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      Current radiotracers to image neurodegenerative diseases

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          Abstract

          The term of neurodegenerative diseases covers a heterogeneous group of disorders that are distinguished by progressive degeneration of the structure and function of the nervous system such as dementias, movement disorders, motor neuron disorders, as well as some prion disorders. In recent years, a paradigm shift started for the diagnosis of neurodegenerative diseases, for which successively clinical testing is supplemented by biomarker information. In research scenarios, it was even proposed recently to substitute the current syndromic by a biological definition of Alzheimer’s diseases. PET examinations with various radiotracers play an important role in providing non-invasive biomarkers and co-morbidity information in neurodegeneration. Information on co-morbidity, e.g. Aβ plaques and Lewy-bodies or Aβ plaques in patients with aphasia or the absence of Aβ plaques in clinical AD patients are of interest to expand our knowledge about the pathogenesis of different phenotypically defined neurodegenerative diseases. Moreover, this information is also important in therapeutic trials targeting histopathological abnormalities.

          The aim of this review is to present an overview of the currently available radiotracers for imaging neurodegenerative diseases in research and in routine clinical settings. In this context, we also provide a short summary of the most frequent neurodegenerative diseases from a nuclear medicine point of view, their clinical and pathophysiological as well as nuclear imaging characteristics, and the resulting need for new radiotracers.

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          Most cited references75

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          The cholinergic hypothesis of geriatric memory dysfunction.

          Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.
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            Tau protein isoforms, phosphorylation and role in neurodegenerative disorders.

            Tau proteins belong to the family of microtubule-associated proteins. They are mainly expressed in neurons where they play an important role in the assembly of tubulin monomers into microtubules to constitute the neuronal microtubules network. Microtubules are involved in maintaining the cell shape and serve as tracks for axonal transport. Tau proteins also establish some links between microtubules and other cytoskeletal elements or proteins. Tau proteins are translated from a single gene located on chromosome 17. Their expression is developmentally regulated by an alternative splicing mechanism and six different isoforms exist in the human adult brain. Tau proteins are the major constituents of intraneuronal and glial fibrillar lesions described in Alzheimer's disease and numerous neurodegenerative disorders referred to as 'tauopathies'. Molecular analysis has revealed that an abnormal phosphorylation might be one of the important events in the process leading to their aggregation. Moreover, a specific set of pathological tau proteins exhibiting a typical biochemical pattern, and a different regional and laminar distribution could characterize each of these disorders. Finally, a direct correlation has been established between the progressive involvement of the neocortical areas and the increasing severity of dementia, suggesting that pathological tau proteins are reliable marker of the neurodegenerative process. The recent discovery of tau gene mutations in frontotemporal dementia with parkinsonism linked to chromosome 17 has reinforced the predominant role attributed to tau proteins in the pathogenesis of neurodegenerative disorders, and underlined the fact that distinct sets of tau isoforms expressed in different neuronal populations could lead to different pathologies.
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              Decreased Expression of Synapse-Related Genes and Loss of Synapses in Major Depressive Disorder

              Previous imaging and postmortem studies have reported a reduction in brain volume and a decrease in the size and density of neurons in the dorsolateral prefrontal cortex (dlPFC, area 9) of subjects with major depressive disorder (MDD). 1,2 These findings suggest that synapse number and function are decreased in dlPFC of depressed patients. However, there has been no direct evidence for synapse loss in MDD and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal decreased expression of synaptic function-related genes in dlPFC of MDD subjects and a corresponding reduction in the number of synapses. We also identify a transcriptional repressor that is increased in MDD, and that when expressed in PFC neurons is sufficient to decrease expression of synapse-related genes, cause loss of spines and dendrites, and produce depressive behavior in rodent models of depression.
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                Author and article information

                Contributors
                +49-341-9718264 , Solveig.Tiepolt@medizin.uni-leipzig.de
                Marianne.Patt@medizin.uni-leipzig.de
                Gayane.Aghakhanyan@medizin.uni-leipzig.de
                Philipp.Meyer@medizin.uni-leipzig.de
                Swen.Hesse@medizin.uni-leipzig.de
                Henryk.Barthel@medizin.uni-leipzig.de
                Osama.Sabri@medizin.uni-leipzig.de
                Journal
                EJNMMI Radiopharm Chem
                EJNMMI Radiopharm Chem
                EJNMMI Radiopharmacy and Chemistry
                Springer International Publishing (Cham )
                2365-421X
                26 July 2019
                26 July 2019
                December 2019
                : 4
                : 17
                Affiliations
                ISNI 0000 0001 2230 9752, GRID grid.9647.c, Department of Nuclear Medicine, , University of Leipzig, ; Liebigstraße 18, 04103 Leipzig, Germany
                Author information
                http://orcid.org/0000-0003-0378-8334
                Article
                70
                10.1186/s41181-019-0070-7
                6660543
                31659510
                57d690a7-97a2-40f0-b405-41ee7a73edbd
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 27 March 2019
                : 16 July 2019
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                alzheimer’s disease,parkinsonian syndromes,primary progressive aphasia,frontotemporal dementia,pet,spect,ß-amyloid,tau,cholinergic system,dopaminergic system

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