Tau Pathology Distribution in Alzheimer's disease Corresponds Differentially to Cognition-Relevant Functional Brain Networks.

Oskar Hansson,Michael Schöll,Douglas Hägerström,Tomas Ohlsson,Michel J Grothe,Jonas Jögi,Ruben Smith,Tor Olof Strandberg

doi:10.3389/fnins.2017.00167

Abstract

Neuropathological studies have shown that the typical neurofibrillary pathology of hyperphosphorylated tau protein in Alzheimer's disease (AD) preferentially affects specific brain regions whereas others remain relatively spared. It has been suggested that the distinct regional distribution profile of tau pathology in AD may be a consequence of the intrinsic network structure of the human brain. The spatially distributed brain regions that are most affected by the spread of tau pathology may hence reflect an interconnected neuronal system. Here, we characterized the brain-wide regional distribution profile of tau pathology in AD using 18F-AV 1451 tau-sensitive positron emission tomography (PET) imaging, and studied this pattern in relation to the functional network organization of the human brain. Specifically, we quantified the spatial correspondence of the regional distribution pattern of PET-evidenced tau pathology in AD with functional brain networks characterized by large-scale resting state functional magnetic resonance imaging (rs-fMRI) data in healthy subjects. Regional distribution patterns of increased PET-evidenced tau pathology in AD compared to controls were characterized in two independent samples of prodromal and manifest AD cases (the Swedish BioFINDER study, n = 44; the ADNI study, n = 35). In the BioFINDER study we found that the typical AD tau pattern involved predominantly inferior, medial, and lateral temporal cortical areas, as well as the precuneus/posterior cingulate, and lateral parts of the parietal and occipital cortex. This pattern overlapped primarily with the dorsal attention, and to some extent with higher visual, limbic and parts of the default-mode network. PET-evidenced tau pathology in the ADNI replication sample, which represented a more prodromal group of AD cases, was less pronounced but showed a highly similar spatial distribution profile, suggesting an earlier-stage snapshot of a consistently progressing regional pattern. In conclusion, the present study indicates that the regional deposition of tau aggregates in AD predominantly affects higher-order cognitive over primary sensory-motor networks, but does not appear to be specific for the default-mode or related limbic networks.

Highlights

The brain can be subdivided into a number of intrinsic connectivity networks (ICNs), which have been established mainly through interpretation of large resting-state functional magnetic resonance imaging datasets (Power et al, 2011; Yeo et al, 2011)
We examined the spatial distribution of 18F-AV-1451 retention, likely representing the presence of hyperphosporylated tau pathology, in the brains of prodromal and clinically manifest Alzheimer’s disease (AD) patients in relation to the spatial extent of predefined templates of functional brain networks
The regional tau distribution profiles were very similar between the independent BioFINDER and Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohorts of our study, despite obvious differences in recruitment criteria, positron emission tomography (PET) scanning platforms, disease severity, and age

Summary

Introduction

The brain can be subdivided into a number of intrinsic connectivity networks (ICNs), which have been established mainly through interpretation of large resting-state functional magnetic resonance imaging (rs-fMRI) datasets (Power et al, 2011; Yeo et al, 2011) These networks have been found to be disrupted in a distinct manner in Alzheimer’s disease (AD), directly affecting cognitive performance (Pievani et al, 2011). This study further found substantial dissociation between correspondence of imaging-derived measures of Aβ pathology, measures of neurodegeneration proxied by glucose hypometabolism and gray matter atrophy, and ICNs (Grothe and Teipel, 2016) Hyperphosphorylated tau, another misfolded protein to accumulate in AD, is known to be closer related to neurodegeneration and cognitive impairment than Aβ (SerranoPozo et al, 2011; Nelson et al, 2012). These nested stages of progressing tau pathology could recently be replicated in vivo using tau PET (Schwarz et al, 2016; Schöll et al, 2016)

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