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      Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease

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          Abstract

          Bejanin et al. explore the relationship between tau pathology ( 18F-AV-1451-PET) and cognitive impairment in Alzheimer’s disease, and the potential moderating effect of amyloid and atrophy on this relationship. Regional associations between tau and cognitive impairment are weakly related to amyloid load, but are in part mediated by grey matter volumes.

          Abstract

          Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer’s disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer’s disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer’s disease ( n = 5) or probable Alzheimer’s disease dementia ( n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid ( 11C-PiB) positron emission tomography and tau ( 18F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, 11C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both 18F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased 18F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior temporal lobe and supramarginal gyrus; executive functions: bilateral frontoparietal regions; visuospatial functions: right more than left occipitotemporal regions). This pattern of regional associations remained essentially unchanged—although less spatially extended—when grey matter volume or 11C-PiB uptake maps were added as covariates. Mediation analyses revealed both direct and grey matter-mediated effects of 18F-AV-1451 uptake on cognitive performance. Together, these results show that tau pathology is related in a region-specific manner to cognitive impairment in Alzheimer’s disease. These regional relationships are weakly related to amyloid burden, but are in part mediated by grey matter volumes. This suggests that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted to, grey matter loss. These results might have implications for future therapeutic trials targeting tau pathology.

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          Author and article information

          Journal
          Brain
          Brain
          brainj
          Brain
          Oxford University Press
          0006-8950
          1460-2156
          December 2017
          07 October 2017
          01 December 2018
          : 140
          : 12
          : 3286-3300
          Affiliations
          [1 ]Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA
          [2 ]Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA
          [3 ]Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA
          Author notes
          Correspondence to: Alexandre Bejanin University of California, San Francisco (UCSF) Memory and Aging Center MC: 1207 675 Nelson Rising Lane, Suite 190 San Francisco, CA 94158, USA E-mail: bejanin@ 123456cyceron.fr
          Article
          PMC5841139 PMC5841139 5841139 awx243
          10.1093/brain/awx243
          5841139
          29053874
          3ea0738d-b779-4037-9b96-3e3cb70f8169
          © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com
          History
          : 8 April 2017
          : 3 July 2017
          : 3 August 2017
          Page count
          Pages: 15
          Funding
          Funded by: National Institute on Aging 10.13039/100000049
          Award ID: R01-AG045611
          Award ID: R01-AG034570
          Award ID: P50-AG023501
          Award ID: P01-AG019724
          Award ID: U01-AG052943
          Funded by: National Institute of Neurological Disorders and Stroke 10.13039/100000065
          Award ID: R01-NS050915
          Award ID: K24-DC015544
          Categories
          Original Articles

          tau,amyloid,Alzheimer’s disease,cognitive impairment,atrophy

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