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      Early Biomarkers of Neurodegenerative and Neurovascular Disorders in Diabetes

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          Abstract

          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.

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          Parkinson disease

          Werner Poewe, Klaus Seppi, Caroline M Tanner … (2017)
          Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population ≥65 years of age. Neuronal loss in the substantia nigra, which causes striatal dopamine deficiency, and intracellular inclusions containing aggregates of α-synuclein are the neuropathological hallmarks of Parkinson disease. Multiple other cell types throughout the central and peripheral autonomic nervous system are also involved, probably from early disease onwards. Although clinical diagnosis relies on the presence of bradykinesia and other cardinal motor features, Parkinson disease is associated with many non-motor symptoms that add to overall disability. The underlying molecular pathogenesis involves multiple pathways and mechanisms: α-synuclein proteostasis, mitochondrial function, oxidative stress, calcium homeostasis, axonal transport and neuroinflammation. Recent research into diagnostic biomarkers has taken advantage of neuroimaging in which several modalities, including PET, single-photon emission CT (SPECT) and novel MRI techniques, have been shown to aid early and differential diagnosis. Treatment of Parkinson disease is anchored on pharmacological substitution of striatal dopamine, in addition to non-dopaminergic approaches to address both motor and non-motor symptoms and deep brain stimulation for those developing intractable L-DOPA-related motor complications. Experimental therapies have tried to restore striatal dopamine by gene-based and cell-based approaches, and most recently, aggregation and cellular transport of α-synuclein have become therapeutic targets. One of the greatest current challenges is to identify markers for prodromal disease stages, which would allow novel disease-modifying therapies to be started earlier.
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            MicroRNA

            Thomas Lu, Marc Rothenberg (2018)
            MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene-expression posttranscriptionally. MiRNA research in allergy is expanding because miRNAs are crucial regulators of gene expression and promising candidates for biomarker development. MiRNA mimics and miRNA inhibitors currently in preclinical development have shown promise as novel therapeutic agents. Multiple technological platforms have been developed for miRNA isolation, miRNA quantitation, miRNA profiling, miRNA target detection, and modulating miRNA levels in vitro and in vivo. Here we will review the major technological platforms with consideration given for the advantages and disadvantages of each platform.
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              Amyloid beta: structure, biology and structure-based therapeutic development

              H. Xu, Guo-Fang Chen, Ting-hai Xu … (2017)
              Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β- and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ inhibitors or modulators of β- and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.
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                Author and article information

                Journal
                Journal ID (nlm-ta): J Clin Med
                Journal ID (iso-abbrev): J Clin Med
                Journal ID (publisher-id): jcm
                Title: Journal of Clinical Medicine
                Publisher: MDPI
                ISSN (Electronic): 2077-0383
                Publication date (Electronic): 30 August 2020
                Publication date Collection: September 2020
                Volume: 9
                Issue: 9
                Electronic Location Identifier: 2807
                Affiliations
                [1 ]1st Chair and Department of Cardiology, Medical University of Warsaw, 02-097 Warsaw, Poland; dominika.siwik@ 123456gmail.com (D.S.); gmgajewska@ 123456gmail.com (M.G.); tmazurek@ 123456kardia.edu.pl (T.M.); krzysztof.filipiak@ 123456wum.edu.pl (K.J.F.)
                [2 ]1st Department of Cardiology, Medical University of Gdansk, 80-211 Gdansk, Poland; jamilosz@ 123456gmail.com
                [3 ]Department of Experimental and Clinical Pharmacology, Centre for Preclinical Research and Technology, Medical University of Warsaw, 80-211 Warsaw, Poland; mpostula@ 123456wum.edu.pl (M.P.); ceyileten@ 123456wum.edu.pl (C.E.)
                Author notes
                Author information
                https://orcid.org/0000-0001-5083-7587
                https://orcid.org/0000-0002-3693-8741
                https://orcid.org/0000-0002-7826-4458
                Article
                Publisher ID: jcm-09-02807
                DOI: 10.3390/jcm9092807
                PMC ID: 7564566
                PubMed ID: 32872672
                SO-VID: 60d4921c-b6c4-4e6a-a72c-7d9bbb10d3aa
                Copyright © © 2020 by the authors.
                License:

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                Date received : 31 July 2020
                Date accepted : 28 August 2020
                Categories
                Subject: Review

                Keywords: diabetes mellitus complications,neurovascular,neurodegenerative,stroke,dementia,biomarkers,microrna,growth factors,oxidative stress,pd,ad,mci,dm
                Data availability:
                Keywords: diabetes mellitus complications, neurovascular, neurodegenerative, stroke, dementia, biomarkers, microrna, growth factors, oxidative stress, pd, ad, mci, dm

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