinosa, Juan-Carlos; Torres, Juan-Maria; Martín-Burriel, Inmaculada	MicroRNA Alterations in a Tg501 Mouse Model of Prion Disease	Biomolecules	EN	Article	prion diseases; scrapie; microRNA; biomarkers	MicroRNAs (miRNAs) may contribute to the development and pathology of many neurodegenerative diseases, including prion diseases. They are also promising biomarker candidates due to their stability in body fluids. We investigated miRNA alterations in a Tg501 mouse model of prion diseases that expresses a transgene encoding the goat prion protein (PRNP). Tg501 mice intracranially inoculated with mouse-adapted goat scrapie were compared with age-matched, mock inoculated controls in preclinical and clinical stages. Small RNA sequencing from the cervical spinal cord indicated that miR-223-3p, miR-151-3p, and miR-144-5p were dysregulated in scrapie-inoculated animals before the onset of symptoms. In clinical-stage animals, 23 significant miRNA alterations were found. These miRNAs were predicted to modify the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways including prion disease, extracellular matrix interactions, glutaminergic synapse, axon guidance, and transforming growth factor-beta signaling. MicroRNAs miR-146a-5p (up in cervical spinal cord) and miR-342-3p (down in cervical spinal cord, cerebellum and plasma), both indicated in neurodegenerative diseases earlier, were verified by quantitative real-time polymerase chain reaction (qRT-PCR). Minimal changes observed before the disease onset suggests that most miRNA alterations observed here are driven by advanced prion-associated pathology, possibly limiting their use as diagnostic markers. However, the results encourage further mechanistic studies on miRNA-regulated pathways involved in these neurodegenerative conditions.	Laboratorio de Genética Bioquímica (LAGENBIO), Facultad de Veterinaria, University of Zaragoza, 50013 Zaragoza, Spain	toivonen@unizar.es; davidsanzrubio91@gmail.com; oscarlzpz@gmail.com; marin.alba@inia.es; rbolea@unizar.es; osta@unizar.es; badiola@unizar.es; pilarzar@unizar.es; espinosa.juan@inia.es; jmtorres@inia.es; minma@unizar.es	10.3390/biom10060908	2020	10	6	-	-	908	-
Nourse, Jamie; Spada, Stefano; Danckwardt, Sven	Emerging Roles of RNA 3′-end Cleavage and Polyadenylation in Pathogenesis, Diagnosis and Therapy of Human Disorders	Biomolecules	EN	Review	3′ end processing; cleavage and polyadenylation; alternative polyadenylation; cardiovascular disorders; neurodegenerative disorders; cancer; disease; biomarker; therapy	A crucial feature of gene expression involves RNA processing to produce 3′ ends through a process termed 3′ end cleavage and polyadenylation (CPA). This ensures the nascent RNA molecule can exit the nucleus and be translated to ultimately give rise to a protein which can execute a function. Further, alternative polyadenylation (APA) can produce distinct transcript isoforms, profoundly expanding the complexity of the transcriptome. CPA is carried out by multi-component protein complexes interacting with multiple RNA motifs and is tightly coupled to transcription, other steps of RNA processing, and even epigenetic modifications. CPA and APA contribute to the maintenance of a multitude of diverse physiological processes. It is therefore not surprising that disruptions of CPA and APA can lead to devastating disorders. Here, we review potential CPA and APA mechanisms involving both loss and gain of function that can have tremendous impacts on health and disease. Ultimately we highlight the emerging diagnostic and therapeutic potential CPA and APA offer.	Institute for Clinical Chemistry and Laboratory Medicine, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany	james.nourse@unimedizin-mainz.de; stefano.spada@unimedizin-mainz.de; sven.danckwardt@unimedizin-mainz.de	10.3390/biom10060915	2020	10	6	-	-	915	-
Fernández-Vega Cueto, Andrés; Álvarez, Lydia; García, Montserrat; Artime, Enol; Álvarez Barrios, Ana; Rodríguez-Uña, Ignacio; Coca-Prados, Miguel; González-Iglesias, Héctor	Systemic Alterations of Immune Response-Related Proteins during Glaucoma Development in the Murine Model DBA/2J	Diagnostics	EN	Article	glaucoma; DBA/2J mouse model; blood; biomarkers; immune response; complement system	Animal models of glaucoma, a neurodegenerative disease affecting the retina, offer the opportunity to study candidate molecular biomarkers throughout the disease. In this work, the DBA/2J glaucomatous mouse has been used to study the systemic levels of several proteins previously identified as potential biomarkers of glaucoma, along the pre- to post-glaucomatous transition. Serum samples obtained from glaucomatous and control mice at 4, 10, and 14 months, were classified into different experimental groups according to the optic nerve damage at 14 months old. Quantifications of ten serum proteins were carried out by enzyme immunoassays. Changes in the levels of some of these proteins in the transition to glaucomatous stages were identified, highlighting the significative decrease in the concentration of complement C4a protein. Moreover, the five-protein panel consisting of complement C4a, complement factor H, ficolin-3, apolipoprotein A4, and transthyretin predicted the transition to glaucoma in 78% of cases, and to the advanced disease in 89%. Our data, although still preliminary, suggest that disease development in DBA/2J mice is associated with important molecular changes in immune response and complement system proteins and demonstrate the utility of this model in identifying, at systemic level, potential markers for the diagnosis of glaucoma.	Instituto Oftalmológico Fernández-Vega, Avenida Doctores Fernández-Vega, 34, 33012 Oviedo, Spain	afvega89@gmail.com; l.alvarez@fio.as; mgarciadiaz@fio.as; enol.artime@fio.as; uo245562@uniovi.es; irodriguezu@fernandez-vega.com; miguel.coca-prados@yale.edu; h.gonzalez@fio.as	10.3390/diagnostics10060425	2020	10	6	-	-	425	-
Song, Chao; Que, Suya; Heimer, Lucas; Que, Long	On-Chip Detection of the Biomarkers for Neurodegenerative Diseases: Technologies and Prospects	Micromachines	EN	Review	neurodegenerative diseases; on-chip detection; point-of-care diagnostics	Alzheimer’s disease (AD), Parkinson’s disease (PD) and glaucoma are all regarded as neurodegenerative diseases (neuro-DDs) because these diseases are highly related to the degeneration loss of functions and death of neurons with aging. The conventional diagnostic methods such as neuroimaging for these diseases are not only expensive but also time-consuming, resulting in significant financial burdens for patients and public health challenge for nations around the world. Hence early detection of neuro-DDs in a cost-effective and rapid manner is critically needed. For the past decades, some chip-based detection technologies have been developed to address this challenge, showing great potential in achieving point-of-care (POC) diagnostics of neuro-DDs. In this review, chip-based detection of neuro-DDs’ biomarkers enabled by different transducing mechanisms is evaluated.	Electrical and Computer Engineering Department, Iowa State University, Ames, IA 50011, USA	csong@iastate.edu; 889264que@ames.k12.ia.us; ljheimer@iastate.edu; lque@iastate.edu	10.3390/mi11070629	2020	11	7	-	-	629	-
Kutchy, Naseer; Peeples, Eric; Sil, Susmita; Liao, Ke; Chivero, Ernest; Hu, Guoku; Buch, Shilpa	Extracellular Vesicles in Viral Infections of the Nervous System	Viruses	EN	Review	virus; HIV-1; Zika; exosome; neurodegenerative diseases	Almost all types of cells release extracellular vesicles (EVs) into the extracellular space. EVs such as exosomes and microvesicles are membrane-bound vesicles ranging in size from 30 to 1000 nm in diameter. Under normal conditions, EVs mediate cell to cell as well as inter-organ communication via the shuttling of their cargoes which include RNA, DNA and proteins. Under pathological conditions, however, the number, size and content of EVs are found to be altered and have been shown to play crucial roles in disease progression. Emerging studies have demonstrated that EVs are involved in many aspects of viral infection-mediated neurodegenerative diseases. In the current review, we will describe the interactions between EV biogenesis and the release of virus particles while also reviewing the role of EVs in various viral infections, such as HIV-1, HTLV, Zika, CMV, EBV, Hepatitis B and C, JCV, and HSV-1. We will also discuss the potential uses of EVs and their cargoes as biomarkers and therapeutic vehicles for viral infections.	Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5880, USA	naseer.kutchy@unmc.edu; epeeples@childrensomaha.org; susmita.sil@unmc.edu; ke.liao@unmc.edu; ernest.chivero@unmc.edu; guoku.hu@unmc.edu; sbuch@unmc.edu	10.3390/v12070700	2020	12	7	-	-	700	-
Connolly, Owen; Le Gall, Laura; McCluskey, Gavin; Donaghy, Colette; Duddy, William; Duguez, Stephanie	A Systematic Review of Genotype–Phenotype Correlation across Cohorts Having Causal Mutations of Different Genes in ALS	Journal of Personalized Medicine	EN	Review	ALS; MND; ALS variants; genotype–phenotype; ALS genes	Amyotrophic lateral sclerosis is a rare and fatal neurodegenerative disease characterised by progressive deterioration of upper and lower motor neurons that eventually culminates in severe muscle atrophy, respiratory failure and death. There is a concerning lack of understanding regarding the mechanisms that lead to the onset of ALS and as a result there are no reliable biomarkers that aid in the early detection of the disease nor is there an effective treatment. This review first considers the clinical phenotypes associated with ALS, and discusses the broad categorisation of ALS and ALS-mimic diseases into upper and lower motor neuron diseases, before focusing on the genetic aetiology of ALS and considering the potential relationship of mutations of different genes to variations in phenotype. For this purpose, a systematic review is conducted collating data from 107 original published clinical studies on monogenic forms of the disease, surveying the age and site of onset, disease duration and motor neuron involvement. The collected data highlight the complexity of the disease’s genotype–phenotype relationship, and thus the need for a nuanced approach to the development of clinical assays and therapeutics.	Northern Ireland Center for Stratified/Personalised Medicine, Biomedical Sciences Research Institute, Ulster University, Londonderry BT47 6SB, Northern Ireland, UK	connolly-o4@ulster.ac.uk; le_gall-l@ulster.ac.uk; gmccluskey05@qub.ac.uk; coletteg.donaghy@westerntrust.hscni.net; w.duddy@ulster.ac.uk; s.duguez@ulster.ac.uk	10.3390/jpm10030058	2020	10	3	-	-	58	-
Urbizu, Aintzane; Beyer, Katrin	Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy	International Journal of Molecular Sciences	EN	Review	Parkinson’s disease; dementia with Lewy bodies; Lewy body diseases; epigenetics; DNA methylation; histone modification; alpha-synuclein	Lewy body disorders (LBD) include Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). They are synucleinopathies with a heterogeneous clinical manifestation. As a cause of neuropathological overlap with other neurodegenerative diseases, the establishment of a correct clinical diagnosis is still challenging, and clinical management may be difficult. The combination of genetic variation and epigenetic changes comprising gene expression-modulating DNA methylation and histone alterations modifies the phenotype, disease course, and susceptibility to disease. In this review, we summarize the results achieved in the deciphering of the LBD epigenome. To provide an appropriate context, first LBD genetics is briefly outlined. Afterwards, a detailed review of epigenetic modifications identified for LBD in human cells, postmortem, and peripheral tissues is provided. We also focus on the difficulty of identifying epigenome-related biomarker candidates and discuss the results obtained so far. Additionally, epigenetic changes as therapeutic targets, as well as different epigenome-based treatments, are revised. The number of studies focusing on PD is relatively limited and practically inexistent for DLB. There is a lack of replication studies, and some results are even contradictory, probably due to differences in sample collection and analytical techniques. In summary, we show the current achievements and directions for future research.	Department of Pathology, Germans Trias i Pujol Research Institute, 08916 Badalona, Spain	aurbizu@igtp.cat; kbeyer@igtp.cat	10.3390/ijms21134718	2020	21	13	-	-	4718	-
Kim, Hyojung; Kang, Seok-Jae; Jo, Young; Park, Sanggyu; Yun, Seung; Lee, Yun-Song; Kim, Hee-Tae; Lee, Nae-Eung; Kim, Yong-Sang; Cho, Seok; Lee, Yunjong	Novel Nasal Epithelial Cell Markers of Parkinson’s Disease Identified Using Cells Treated with α-Synuclein Preformed Fibrils	Journal of Clinical Medicine	EN	Article	nasal epithelial cell model; Parkinson’s disease; RPMI-2650 cells; olfactory biomarker; α-synuclein preformed fibril; olfactory dysfunction	Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, characterized by olfactory dysfunction in the early stages. α-Synuclein pathologies in the olfactory organs are shown to spread to the brain through the nose-brain axis. We first developed a nasal epithelial PD cellular model by treating RPMI-2650 cells with α-synuclein preformed fibrils (PFF). Upon uptake of PFF, RPMI-2650 cells showed mitochondrial proteome alteration and downregulation of parkin, which has previously been identified as a nasal biomarker of PD. Functional cluster analysis of differentially expressed genes in RPMI-2650 cells revealed various pathways affected by α-synuclein pathology, including the detection of chemical stimulus involved in sensory perception, olfactory receptor activity, and sensory perception of smell. Among genes that were most affected, we validated, by real-time quantitative PCR, the downregulation of MAP3K8, OR10A4, GRM2, OR51B6, and OR9A2, as well as upregulation of IFIT1B, EPN1, OR1D5, LCN, and OTOL1 in PFF-treated RPMI-2650 cells. Subsequent analyses of clinical samples showed a downregulation of OR10A4 and OR9A2 transcripts and an upregulation of IFIT1B in cells isolated from the nasal fluid of PD patients, as compared to those from the controls (cutoff value = 0.5689 for OR9A2, with 72.4% sensitivity and 75% specificity, and 1.4658 for IFIT1B, with 81.8% sensitivity and 77.8% specificity). Expression levels of these nasal PD markers were not altered in nasal fluid cells from SWEDD (scans without evidence of dopaminergic deficits) patients with PD-like motor symptoms. These nasal markers were significantly altered in patients of PD with hyposmia compared to the control hyposmic subjects. Our results validated the α-synuclein-treated nasal epithelial cell model to identify novel biomarkers for PD and suggest the utility of olfactory transcripts, along with olfactory dysfunction, in the diagnosis of PD.	Department of Pharmacology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 16419, Korea	hjung93@skku.edu; go2dream@hanmail.net; jym1358@hanmail.net; hoho2027@naver.com; spyun@gnu.ac.kr; yslee@skku.edu; kimht@hanyang.ac.kr; nelee@skku.edu; yongsang@skku.edu; shcho@hanyang.ac.kr; ylee69@skku.edu	10.3390/jcm9072128	2020	9	7	-	-	2128	-
Villa, Chiara; Lavitrano, Marialuisa; Salvatore, Elena; Combi, Romina	Molecular and Imaging Biomarkers in Alzheimer’s Disease: A Focus on Recent Insights	Journal of Personalized Medicine	EN	Review	Alzheimer’s disease; biomarker; amyloid beta; neuroimaging; cerebrospinal fluid	Alzheimer’s disease (AD) is the most common neurodegenerative disease among the elderly, affecting millions of people worldwide and clinically characterized by a progressive and irreversible cognitive decline. The rapid increase in the incidence of AD highlights the need for an easy, efficient and accurate diagnosis of the disease in its initial stages in order to halt or delay the progression. The currently used diagnostic methods rely on measures of amyloid-β (Aβ), phosphorylated (p-tau) and total tau (t-tau) protein levels in the cerebrospinal fluid (CSF) aided by advanced neuroimaging techniques like positron emission tomography (PET) and magnetic resonance imaging (MRI). However, the invasiveness of these procedures and the high cost restrict their utilization. Hence, biomarkers from biological fluids obtained using non-invasive methods and novel neuroimaging approaches provide an attractive alternative for the early diagnosis of AD. Such biomarkers may also be helpful for better understanding of the molecular mechanisms underlying the disease, allowing differential diagnosis or at least prolonging the pre-symptomatic stage in patients suffering from AD. Herein, we discuss the advantages and limits of the conventional biomarkers as well as recent promising candidates from alternative body fluids and new imaging techniques.	School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy	chiara.villa@unimib.it; m.lavitrano@ieos.cnr.it; elena.salvatore@unina.it; romina.combi@unimib.it	10.3390/jpm10030061	2020	10	3	-	-	61	-
Vassileff, Natasha; Vella, Laura; Rajapaksha, Harinda; Shambrook, Mitch; Kenari, Amirmohammad; McLean, Catriona; Hill, Andrew; Cheng, Lesley	Revealing the Proteome of Motor Cortex Derived Extracellular Vesicles Isolated from Amyotrophic Lateral Sclerosis Human Postmortem Tissues	Cells	EN	Article	Amyotrophic Lateral Sclerosis; ALS; proteomics; exosomes; motor cortex derived extracellular vesicles; extracellular vesicles	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.	The Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Bundoora, VIC 3083, Australia	18491406@students.latrobe.edu.au; laura.vella@florey.edu.au; k.rajapaksha@latrobe.edu.au; m.shambrook@latrobe.edu.au; 18039356@students.latrobe.edu.au; c.mclean@alfred.org.au; andrew.hill@latrobe.edu.au; l.cheng@latrobe.edu.au	10.3390/cells9071709	2020	9	7	-	-	1709	-
Omar, Syed; Preddy, John	Advantages and Pitfalls in Fluid Biomarkers for Diagnosis of Alzheimer’s Disease	Journal of Personalized Medicine	EN	Review	Alzheimer’s disease; cerebrospinal fluid; amyloid beta peptide; total tau; phosphorylated tau; diagnosis	Alzheimer’s disease (AD) is a commonly occurring neurodegenerative disease in the advanced-age population, with a doubling of prevalence for each 5 years of age above 60 years. In the past two decades, there has been a sustained effort to find suitable biomarkers that may not only aide with the diagnosis of AD early in the disease process but also predict the onset of the disease in asymptomatic individuals. Current diagnostic evidence is supportive of some biomarker candidates isolated from cerebrospinal fluid (CSF), including amyloid beta peptide (Aβ), total tau (t-tau), and phosphorylated tau (p-tau) as being involved in the pathophysiology of AD. However, there are a few biomarkers that have been shown to be helpful, such as proteomic, inflammatory, oral, ocular and olfactory in the early detection of AD, especially in the individuals with mild cognitive impairment (MCI). To date, biomarkers are collected through invasive techniques, especially CSF from lumbar puncture; however, non-invasive (radio imaging) methods are used in practice to diagnose AD. In order to reduce invasive testing on the patients, present literature has highlighted the potential importance of biomarkers in blood to assist with diagnosing AD.	Rural Clinical School, Faculty of Medicine, University of New South Wales, Wagga Wagga, NSW 2650, Australia	haris.omar@unsw.edu.au; j.preddy@unsw.edu.au	10.3390/jpm10030063	2020	10	3	-	-	63	-
Katayama, Takayuki; Sawada, Jun; Takahashi, Kae; Yahara, Osamu	Cerebrospinal Fluid Biomarkers in Parkinson’s Disease: A Critical Overview of the Literature and Meta-Analyses	Brain Sciences	EN	Opinion	Parkinson’s disease; cerebrospinal fluid; α-synuclein; amyloid β42; tau; neurofilament light chain	Parkinson’s disease (PD) is a common neurodegenerative disorder; however, well-established biochemical markers have not yet been identified. This review article covers several candidate cerebrospinal fluid (CSF) biomarkers for PD based on the recent literature and meta-analysis data. The decrease of α-synuclein in PD is supported by meta-analyses with modest reproducibility, and a decrease of amyloid β42 is seen as a prognostic marker for cognitive decline. Tau, phosphorylated tau (p-tau), and neurofilament light chains have been used to discriminate PD from other neurodegenerative disorders. This article also describes more hopeful biochemical markers, such as neurotransmitters, oxidative stress markers, and other candidate biomarkers.	Department of Neurology, Asahikawa City Hospital, 1-1-65 Kinseicho, Asahikawa 070-8610, Japan	katataka@gmail.com; sawajun@asahikawa-med.ac.jp; kae.t-452@live.jp; oyahara@kca.biglobe.ne.jp	10.3390/brainsci10070466	2020	10	7	-	-	466	-
Fernández-Mendívil, Cristina; Arreola, Miguel; Hohsfield, Lindsay; Green, Kim; Lopez, Manuela	Aging and Progression of Beta-Amyloid Pathology in Alzheimer’s Disease Correlates with Microglial Heme-Oxygenase-1 Overexpression	Antioxidants	EN	Article	Heme oxygenase-1; microglia; Alzheimer’s disease; beta-amyloid plaques	Neuroinflammation and oxidative stress are being recognized as characteristic hallmarks in many neurodegenerative diseases, especially those that portray proteinopathy, such as Alzheimer’s disease (AD). Heme-oxygenase 1 (HO-1) is an inducible enzyme with antioxidant and anti-inflammatory properties, while microglia are the immune cells in the central nervous system. To elucidate the brain expression profile of microglial HO-1 in aging and AD-progression, we have used the 5xFAD (five familial AD mutations) mouse model of AD and their littermates at different ages (four, eight, 12, and 18 months). Total brain expression of HO-1 was increased with aging and such increase was even higher in 5xFAD animals. In co-localization studies, HO-1 expression was mainly found in microglia vs. other brain cells. The percentage of microglial cells expressing HO-1 and the amount of HO-1 expressed within microglia increased progressively with aging. Furthermore, this upregulation was increased by 2–3-fold in the elder 5xFAD mice. In addition, microglia overexpressing HO-1 was predominately found surrounding beta-amyloid plaques. These results were corroborated using postmortem brain samples from AD patients, where microglial HO-1 was found up-regulated in comparison to brain samples from aged matched non-demented patients. This study demonstrates that microglial HO-1 expression increases with aging and especially with AD progression, highlighting HO-1 as a potential biomarker or therapeutic target for AD.	Institute Teofilo Hernando for Drug Discovery, Department of Pharmacology, School of Medicine, Universidad Autónoma de Madrid, 28029 Madrid, Spain	cristina.fernandezm@uam.es; maarreol@uci.edu; lindsay.hohsfield@uci.edu; kngreen@uci.edu; manuela.garcia@uam.es	10.3390/antiox9070644	2020	9	7	-	-	644	-
Peña-Bautista, Carmen; Álvarez, Lourdes; Durand, Thierry; Vigor, Claire; Cuevas, Ana; Baquero, Miguel; Vento, Máximo; Hervás, David; Cháfer-Pericás, Consuelo	Clinical Utility of Plasma Lipid Peroxidation Biomarkers in Alzheimer’s Disease Differential Diagnosis	Antioxidants	EN	Article	plasma; lipid peroxidation; Alzheimer’s disease; differential diagnosis; clinical validation	Background: Differential diagnosis of Alzheimer’s disease (AD) is a complex task due to the clinical similarity among neurodegenerative diseases. Previous studies showed the role of lipid peroxidation in early AD development. However, the clinical validation of potential specific biomarkers in minimally invasive samples constitutes a great challenge in early AD diagnosis. Methods: Plasma samples from participants classified into AD (n = 138), non-AD (including MCI and other dementias not due to AD) (n = 70) and healthy (n = 50) were analysed. Lipid peroxidation compounds (isoprostanes, isofurans, neuroprostanes, neurofurans) were determined by ultra-performance liquid chromatography coupled with tandem mass spectrometry. Statistical analysis for biomarkers’ clinical validation was based on Elastic Net. Results: A two-step diagnosis model was developed from plasma lipid peroxidation products to diagnose early AD specifically, and a bootstrap validated AUC of 0.74 was obtained. Conclusion: A promising AD differential diagnosis model was developed. It was clinically validated as a screening test. However, further external validation is required before clinical application.	Neonatal Research Unit, Health Research Institute La Fe, 46026 Valencia, Spain	carpebau@alumni.uv.es; lourdes.alvsa@gmail.com; thierry.durand@umontpellier.fr; claire.vigor@umontpellier.fr; anais85@gmail.com; miquelbaquero@gmail.com; maximo.vento@uv.es; bioestadistica@iislafe.es; m.consuelo.chafer@uv.es	10.3390/antiox9080649	2020	9	8	-	-	649	-
Kinoshita, Chisato; Okamoto, Yayoi; Aoyama, Koji; Nakaki, Toshio	MicroRNA: A Key Player for the Interplay of Circadian Rhythm Abnormalities, Sleep Disorders and Neurodegenerative Diseases	Clocks &amp; Sleep	EN	Review	microRNA; circadian rhythm; clock gene; sleep disorder; neurodegenerative disease; biomarker; therapeutic	Circadian rhythms are endogenous 24-h oscillators that regulate the sleep/wake cycles and the timing of biological systems to optimize physiology and behavior for the environmental day/night cycles. The systems are basically generated by transcription–translation feedback loops combined with post-transcriptional and post-translational modification. Recently, evidence is emerging that additional non-coding RNA-based mechanisms are also required to maintain proper clock function. MicroRNA is an especially important factor that plays critical roles in regulating circadian rhythm as well as many other physiological functions. Circadian misalignment not only disturbs the sleep/wake cycle and rhythmic physiological activity but also contributes to the development of various diseases, such as sleep disorders and neurodegenerative diseases. The patient with neurodegenerative diseases often experiences profound disruptions in their circadian rhythms and/or sleep/wake cycles. In addition, a growing body of recent evidence implicates sleep disorders as an early symptom of neurodegenerative diseases, and also suggests that abnormalities in the circadian system lead to the onset and expression of neurodegenerative diseases. The genetic mutations which cause the pathogenesis of familial neurodegenerative diseases have been well studied; however, with the exception of Huntington’s disease, the majority of neurodegenerative diseases are sporadic. Interestingly, the dysfunction of microRNA is increasingly recognized as a cause of sporadic neurodegenerative diseases through the deregulated genes related to the pathogenesis of neurodegenerative disease, some of which are the causative genes of familial neurodegenerative diseases. Here we review the interplay of circadian rhythm disruption, sleep disorders and neurodegenerative disease, and its relation to microRNA, a key regulator of cellular processes.	Department of Pharmacology, Teikyo University School of Medicine, 2-11-1 Kaga, Itabashi, Tokyo 173-8605, Japan	ciitaka@med.teikyo-u.ac.jp; yayoimya841@med.teikyo-u.ac.jp; kaoyama@med.teikyo-u.ac.jp; nakaki@med.teikyo-u.ac.jp	10.3390/clockssleep2030022	2020	2	3	-	-	22	-
Jusril, Nor; Muhamad Juhari, Ain; Abu Bakar, Syahrul; Md Saad, Wan; Adenan, Mohd	Combining In Silico and In Vitro Studies to Evaluate the Acetylcholinesterase Inhibitory Profile of Different Accessions and the Biomarker Triterpenes of Centella asiatica	Molecules	EN	Article	Centella asiatica; acetylcholinesterase; triterpenes; molecular docking; in silico; in vitro	Alzheimer’s disease (AD) is a neurodegenerative disease and the most cause of dementia in elderly adults. Acetylcholinesterase (AChE) is an important beneficial target for AD to control cholinergic signaling deficit. Centella asiatica (CA) has proven to be rich with active ingredients for memory enhancement. In the present study, the chemical profiling of three accession extracts of CA namely SECA-K017, SECA-K018, and, SECA-K019 were performed using high-performance liquid chromatography (HPLC). Four biomarker triterpene compounds were detected in all CA accessions. Quantitative analysis reveals that madecassoside was the highest triterpene in all the CA accessions. The biomarker compounds and the ethanolic extracts of three accessions were investigated for their acetylcholinesterase (AChE) inhibitory activity using Ellman’s spectrophotometer method. The inhibitory activity of the triterpenes and accession extracts was compared with the standard AChE inhibitor eserine. The results from the in vitro study showed that the triterpene compounds exhibited an AChE inhibitory activity with the half-maximal inhibitory concentration (IC50) values between 15.05 ± 0.05 and 59.13 ± 0.18 µg/mL. Asiatic acid was found to possess strong AChE inhibitory activity followed by madecassic acid. Among the CA accession extracts, SECA-K017 and SECA-K018 demonstrated a moderate AChE inhibitory activity with an IC50 value of 481.5 ± 0.13 and 763.5 ± 0.16 µg/mL, respectively from the in silico docking studies, it is observed that asiatic acid and madecassic acid showed very good interactions with the active sites and fulfilled docking parameters against AChE. The present study suggested that asiatic acid and madecassic acid in the CA accessions could be responsible for the AChE inhibitory action and could be used as markers to guide further studies on CA as potential natural products for the treatment of AD.	Faculty of Applied Sciences, Universiti Teknologi MARA, Shah Alam 40450, Selangor Darul Ehsan, Malaysia	atiqahjusril93@gmail.com; ainnrnjhh@gmail.com; syahrulimran@uitm.edu.my; wanmaz755@uitm.edu.my; mohdilham@uitm.edu.my	10.3390/molecules25153353	2020	25	15	-	-	3353	-
S. Clemente, Gonçalo; van Waarde, Aren; F. Antunes, Inês; Dömling, Alexander; H. Elsinga, Philip	Arginase as a Potential Biomarker of Disease Progression: A Molecular Imaging Perspective	International Journal of Molecular Sciences	EN	Review	arginase; nitric oxide; arginase inhibitors; molecular imaging; positron emission tomography (PET)	Arginase is a widely known enzyme of the urea cycle that catalyzes the hydrolysis of L-arginine to L-ornithine and urea. The action of arginase goes beyond the boundaries of hepatic ureogenic function, being widespread through most tissues. Two arginase isoforms coexist, the type I (Arg1) predominantly expressed in the liver and the type II (Arg2) expressed throughout extrahepatic tissues. By producing L-ornithine while competing with nitric oxide synthase (NOS) for the same substrate (L-arginine), arginase can influence the endogenous levels of polyamines, proline, and NO•. Several pathophysiological processes may deregulate arginase/NOS balance, disturbing the homeostasis and functionality of the organism. Upregulated arginase expression is associated with several pathological processes that can range from cardiovascular, immune-mediated, and tumorigenic conditions to neurodegenerative disorders. Thus, arginase is a potential biomarker of disease progression and severity and has recently been the subject of research studies regarding the therapeutic efficacy of arginase inhibitors. This review gives a comprehensive overview of the pathophysiological role of arginase and the current state of development of arginase inhibitors, discussing the potential of arginase as a molecular imaging biomarker and stimulating the development of novel specific and high-affinity arginase imaging probes.	Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, University of Groningen, 9713 GZ Groningen, The Netherlands	g.dos.santos.clemente@umcg.nl; a.van.waarde@umcg.nl; i.farinha.antunes@umcg.nl; a.s.s.domling@rug.nl; p.h.elsinga@umcg.nl	10.3390/ijms21155291	2020	21	15	-	-	5291	-
Iannuzzi, Filomena; Sirabella, Rossana; Canu, Nadia; Maier, Thorsten; Annunziato, Lucio; Matrone, Carmela	Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients	Cells	EN	Article	amyloid precursor protein; amyloid beta; Fyn tyrosine kinase; Tyr682 residue; YENPTY domain	Alzheimer’s disease (AD) is an incurable neurodegenerative disorder with a few early detection strategies. We previously proposed the amyloid precursor protein (APP) tyrosine 682 (Tyr682) residue as a valuable target for the development of new innovative pharmacologic or diagnostic interventions in AD. Indeed, when APP is phosphorylated at Tyr682, it is forced into acidic neuronal compartments where it is processed to generate neurotoxic amyloid β peptides. Of interest, Fyn tyrosine kinase (TK) interaction with APP Tyr682 residue increases in AD neurons. Here we proved that when Fyn TK was overexpressed it elicited APP Tyr682 phosphorylation in neurons from healthy donors and promoted the amyloidogenic APP processing with Aβ peptides accumulation and neuronal death. Phosphorylation of APP at Tyr (pAPP-Tyr) increased in neurons of AD patients and AD neurons that exhibited high pAPP-Tyr also had higher Fyn TK activity. Fyn TK inhibition abolished the pAPP-Tyr and reduced Aβ42 secretion in AD neurons. In addition, the multidomain adaptor protein Fe65 controlled the Fyn-mediated pAPP-Tyr, warranting the possibility of targeting the Fe65-APP-Fyn pathway to develop innovative strategies in AD. Altogether, these results strongly emphasize the relevance of focusing on pAPP Tyr682 either for diagnostic purposes, as an early biomarker of the disease, or for pharmacological targeting, using Fyn TKI.	Department of Biomedicine, Aarhus University, Aarhus C, 8000 Aarhus, Denmark	filomena.iannuzzi@biomed.au.dk; sirabell@unina.it; nadia.canu@uniroma2.it; thorstenjuergen.maier@pei.de; lannunzi@unina.it; carmela.matrone@unina.it	10.3390/cells9081807	2020	9	8	-	-	1807	-
Apter, B.; Lapshina, N.; Barhom, H.; Fainberg, B.; Handelman, A.; Accardo, A.; Diaferia, C.; Ginzburg, P.; Morelli, G.; Rosenman, G.	Fluorescence Phenomena in Amyloid and Amyloidogenic Bionanostructures	Crystals	EN	Review	bioimaging; fluorescence labels; fluorescent dyes for imaging of amyloid fibrils; peptide-based materials; PEGylated peptides; peptide nanostructures; peptide aggregates; thermally induced refolding helix-like→β-sheet and intrinsic visible fluorescence in amyloid and amyloidogenic β-sheet nanostructures; fluorescence in polymer/peptide thin films and fibers; reabsorption mechanism of fluorescence long-range propagation; visible fluorescent bionanodots	Nanoscale optical labeling is an advanced bioimaging tool. It is mostly based on fluorescence (FL) phenomena and enables the visualization of single biocells, bacteria, viruses, and biological tissues, providing monitoring of functional biosystems in vitro and in vivo, and the imaging-guided transportation of drug molecules. There is a variety of FL biolabels such as organic molecular dyes, genetically encoded fluorescent proteins (green fluorescent protein and homologs), semiconductor quantum dots, carbon dots, plasmonic metal gold-based nanostructures and more. In this review, a new generation of FL biolabels based on the recently found biophotonic effects of visible FL are described. This intrinsic FL phenomenon is observed in any peptide/protein materials folded into β-sheet secondary structures, irrespective of their composition, complexity, and origin. The FL effect has been observed both in natural amyloid fibrils, associated with neurodegenerative diseases (Alzheimer’s, Parkinson’s, and more), and diverse synthetic peptide/protein structures subjected to thermally induced biological refolding helix-like→β-sheet. This approach allowed us to develop a new generation of FL peptide/protein bionanodots radiating multicolor, tunable, visible FL, covering the entire visible spectrum in the range of 400–700 nm. Newly developed biocompatible nanoscale biomarkers are considered as a promising tool for emerging precise biomedicine and advanced medical nanotechnologies (high-resolution bioimaging, light diagnostics, therapy, optogenetics, and health monitoring).	Faculty of Engineering, Holon Institute of Technology, Holon 581200, Israel	apter@hit.ac.il; lapshina.nadezda@gmail.com; hani.barhom@gmail.com; fainberg@hit.ac.il; handelmana@hit.ac.il; antonella.accardo@unina.it; carlo.diaferia@unina.it; pginzburg@tauex.tau.ac.il; giancarlo.morelli@unina.it; gilr@eng.tau.ac.il	10.3390/cryst10080668	2020	10	8	-	-	668	-
Khan, Andleeb; Jahan, Sadaf; Imtiyaz, Zuha; Alshahrani, Saeed; Antar Makeen, Hafiz; Mohammed Alshehri, Bader; Kumar, Ajay; Arafah, Azher; Rehman, Muneeb	Neuroprotection: Targeting Multiple Pathways by Naturally Occurring Phytochemicals	Biomedicines	EN	Review	neurodegenerative diseases; phytochemicals; natural products; neuroprotection	With the increase in the expectancy of the life span of humans, neurodegenerative diseases (NDs) have imposed a considerable burden on the family, society, and nation. In defiance of the breakthroughs in the knowledge of the pathogenesis and underlying mechanisms of various NDs, very little success has been achieved in developing effective therapies. This review draws a bead on the availability of the nutraceuticals to date for various NDs (Alzheimer’s disease, Parkinson’s disease, Amyotrophic lateral sclerosis, Huntington’s disease, vascular cognitive impairment, Prion disease, Spinocerebellar ataxia, Spinal muscular atrophy, Frontotemporal dementia, and Pick’s disease) focusing on their various mechanisms of action in various in vivo and in vitro models of NDs. This review is distinctive in its compilation to critically review preclinical and clinical studies of the maximum phytochemicals in amelioration and prevention of almost all kinds of neurodegenerative diseases and address their possible mechanism of action. PubMed, Embase, and Cochrane Library searches were used for preclinical studies, while ClinicalTrials.gov and PubMed were searched for clinical updates. The results from preclinical studies demonstrate the efficacious effects of the phytochemicals in various NDs while clinical reports showing mixed results with promise for phytochemical use as an adjunct to the conventional treatment in various NDs. These studies together suggest that phytochemicals can significantly act upon different mechanisms of disease such as oxidative stress, inflammation, apoptotic pathways, and gene regulation. However, further clinical studies are needed that should include the appropriate biomarkers of NDs and the effect of phytochemicals on them as well as targeting the appropriate population.	Department of Pharmacology and Toxicology, College of Pharmacy, Jazan University, Jazan 45142, Saudi Arabia	drandleebkhan@gmail.com; ; ; ; ; ; ; ; 	10.3390/biomedicines8080284	2020	8	8	-	-	284	-
Grant, Stephanie; DeMorrow, Sharon	Bile Acid Signaling in Neurodegenerative and Neurological Disorders	International Journal of Molecular Sciences	EN	Review	bile acid receptors; neuroprotective; tauroursodeoxycholic acid; ursodeoxycholic acid; alzheimer’s disease; parkinson’s disease; multiple sclerosis; hepatic encephalopathy	Bile acids are commonly known as digestive agents for lipids. The mechanisms of bile acids in the gastrointestinal track during normal physiological conditions as well as hepatic and cholestatic diseases have been well studied. Bile acids additionally serve as ligands for signaling molecules such as nuclear receptor Farnesoid X receptor and membrane-bound receptors, Takeda G-protein-coupled bile acid receptor and sphingosine-1-phosphate receptor 2. Recent studies have shown that bile acid signaling may also have a prevalent role in the central nervous system. Some bile acids, such as tauroursodeoxycholic acid and ursodeoxycholic acid, have shown neuroprotective potential in experimental animal models and clinical studies of many neurological conditions. Alterations in bile acid metabolism have been discovered as potential biomarkers for prognosis tools as well as the expression of various bile acid receptors in multiple neurological ailments. This review explores the findings of recent studies highlighting bile acid-mediated therapies and bile acid-mediated signaling and the roles they play in neurodegenerative and neurological diseases.	Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA	stephanie.grant@austin.utexas.edu; sharon.demorrow@austin.utexas.edu	10.3390/ijms21175982	2020	21	17	-	-	5982	-
Catanesi, Mariano; d’Angelo, Michele; Tupone, Maria; Benedetti, Elisabetta; Giordano, Antonio; Castelli, Vanessa; Cimini, Annamaria	MicroRNAs Dysregulation and Mitochondrial Dysfunction in Neurodegenerative Diseases	International Journal of Molecular Sciences	EN	Review	miRNAs; mitochondrial dysfunction; reactive oxygen species; neurodegenerative disease; aging	Neurodegenerative diseases are debilitating and currently incurable conditions causing severe cognitive and motor impairments, defined by the progressive deterioration of neuronal structure and function, eventually causing neuronal loss. Understand the molecular and cellular mechanisms underlying these disorders are essential to develop therapeutic approaches. MicroRNAs (miRNAs) are short non-coding RNAs implicated in gene expression regulation at the post-transcriptional level. Moreover, miRNAs are crucial for different processes, including cell growth, signal transmission, apoptosis, cancer and aging-related neurodegenerative diseases. Altered miRNAs levels have been associated with the formation of reactive oxygen species (ROS) and mitochondrial dysfunction. Mitochondrial dysfunction and ROS formation occur in many neurodegenerative diseases such as Alzheimer’s, Parkinson’s and Huntington’s diseases. The crosstalk existing among oxidative stress, mitochondrial dysfunction and miRNAs dysregulation plays a pivotal role in the onset and progression of neurodegenerative diseases. Based on this evidence, in this review, with a focus on miRNAs and their role in mitochondrial dysfunction in aging-related neurodegenerative diseases, with a focus on their potential as diagnostic biomarkers and therapeutic targets.	Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy	mcatanesi@unite.it; michele.dangelo@univaq.it; mariagrazia.tupone@univaq.it; elisabetta.benedetti@univaq.it; antonio.giordano@temple.edu; vanessa.castelli@univaq.it; annamaria.cimini@univaq.it	10.3390/ijms21175986	2020	21	17	-	-	5986	-
Toyos-Rodríguez, Celia; García-Alonso, Francisco; de la Escosura-Muñiz, Alfredo	Electrochemical Biosensors Based on Nanomaterials for Early Detection of Alzheimer’s Disease	Sensors	EN	Review	Alzheimer’s disease; neurodegenerative diseases; nanoparticles; labels; electroactivity; electrocatalysis; electrochemistry; immunosensors; biosensors; nanomaterials	Alzheimer’s disease (AD) is an untreatable neurodegenerative disease that initially manifests as difficulty to remember recent events and gradually progresses to cognitive impairment. The incidence of AD is growing yearly as life expectancy increases, thus early detection is essential to ensure a better quality of life for diagnosed patients. To reach that purpose, electrochemical biosensing has emerged as a cost-effective alternative to traditional diagnostic techniques, due to its high sensitivity and selectivity. Of special relevance is the incorporation of nanomaterials in biosensors, as they contribute to enhance electron transfer while promoting the immobilization of biological recognition elements. Moreover, nanomaterials have also been employed as labels, due to their unique electroactive and electrocatalytic properties. The aim of this review is to add value in the advances achieved in the detection of AD biomarkers, the strategies followed for the incorporation of nanomaterials and its effect in biosensors performance.	NanoBioAnalysis Group-Department of Physical and Analytical Chemistry, University of Oviedo, Julián Clavería 8, 33006 Oviedo, Spain	toyoscelia@uniovi.es; fjga@uniovi.es; alfredo.escosura@uniovi.es	10.3390/s20174748	2020	20	17	-	-	4748	-
Irrera, Natasha; Russo, Massimo; Pallio, Giovanni; Bitto, Alessandra; Mannino, Federica; Minutoli, Letteria; Altavilla, Domenica; Squadrito, Francesco	The Role of NLRP3 Inflammasome in the Pathogenesis of Traumatic Brain Injury	International Journal of Molecular Sciences	EN	Review	traumatic brain injury; NLRP3 inflammasome; neuroinflammation; pyroptosis; SARS-CoV-2	Traumatic brain injury (TBI) represents an important problem of global health. The damage related to TBI is first due to the direct injury and then to a secondary phase in which neuroinflammation plays a key role. NLRP3 inflammasome is a component of the innate immune response and different diseases, such as neurodegenerative diseases, are characterized by NLRP3 activation. This review aims to describe NLRP3 inflammasome and the consequences related to its activation following TBI. NLRP3, caspase-1, IL-1β, and IL-18 are significantly upregulated after TBI, therefore, the use of nonspecific, but mostly specific NLRP3 inhibitors is useful to ameliorate the damage post-TBI characterized by neuroinflammation. Moreover, NLRP3 and the molecules associated with its activation may be considered as biomarkers and predictive factors for other neurodegenerative diseases consequent to TBI. Complications such as continuous stimuli or viral infections, such as the SARS-CoV-2 infection, may worsen the prognosis of TBI, altering the immune response and increasing the neuroinflammatory processes related to NLRP3, whose activation occurs both in TBI and in SARS-CoV-2 infection. This review points out the role of NLRP3 in TBI and highlights the hypothesis that NLRP3 may be considered as a potential therapeutic target for the management of neuroinflammation in TBI.	Department of Clinical and Experimental Medicine, University of Messina, c/o AOU Policlinico G. Martino, Via C. Valeria Gazzi, 98,125 Messina, Italy	nirrera@unime.it; russom@unime.it; gpallio@unime.it; abitto@unime.it; fmannino@unime.it; lminutoli@unime.it; daltavilla@unime.it; fsquadrito@unime.it	10.3390/ijms21176204	2020	21	17	-	-	6204	-
Gasecka, Aleksandra; Siwik, Dominika; Gajewska, Magdalena; Jaguszewski, Miłosz; Mazurek, Tomasz; Filipiak, Krzysztof; Postuła, Marek; Eyileten, Ceren	Early Biomarkers of Neurodegenerative and Neurovascular Disorders in Diabetes	Journal of Clinical Medicine	EN	Review	diabetes mellitus complications; neurovascular; neurodegenerative; stroke; dementia; biomarkers; microRNA; growth factors; oxidative stress; PD; AD; MCI; DM	Diabetes mellitus (DM) is a common disease worldwide. There is a strong association between DM and neurovascular and neurodegenerative disorders. The first group mainly consists of diabetic retinopathy, diabetic neuropathy and stroke, whereas, the second group includes Alzheimer’s disease, Parkinson’s disease, mild cognitive impairment and dementia. The aforementioned diseases have a common pathophysiological background including insulin resistance, oxidative stress, atherosclerosis and vascular injury. The increasing prevalence of neurovascular and neurodegenerative disorders among diabetic patients has resulted in an urgent need to develop biomarkers for their prediction and/or early detection. The aim of this review is to present the potential application of the most promising biomarkers of diabetes-related neurodegenerative and neurovascular disorders, including amylin, β-amyloid, C-reactive protein (CRP), dopamine, gamma-glutamyl transferase (GGT), glycogen synthase kinase 3β, homocysteine, microRNAs (mi-RNAs), paraoxonase 1, phosphoinositide 3-kinases, tau protein and various growth factors. The most clinically promising biomarkers of neurovascular and neurodegenerative complications in DM are hsCRP, GGT, homocysteine and miRNAs. However, all biomarkers discussed in this review could become a part of the potential multi-biomarker screening panel for diabetic patients at risk of neurovascular and neurodegenerative complications.	1st Chair and Department of Cardiology, Medical University of Warsaw, 02-097 Warsaw, Poland	aleksandra.gasecka@wum.edu.pl; dominika.siwik@gmail.com; gmgajewska@gmail.com; jamilosz@gmail.com; tmazurek@kardia.edu.pl; krzysztof.filipiak@wum.edu.pl; mpostula@wum.edu.pl; ceyileten@wum.edu.pl	10.3390/jcm9092807	2020	9	9	-	-	2807	-
Corey-Bloom, Jody; Fischer, Ryan; Kim, Aeri; Snell, Chase; Parkin, Georgia; Granger, Douglas; Granger, Steven; Thomas, Elizabeth	Levels of Interleukin-6 in Saliva, but Not Plasma, Correlate with Clinical Metrics in Huntington’s Disease Patients and Healthy Control Subjects	International Journal of Molecular Sciences	EN	Article	peripheral; neurodegenerative; cytokine; biomarker; saliva; biofluid	Growing evidence suggests that inflammatory responses, in both the brain and peripheral tissues, contribute to disease pathology in Huntington’s disease (HD), an inherited, progressive neurodegenerative disorder typically affecting adults in their 30–40 s. Hence, studies of inflammation-related markers in peripheral fluids might be useful to better characterize disease features. In this study, we measured levels of C-reactive protein (CRP), Interleukin-6 (IL-6), interleukin 1 beta (IL-1B), and alpha-amylase (AA) in saliva and plasma from n = 125 subjects, including n = 37 manifest HD patients, n = 36 premanifest patients, and n = 52 healthy controls, using immunoassays. We found increases in salivary levels of IL-6, IL-1B and CRP across different disease groups and increased levels of IL-6 in the plasma of HD patients as compared to premanifest patients and controls. The levels of salivary IL-6 were significantly correlated with each of the other salivary markers, as well as with IL-6 levels measured in plasma. Further, salivary IL-6 and IL-1B levels were significantly positively correlated with Total Motor Score (TMS) and chorea scores and negatively correlated with Total Functional Capacity (TFC) in HD patients, whereby in healthy control subjects, IL-6 was significantly negatively correlated with Montreal Cognitive Assessment (MoCA) and the Symbol Digit Modalities test (SDM). Interestingly, the plasma levels of IL-6 did not show similar correlations to any clinical measures in either HD or control subjects. These findings suggest that salivary IL-6 is particularly relevant as a potential non-invasive biomarker for HD symptoms. The advent of an effective, dependable salivary biomarker would meet the urgent need for a less invasive means of identifying and monitoring HD disease progression.	Department of Neurosciences, University of California, San Diego, CA 92037, USA	jcoreybloom@health.ucsd.edu; rfischer@salimetrics.com; aerikim@ucsd.edu; cmsnell@health.ucsd.edu; gparkin@hs.uci.edu; dagrange@uci.edu; sgranger@salimetrics.com; eathoma1@hs.uci.edu	10.3390/ijms21176363	2020	21	17	-	-	6363	-
Manna, Ida; De Benedittis, Selene; Quattrone, Andrea; Maisano, Domenico; Iaccino, Enrico; Quattrone, Aldo	Exosomal miRNAs as Potential Diagnostic Biomarkers in Alzheimer’s Disease	Pharmaceuticals	EN	Review	neurodegeneration; Alzheimer’s disease; biomarkers; miRNAs; exosomes; exosomal miRNAs	Alzheimer’s disease (AD), a neurodegenerative disease, is linked to a variety of internal and external factors present from the early stages of the disease. There are several risk factors related to the pathogenesis of AD, among these exosomes and microRNAs (miRNAs) are of particular importance. Exosomes are nanocarriers released from many different cell types, including neuronal cells. Through the transfer of bioactive molecules, they play an important role both in the maintenance of physiological and in pathological conditions. Exosomes could be carriers of potential biomarkers useful for the assessment of disease progression and for therapeutic applications. miRNAs are small noncoding endogenous RNA sequences active in the regulation of protein expression, and alteration of miRNA expression can result in a dysregulation of key genes and pathways that contribute to disease development. Indeed, the involvement of exosomal miRNAs has been highlighted in various neurodegenerative diseases, and this opens the possibility that dysregulated exosomal miRNA profiles may influence AD disease. The advances in exosome-related biomarker detection in AD are summarized. Finally, in this review, we highlight the use of exosomal miRNAs as essential biomarkers in preclinical and clinical studies in Alzheimer’s disease, also taking a look at their potential clinical value.	Institute of Molecular Bioimaging and Physiology (IBFM), National Research Council (CNR), Section of Germaneto, 88100 Catanzaro, Italy	ida.manna@cnr.it; selene.db90@gmail.com; an.quattrone@hotmail.it; maisano@unicz.it; iaccino@unicz.it; quattrone@unicz.it	10.3390/ph13090243	2020	13	9	-	-	243	-
Beeraka, Narasimha; Doreswamy, Shalini; Sadhu, Surya; Srinivasan, Asha; Pragada, Rajeswara; Madhunapantula, SubbaRao; Aliev, Gjumrakch	The Role of Exosomes in Stemness and Neurodegenerative Diseases—Chemoresistant-Cancer Therapeutics and Phytochemicals	International Journal of Molecular Sciences	EN	Review	exosomes; cancers; miRNAs; lncRNAs; stemness; chemo-/radio-resistance; angiogenesis; metastasis; neurodegeneration; phytochemicals	Exosomes exhibit a wide range of biological properties and functions in the living organisms. They are nanometric vehicles and used for delivering drugs, as they are biocompatible and minimally immunogenic. Exosomal secretions derived from cancer cells contribute to metastasis, immortality, angiogenesis, tissue invasion, stemness and chemo/radio-resistance. Exosome-derived microRNAs (miRNAs) and long non-coding RNAs (lnc RNAs) are involved in the pathophysiology of cancers and neurodegenerative diseases. For instance, exosomes derived from mesenchymal stromal cells, astrocytes, macrophages, and acute myeloid leukemia (AML) cells are involved in the cancer progression and stemness as they induce chemotherapeutic drug resistance in several cancer cells. This review covered the recent research advances in understanding the role of exosomes in cancer progression, metastasis, angiogenesis, stemness and drug resistance by illustrating the modulatory effects of exosomal cargo (ex. miRNA, lncRNAs, etc.) on cell signaling pathways involved in cancer progression and cancer stem cell growth and development. Recent reports have implicated exosomes even in the treatment of several cancers. For instance, exosomes-loaded with novel anti-cancer drugs such as phytochemicals, tumor-targeting proteins, anticancer peptides, nucleic acids are known to interfere with drug resistance pathways in several cancer cell lines. In addition, this review depicted the need to develop exosome-based novel diagnostic biomarkers for early detection of cancers and neurodegenerative disease. Furthermore, the role of exosomes in stroke and oxidative stress-mediated neurodegenerative diseases including Alzheimer’s disease (AD), and Parkinson’s disease (PD) is also discussed in this article.	Center of Excellence in Regenerative Medicine and Molecular Biology (CERM), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education &amp;amp; Research (JSS AHER), Mysuru 570015, Karnataka, India	bnmurthy24@gmail.com; shalini.hd98@gmail.com; sprabha125@gmail.com; asha.srinivasan@jssuni.edu.in; profprrau@gmail.com; mvsstsubbarao@jssuni.edu.in; aliev03@gmail.com	10.3390/ijms21186818	2020	21	18	-	-	6818	-
Karaglani, Makrina; Gourlia, Krystallia; Tsamardinos, Ioannis; Chatzaki, Ekaterini	Accurate Blood-Based Diagnostic Biosignatures for Alzheimer’s Disease via Automated Machine Learning	Journal of Clinical Medicine	EN	Article	Alzheimer’s disease; predictive model; machine learning; blood; classifier	Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia and its timely diagnosis remains a major challenge in biomarker discovery. In the present study, we analyzed publicly available high-throughput low-sample -omics datasets from studies in AD blood, by the AutoML technology Just Add Data Bio (JADBIO), to construct accurate predictive models for use as diagnostic biosignatures. Considering data from AD patients and age–sex matched cognitively healthy individuals, we produced three best performing diagnostic biosignatures specific for the presence of AD: A. A 506-feature transcriptomic dataset from 48 AD and 22 controls led to a miRNA-based biosignature via Support Vector Machines with three miRNA predictors (AUC 0.975 (0.906, 1.000)), B. A 38,327-feature transcriptomic dataset from 134 AD and 100 controls led to six mRNA-based statistically equivalent signatures via Classification Random Forests with 25 mRNA predictors (AUC 0.846 (0.778, 0.905)) and C. A 9483-feature proteomic dataset from 25 AD and 37 controls led to a protein-based biosignature via Ridge Logistic Regression with seven protein predictors (AUC 0.921 (0.849, 0.972)). These performance metrics were also validated through the JADBIO pipeline confirming stability. In conclusion, using the automated machine learning tool JADBIO, we produced accurate predictive biosignatures extrapolating available low sample -omics data. These results offer options for minimally invasive blood-based diagnostic tests for AD, awaiting clinical validation based on respective laboratory assays. They also highlight the value of AutoML in biomarker discovery.	Laboratory of Pharmacology, Medical School, Democritus University of Thrace, 68100 Alexandroupolis, Greece	mkaragla@med.duth.gr; krysgourlia@gmail.com; tsamard.it@gmail.com; achatzak@med.duth.gr	10.3390/jcm9093016	2020	9	9	-	-	3016	-
Lin, Chin-Hsien; Chiu, Shu-I; Chen, Ta-Fu; Jang, Jyh-Shing; Chiu, Ming-Jang	Classifications of Neurodegenerative Disorders Using a Multiplex Blood Biomarkers-Based Machine Learning Model	International Journal of Molecular Sciences	EN	Article	Alzheimer’s disease; Parkinson’s disease; frontotemporal dementia; neurodegenerative disorders; biomarkers; deep learning model; linear discriminant analysis; classification; multivariate imputation by chained equations	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.	Department of Neurology, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei 100225, Taiwan	chlin@ntu.edu.tw; shui.chiu@mirlab.org; tfchen@ntu.edu.tw; jang@csie.ntu.edu.tw; mjchiu@ntu.edu.tw	10.3390/ijms21186914	2020	21	18	-	-	6914	-
Weill, Yishay; Zimran, Ari; Zadok, David; Wasser, Lauren; Revel-Vilk, Shoshana; Hanhart, Joel; Dinur, Tama; Arkadir, David; Becker-Cohen, Michal	Macular Ganglion Cell Complex and Peripapillary Retinal Nerve Fiber Layer Thinning in Patients with Type-1 Gaucher Disease	International Journal of Molecular Sciences	EN	Communication	Gaucher disease; retinal thinning; optical coherence tomography; retinal nerve fiber layer; retinal ganglion cells; ganglion cell complex; neurodegenerative disorder	Type-1 Gaucher disease (GD1) is considered to be non- neuronopathic however recent evidence of neurological involvement continues to accumulate. There is limited evidence of retinal abnormalities in GD1. The purpose of this study was to evaluate the retinal findings of patients with GD1. Thirty GD1 individuals and 30 healthy volunteers between the ages 40–75 years were prospectively enrolled. Macular and optic nerve optical coherence tomography (OCT) scans of both eyes of each patient were performed and thickness maps were compared between groups. Patients with a known neurodegenerative disease, glaucoma, high myopia and previous intraocular surgeries were excluded. It was shown that patients with GD1 presented with higher incidence of abnormal pRNFL OCT scan and showed significantly thinner areas of pRNFL and macular ganglion cell complex (GCC) when compared to a healthy control population. Changes in retinal thickness were not associated with GD1 genotype, treatment status, disease monitoring biomarker (lyso-Gb1) and severity score index (Zimran SSI). Further investigations are needed to determine whether these findings possess functional visual implications and if retinal thinning may serve as biomarker for the development of future neurodegenerative disease in this population.	Department of Ophthalmology, Shaare Zedek Medical Center, Jerusalem 9103102, Israel	yishayweill@gmail.com; azimran@gmail.com; davzadok@gmail.com; lauriew21@gmail.com; srevelvilk@gmail.com; hanhart@szmc.org.il; dinurtama@gmail.com; arkadir@gmail.com; michalbec@gmail.com	10.3390/ijms21197027	2020	21	19	-	-	7027	-
Sidorova, Yulia; Domanskyi, Andrii	Detecting Oxidative Stress Biomarkers in Neurodegenerative Disease Models and Patients	Methods and Protocols	EN	Protocol	neuroketals; nitrotyrosine; 8-hydroxy-2′-deoxyguanosine; malondialdehyde; immunohistochemistry; neurodereneration; oxidative stress; lipid peroxidation; reactive oxygen species (ROS)	Oxidative stress is prominent in many neurodegenerative diseases. Along with mitochondrial dysfunction and pathological protein aggregation, increased levels of reactive oxygen and nitrogen species, together with impaired antioxidant defense mechanisms, are frequently observed in Alzheimer’s, Parkinson’s, Huntington’s disease and amyotrophic lateral sclerosis. The presence of oxidative stress markers in patients’ plasma and cerebrospinal fluid may aid early disease diagnoses, as well as provide clues regarding the efficacy of experimental disease-modifying therapies in clinical trials. In preclinical animal models, the detection and localization of oxidatively damaged lipids, proteins and nucleic acids helps to identify most vulnerable neuronal populations and brain areas, and elucidate the molecular pathways and the timeline of pathology progression. Here, we describe the protocol for the detection of oxidative stress markers using immunohistochemistry on formaldehyde-fixed, paraffin-embedded tissue sections, applicable to the analysis of postmortem samples and tissues from animal models. In addition, we provide a simple method for the detection of malondialdehyde in tissue lysates and body fluids, which is useful for screening and the identification of tissues and structures in the nervous system which are most affected by oxidative stress.	Institute of Biotechnology, HiLIFE, University of Helsinki, 00014 Helsinki, Finland	yulia.sidorova@helsinki.fi; andrii.domanskyi@helsinki.fi	10.3390/mps3040066	2020	3	4	-	-	66	-