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      Association of Neuropathological Markers in the Parietal Cortex With Antemortem Cognitive Function in Persons With Mild Cognitive Impairment and Alzheimer Disease

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          Abstract

          The associations between cognitive function and neuropathological markers in patients with mild cognitive impairment (MCI) and Alzheimer disease (AD) remain only partly defined. We investigated relationships between antemortem global cognitive scores and β-amyloid (Aβ), tau, TDP-43, synaptic proteins and other key AD neuropathological markers assessed by biochemical approaches in postmortem anterior parietal cortex samples from 36 subjects (12 MCI, 12 AD and 12 not cognitively impaired) from the Religious Orders Study. Overall, the strongest negative correlation coefficients associated with global cognitive scores were obtained for insoluble phosphorylated tau ( r 2 = −0.484), insoluble Aβ42 ( r 2 = −0.389) and neurofibrillary tangle counts ( r 2 = −0.494) (all p < 0.001). Robust inverse associations with cognition scores were also established for TDP-43-positive cytoplasmic inclusions ( r 2 = −0.476), total insoluble tau ( r 2 = −0.385) and Aβ plaque counts ( r 2 = −0.426). Sarkosyl (SK)- or formic acid (FA)-extracted tau showed similar interrelations. On the other hand, synaptophysin ( r 2 = +0.335), pS403/404 TDP-43 ( r 2 = +0.265) and septin-3 ( r 2 = +0.257) proteins positively correlated with cognitive scores. This study suggests that tau and Aβ42 in their insoluble aggregated forms, synaptic proteins and TDP-43 are the markers in the parietal cortex that are most strongly associated with cognitive function. This further substantiates the relevance of investigating these markers to understand the pathogenesis of AD and develop therapeutic tools.

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          Neurofibrillary tangles but not senile plaques parallel duration and severity of Alzheimer's disease.

          We studied the accumulation of neurofibrillary tangles (NFTs) and senile plaques (SPs) in 10 Alzheimer's disease patients who had been examined during life. We counted NFTs and SPs in 13 cytoarchitectural regions representing limbic, primary sensory, and association cortices, and in subcortical neurotransmitter-specific areas. The degree of neuropathologic change was compared with the severity of dementia, as assessed by the Blessed Dementia Scale and duration of illness. We found that (1) the severity of dementia was positively related to the number of NFTs in neocortex, but not to the degree of SP deposition; (2) NFTs accumulate in a consistent pattern reflecting hierarchic vulnerability of individual cytoarchitectural fields; (3) NFTs appeared in the entorhinal cortex, CA1/subiculum field of the hippocampal formation, and the amygdala early in the disease process; and (4) the degree of SP deposition was also related to a hierarchic vulnerability of certain brain areas to accumulate SPs, but the pattern of SP distribution was different from that of NFT.
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            The parietal cortex and episodic memory: an attentional account.

            The contribution of the parietal cortex to episodic memory is a fascinating scientific puzzle. On the one hand, parietal lesions do not normally yield severe episodic-memory deficits; on the other hand, parietal activations are seen frequently in functional-neuroimaging studies of episodic memory. A review of these two categories of evidence suggests that the answer to the puzzle requires us to distinguish between the contributions of dorsal and ventral parietal regions and between the influence of top-down and bottom-up attention on memory.
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              Overview and findings from the religious orders study.

              The Religious Orders Study is a longitudinal clinical-pathologic cohort study of aging and Alzheimer's disease (AD). In this manuscript, we summarize the study methods including the study design and describe the clinical evaluation, assessment of risk factors, collection of ante-mortem biological specimens, brain autopsy and collection of selected postmortem data. (1) review the relation of neuropathologic indices to clinical diagnoses and cognition proximate to death; (2) examine the relation of risk factors to clinical outcomes; (3) examine the relation of risk factors to measures of neuropathology; and (4) summarize additional study findings. We then discuss and contextualize the study findings.
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                Author and article information

                Contributors
                Journal
                J Neuropathol Exp Neurol
                J. Neuropathol. Exp. Neurol
                jnen
                Journal of Neuropathology and Experimental Neurology
                Oxford University Press
                0022-3069
                1554-6578
                February 2017
                31 January 2017
                31 January 2017
                : 76
                : 2
                : 70-88
                Affiliations
                Faculté de pharmacie, Université Laval, Québec, QC, Canada
                Centre Hospitalier Universitaire de Québec (CHU-Q) Research Center, Neuroscience Axis, Québec, QC, Canada
                Faculté de pharmacie, Université Laval, Québec, QC, Canada
                Centre Hospitalier Universitaire de Québec (CHU-Q) Research Center, Neuroscience Axis, Québec, QC, Canada
                Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement (RID-AGE) Research Group, University of Lille, INSERM U1167, Lille University Medical Center, Institut Pasteur de Lille, Lille, France (CD)
                Faculté de pharmacie, Université Laval, Québec, QC, Canada
                Centre Hospitalier Universitaire de Québec (CHU-Q) Research Center, Neuroscience Axis, Québec, QC, Canada
                Faculté de pharmacie, Université Laval, Québec, QC, Canada
                Centre Hospitalier Universitaire de Québec (CHU-Q) Research Center, Neuroscience Axis, Québec, QC, Canada
                Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL
                Faculté de pharmacie, Université Laval, Québec, QC, Canada
                Centre Hospitalier Universitaire de Québec (CHU-Q) Research Center, Neuroscience Axis, Québec, QC, Canada
                Author notes
                Send correspondence to: Frédéric Calon, PhD, Neurosciences Axis, Centre Hospitalier de l'Université Laval (CHUL) Research Center, 2705, Laurier Blvd., Room T2-2-67, Québec, QC G1V 4G2, Canada; E-mail: Frederic.Calon@ 123456crchul.ulaval.ca
                Article
                nlw109
                10.1093/jnen/nlw109
                7526851
                28158844
                407282fc-4c78-4794-b58e-8daadf75f75b
                © 2017 American Association of Neuropathologists, Inc. All rights reserved.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

                History
                Page count
                Pages: 19
                Funding
                Funded by: NIH, DOI 10.13039/100000002;
                Funded by: Alzheimer Society Canada;
                Funded by: Canadian Institutes of Health Research, DOI 10.13039/501100000024;
                Award ID: FC-MOP 102532
                Funded by: Canada Foundation for Innovation, DOI 10.13039/501100000196;
                Award ID: FC-10307
                Funded by: National Institute of Aging, DOI 10.13039/100000049;
                Award ID: P30AG10161
                Award ID: RF1AG15819
                Funded by: Fonds de recherche du Québec - Santé, DOI 10.13039/501100000156;
                Categories
                Original Articles

                alzheimer disease,amyloid-β,mild cognitive impairment,parietal cortex,postmortem,synaptic proteins,tau

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