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      Higher CSF Tau Levels Are Related to Hippocampal Hyperactivity and Object Mnemonic Discrimination in Older Adults

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          Abstract

          Mnemonic discrimination, the ability to distinguish similar events in memory, relies on subregions in the human medial temporal lobes (MTLs). Tau pathology is frequently found within the MTL of older adults and therefore likely to affect mnemonic discrimination, even in healthy older individuals. The MTL subregions that are known to be affected early by tau pathology, the perirhinal-transentorhinal region (area 35) and the anterior-lateral entorhinal cortex (alEC), have recently been implicated in the mnemonic discrimination of objects rather than scenes. Here we used an object-scene mnemonic discrimination task in combination with fMRI recordings and analyzed the relationship between subregional MTL activity, memory performance, and levels of total and phosphorylated tau as well as Aβ42/40 ratio in CSF. We show that activity in alEC was associated with mnemonic discrimination of similar objects but not scenes in male and female cognitively unimpaired older adults. Importantly, CSF tau levels were associated with increased fMRI activity in the hippocampus, and both increased hippocampal activity as well as tau levels were associated with mnemonic discrimination of objects, but again not scenes. This suggests that dysfunction of the alEC-hippocampus object mnemonic discrimination network might be a marker for tau-related cognitive decline.

          SIGNIFICANCE STATEMENT Subregions in the human medial temporal lobe are critically involved in episodic memory and, at the same time, affected by tau pathology. Impaired object mnemonic discrimination performance as well as aberrant activity within the entorhinal-hippocampal circuitry have been reported in earlier studies involving older individuals, but it has thus far remained elusive whether and how tau pathology is implicated in this specific impairment. Using task-related fMRI in combination with measures of tau pathology in CSF, we show that measures of tau pathology are associated with increased hippocampal activity and reduced mnemonic discrimination of similar objects but not scenes. This suggests that object mnemonic discrimination tasks could be promising markers for tau-related cognitive decline.

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          Most cited references 27

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          Pattern separation in the human hippocampal CA3 and dentate gyrus.

          Pattern separation, the process of transforming similar representations or memories into highly dissimilar, nonoverlapping representations, is a key component of many functions ascribed to the hippocampus. Computational models have stressed the role of the hippocampus and, in particular, the dentate gyrus and its projections into the CA3 subregion in pattern separation. We used high-resolution (1.5-millimeter isotropic voxels) functional magnetic resonance imaging to measure brain activity during incidental memory encoding. Although activity consistent with a bias toward pattern completion was observed in CA1, the subiculum, and the entorhinal and parahippocampal cortices, activity consistent with a strong bias toward pattern separation was observed in, and limited to, the CA3/dentate gyrus. These results provide compelling evidence of a key role of the human CA3/dentate gyrus in pattern separation.
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            The Declaration of Helsinki and public health

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              Optimal experimental design for event-related fMRI

               Anders Dale (1999)
              An important challenge in the design and analysis of event‐related or single‐trial functional magnetic resonance imaging (fMRI) experiments is to optimize statistical efficiency, i.e., the accuracy with which the event‐related hemodynamic response to different stimuli can be estimated for a given amount of imaging time. Several studies have suggested that using a fixed inter‐stimulus‐interval (ISI) of at least 15 sec results in optimal statistical efficiency or power and that using shorter ISIs results in a severe loss of power. In contrast, recent studies have demonstrated the feasibility of using ISIs as short as 500 ms while still maintaining considerable efficiency or power. Here, we attempt to resolve this apparent contradiction by a quantitative analysis of the relative efficiency afforded by different event‐related experimental designs. This analysis shows that statistical efficiency falls off dramatically as the ISI gets sufficiently short, if the ISI is kept fixed for all trials. However, if the ISI is properly jittered or randomized from trial to trial, the efficiency improves monotonically with decreasing mean ISI. Importantly, the efficiency afforded by such variable ISI designs can be more than 10 times greater than that which can be achieved by fixed ISI designs. These results further demonstrate the feasibility of using identical experimental designs with fMRI and electro‐/magnetoencephalography (EEG/MEG) without sacrificing statistical power or efficiency of either technique, thereby facilitating comparison and integration across imaging modalities. Hum. Brain Mapping 8:109–114, 1999. © 1999 Wiley‐Liss, Inc.
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                Author and article information

                Journal
                J Neurosci
                J. Neurosci
                jneuro
                jneurosci
                J. Neurosci
                The Journal of Neuroscience
                Society for Neuroscience
                0270-6474
                1529-2401
                30 October 2019
                30 October 2019
                : 39
                : 44
                : 8788-8797
                Affiliations
                1Institute of Cognitive Neurology and Dementia Research (IKND), Otto-von-Guericke University, 39120 Magdeburg, Germany,
                2German Center for Neurodegenerative Diseases (DZNE), 39120 Magdeburg, Germany,
                3Clinical Memory Research Unit, Department of Clinical Sciences Malmö, Lund University, 223 62 Lund, Sweden,
                4Department of Neurology, University Hospital of Bonn, 53127 Bonn, Germany,
                5German Center for Neurodegenerative Diseases (DZNE), 53127 Bonn, Germany,
                6Department of Neurodegeneration and Geriatric Psychiatry, University of Bonn, 53127 Bonn, Germany,
                7Department of Neurology, University Hospital Magdeburg, 39120 Magdeburg, Germany,
                8Department of Psychiatry and Psychotherapy, Otto-von-Guericke University, 39120 Magdeburg, Germany,
                9Department of Psychosomatic Medicine, Rostock University Medical Center, 18147 Rostock, Germany,
                10German Center for Neurodegenerative Diseases, 18147 Rostock, Germany,
                11Department of Biomedical Magnetic Resonance, Otto-von-Guericke University, 39120 Magdeburg, Germany,
                12Department of Psychiatry, University Hospital Cologne, 50937 Cologne, Germany,
                13University College London, Institute of Cognitive Neuroscience, London WC1N 3AZ, United Kingdom,
                14Leibniz Institute of Neurobiology, 39120 Magdeburg, Germany, and
                15Center for Behavioral Brain Sciences, 39120 Magdeburg, Germany
                Author notes
                Correspondence should be addressed to David Berron at david.berron@ 123456med.lu.se .

                Author contributions: D. Berron and E.D. designed research; D. Berron, A.C.-B., D. Bittner, C.D.M., A. Spottke, M.T.H., K.F., A. Schneider, S.J.T., M.W., O.S., F.J., and E.D. performed research; D. Berron analyzed data; D. Berron wrote the first draft of the paper; D. Berron, S.J.T., M.W., O.S., F.J., and E.D. edited the paper; D. Berron wrote the paper.

                Article
                1279-19
                10.1523/JNEUROSCI.1279-19.2019
                6820211
                31541019
                Copyright © 2019 Berron et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License Creative Commons Attribution 4.0 International, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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                Research Articles
                Neurobiology of Disease

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