Sequential stages and distribution patterns of aging-related tau astrogliopathy (ARTAG) in the human brain

Gabor G Kovacs,Theresa Schuck,Edward B Lee,Douglas H Smith,Sharon X Xie,John L Robinson,Virginia M.-Y Lee,John Q Trojanowski

doi:10.1186/s40478-018-0552-y

Gabor G Kovacs, Theresa Schuck + Show 6 more

Open Access

https://doi.org/10.1186/s40478-018-0552-y

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Abstract

Aging-related tau astrogliopathy (ARTAG) describes tau pathology in astrocytes in different locations and anatomical regions. In the present study we addressed the question of whether sequential distribution patterns can be recognized for ARTAG or astroglial tau pathologies in both primary FTLD-tauopathies and non-FTLD-tauopathy cases. By evaluating 687 postmortem brains with diverse disorders we identified ARTAG in 455. We evaluated frequencies and hierarchical clustering of anatomical involvement and used conditional probability and logistic regression to model the sequential distribution of ARTAG and astroglial tau pathologies across different brain regions. For subpial and white matter ARTAG we recognize three and two patterns, respectively, each with three stages initiated or ending in the amygdala. Subependymal ARTAG does not show a clear sequential pattern. For grey matter (GM) ARTAG we recognize four stages including a striatal pathway of spreading towards the cortex and/or amygdala, and the brainstem, and an amygdala pathway, which precedes the involvement of the striatum and/or cortex and proceeds towards the brainstem. GM ARTAG and astrocytic plaque pathology in corticobasal degeneration follows a predominantly frontal-parietal cortical to temporal-occipital cortical, to subcortical, to brainstem pathway (four stages). GM ARTAG and tufted astrocyte pathology in progressive supranuclear palsy shows a striatum to frontal-parietal cortical to temporal to occipital, to amygdala, and to brainstem sequence (four stages). In Pick’s disease cases with astroglial tau pathology an overlapping pattern with PSP can be appreciated. We conclude that tau-astrogliopathy type-specific sequential patterns cannot be simplified as neuron-based staging systems. The proposed cytopathological and hierarchical stages provide a conceptual approach to identify the initial steps of the pathogenesis of tau pathologies in ARTAG and primary FTLD-tauopathies.

Highlights

Deposition of pathologically altered proteins in astrocytes has been increasingly detected in neurodegenerative diseases (NDD) leading to the concept of protein astrogliopathies [33]
We suggested a conceptual link between grey matter (GM) aging-related tau astrogliopathy (ARTAG) and astroglial tau pathologies seen in primary frontotemporal lobar degeneration (FTLD)-tauopathies [35]
The morphology of tau immunoreactive astrocytes varies in the white matter (WM) in progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) and do not always show typical thorn-shaped astrocytes (TSA) morphology

Summary

Introduction

Deposition of pathologically altered proteins in astrocytes has been increasingly detected in neurodegenerative diseases (NDD) leading to the concept of protein astrogliopathies [33]. GFA-like morphologies seen in primary FTLD-tauopathies can represent an early maturation phase of astroglial tau pathology [35], analogously to the concept of pretangles and neurofibrillary tangles [3]. These aspects support the notion that astrocytes might have an early role in primary FTLD-tauopathies as recognized for example in CBD [40]. The distribution patterns and morphology of ARTAG shows overlap with chronic traumatic encephalopathy (CTE) [35, 41, 44]

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