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

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.

Keywords: Alzheimer’s disease; amyloid; atrophy; cognitive impairment; tau.

© 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.

Figures

Figure 1

Voxel-wise results of the independent regressions between episodic memory scores and each imaging modality. (A, D and G) Grey matter volume, (B, E and H) 18F-AV-1451 SUVR and (C, F and I) 11C-PiB DVR. Scatterplots and r2 values were obtained by extracting neuroimaging values from significant clusters. Results are shown in neurologic convention. AD = patients who met McKhann criteria for probable Alzheimer's disease dementia, but did not fulfill criteria for lvPPA or PCA; lvPPA = logopenic variant primary progressive aphasia; PCA = posterior cortical atrophy.

Figure 2

Voxel-wise results of the independent regressions between semantic memory and language scores and each imaging modality. (A and C) Grey matter volume, (B and D) 18F-AV-1451 SUVR and (E)11C-PiB DVR. Scatterplots and r2 values were obtained by extracting neuroimaging values from significant clusters. Note that the relationship between 11C-PiB DVR and semantic memory is not depicted as no significant result was obtained. Results are shown in neurologic convention. AD = patients who met McKhann criteria for probable Alzheimer's disease dementia, but did not fulfill criteria for lvPPA or PCA; lvPPA = logopenic variant primary progressive aphasia; PCA = posterior cortical atrophy.

Figure 3

Voxel-wise results of the independent regressions between executive and visuospatial scores and each imaging modality. (A and C) Grey matter volume, (B and D) 18F-AV-1451 SUVR and (E)11C-PiB DVR. Scatterplots and r2 values were obtained by extracting neuroimaging values from significant clusters. Note that the relationship between 11C-PiB DVR and executive functions is not depicted as no significant result was obtained. Results are shown in neurologic convention. AD = patients who met McKhann criteria for probable Alzheimer's disease dementia, but did not fulfill criteria for lvPPA or PCA; lvPPA = logopenic variant primary progressive aphasia; PCA = posterior cortical atrophy.

Figure 4

Voxel-wise results of the multiple regressions between 18F-AV-1451 SUVR and each cognitive domain score controlling for local grey matter volume and/or local 11C-PiB DVR. Results are shown in neurologic convention.

Figure 5

Partial correlations and summary of the mediation analyses in the brain areas where both 18F-AV-1451 SUVR and grey matter volume were related to cognitive domain scores (P < 0.005, k > 500 mm3). Filled arrows represent significant effects of the mediation analyses (P < 0.05). PC = partial correlation.