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      CSF total tau levels are associated with hippocampal novelty irrespective of hippocampal volume

      research-article
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      Alzheimer's & Dementia : Diagnosis, Assessment & Disease Monitoring
      Elsevier
      Alzheimer's disease (AD), Subjective cognitive decline (SCD), Mild cognitive impairment (MCI), Longitudinal, Cerebrospinal fluid (CSF), Aβ42, Tau, Apolipoprotein E (APOE), Magnetic resonance imaging (MRI), Positron emission tomography (PET)

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          Abstract

          Introduction

          We examined the association between cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease, neural novelty responses, and brain volume in predementia old age.

          Methods

          We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE) study. Seventy-six participants completed task functional magnetic resonance imaging and provided CSF (40 cognitively unimpaired, 21 experiencing subjective cognitive decline, and 15 with mild cognitive impairment). We assessed the correlation between CSF biomarkers and whole-brain functional magnetic resonance imaging novelty responses to scene images.

          Results

          Total tau levels were specifically and negatively associated with novelty responses in the right amygdala and right hippocampus. Mediation analyses showed no evidence that these associations were dependent on the volume of hippocampus/amygdala. No relationship was found between phosphorylated-tau or Aβ 42 levels and novelty responses.

          Discussion

          Our data show that CSF levels of total tau are associated with anatomically specific reductions in novelty processing, which cannot be fully explained by atrophy.

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          Most cited references18

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          Two cortical systems for memory-guided behaviour.

          Although the perirhinal cortex (PRC), parahippocampal cortex (PHC) and retrosplenial cortex (RSC) have an essential role in memory, the precise functions of these areas are poorly understood. Here, we review the anatomical and functional characteristics of these areas based on studies in humans, monkeys and rats. Our Review suggests that the PRC and PHC-RSC are core components of two separate large-scale cortical networks that are dissociable by neuroanatomy, susceptibility to disease and function. These networks not only support different types of memory but also appear to support different aspects of cognition.
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            Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration.

            The microtubule-associated protein tau accumulates in Alzheimer's and other fatal dementias, which manifest when forebrain neurons die. Recent advances in understanding these disorders indicate that brain dysfunction precedes neurodegeneration, but the role of tau is unclear. Here, we show that early tau-related deficits develop not from the loss of synapses or neurons, but rather as a result of synaptic abnormalities caused by the accumulation of hyperphosphorylated tau within intact dendritic spines, where it disrupts synaptic function by impairing glutamate receptor trafficking or synaptic anchoring. Mutagenesis of 14 disease-associated serine and threonine amino acid residues to create pseudohyperphosphorylated tau caused tau mislocalization while creation of phosphorylation-deficient tau blocked the mistargeting of tau to dendritic spines. Thus, tau phosphorylation plays a critical role in mediating tau mislocalization and subsequent synaptic impairment. These data establish that the locus of early synaptic malfunction caused by tau resides in dendritic spines. Copyright © 2010 Elsevier Inc. All rights reserved.
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              • Article: not found

              Neurotoxicity of amyloid β-protein: synaptic and network dysfunction.

              Evidence for an ever-expanding variety of molecular mediators of amyloid β-protein neurotoxicity (membrane lipids, receptor proteins, channel proteins, second messengers and related signaling cascades, cytoskeletal proteins, inflammatory mediators, etc.) has led to the notion that the binding of hydrophobic Aβ assemblies to cellular membranes triggers multiple effects affecting diverse pathways. It appears unlikely that there are only one or two cognate receptors for neurotoxic forms of Aβ and also that there are just one or two assembly forms of the peptide that induce neuronal dysfunction. Rather, various soluble (diffusible) oligomers of Aβ that may be in dynamic equilibrium with insoluble, fibrillar deposits (amyloid plaques) and that can bind to different components of neuronal and non-neuronal plasma membranes appear to induce complex patterns of synaptic dysfunction and network disorganization that underlie the intermittent but gradually progressive cognitive manifestations of the clinical disorder. Modern analyses of this problem utilize electrophysiology coupled with synaptic biochemistry and behavioral phenotyping of animal models to elucidate the affected circuits and assess the effects of potential therapeutic interventions.
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                Author and article information

                Contributors
                Journal
                Alzheimers Dement (Amst)
                Alzheimers Dement (Amst)
                Alzheimer's & Dementia : Diagnosis, Assessment & Disease Monitoring
                Elsevier
                2352-8729
                02 November 2018
                2018
                02 November 2018
                : 10
                : 782-790
                Affiliations
                [a ]Institute of Cognitive Neurology and Dementia Research, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
                [b ]German Center for Neurodegenerative Diseases (DZNE), Magdeburg, Germany
                [c ]Institute of Cognitive Neuroscience, Univ. College London, London, UK
                [d ]Department of Psychiatry and Psychotherapy, University Hospital Magdeburg, Medical Faculty, Magdeburg, Germany
                [e ]Clinic for Neurology, University Hospital Magdeburg, Medical Faculty, Magdeburg, Germany
                [f ]German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
                [g ]Department of Neurology, University of Bonn, Bonn, Germany
                [h ]Department of Neurodegeneration and Geriatric Psychiatry, University Hospital Bonn, Bonn, Germany
                [i ]German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
                [j ]Institute for Stroke and Dementia Research, University Hospital, Munich, Germany
                [k ]German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
                [l ]Section for Dementia Research, Hertie Institute for Clinical Brain Research and Department of Psychiatry and Psychotherapy, University of Tübingen, Tübingen, Germany
                [m ]German Center for Neurodegenerative Diseases (DZNE), Berlin, Germany
                [n ]Charité – Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Institute of Psychiatry and Psychotherapy, Berlin, Germany
                [o ]Department of Psychiatry and Psychotherapy, Berlin, Germany
                [p ]Department of Psychiatry, University of Cologne, Medical Faculty, Cologne, Germany
                [q ]Department of Biomagnetical Resonance, Magdeburg, Germany
                [r ]German Center for Neurodegenerative Diseases (DZNE), Rostock, Germany
                [s ]Department of Psychosomatic Medicine, Rostock University Medical Center, Rostock, Germany
                [t ]German Center for Neurodegenerative Diseases (DZNE), Goettingen, Germany
                [u ]Department of Psychiatry and Psychotherapy, University Medical Center Goettingen, University of Goettingen, Goettingen, Germany
                Author notes
                []Corresponding author. Tel.: +49 391 6725051; Fax: +49 391 67 25060. emrah.duezel@ 123456dzne.de
                Article
                S2352-8729(18)30071-X
                10.1016/j.dadm.2018.10.003
                6280588
                30555890
                354f8b7b-85ab-45e6-8dd5-51ebec4ea51f
                © 2018 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Categories
                CSF Biomarkers

                alzheimer's disease (ad),subjective cognitive decline (scd),mild cognitive impairment (mci),longitudinal,cerebrospinal fluid (csf),aβ42,tau,apolipoprotein e (apoe),magnetic resonance imaging (mri),positron emission tomography (pet)

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