Spatial patterns of the tau-immunoreactive inclusions in eight different tauopathies are consistent with the spread of pathogenic tau

Abstract

Introduction: The tauopathies are a major group of neurodegenerative disorders characterised by the presence of tau-immunoreactive inclusions in the cytoplasm of neurons and glia. The spread of pathogenic tau along neuro-anatomical pathways may play a significant role in the pathogenesis of these disorders. It is hypothesised that such spread should give rise to a characteristic spatial pattern of the tau-immunoreactive neuronal cytoplasmic inclusions (NCI) in the tissue of these disorders. Methods: The aim of this study was to test this hypothesis by comparing the spatial patterns of NCI in regions of the cerebral cortex in eight different tauopathies, viz., Alzheimer's disease (AD), argyrophilic grain disease (AGD), chronic traumatic encephalopathy (CTE), corticobasal degeneration (CBD), frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Guam Parkinsonism-dementia complex (GPDC), Pick's disease (PiD), and progressive supranuclear palsy (PSP). Results: Regardless of disorder, tau isoform, or inclusion morphology, the NCI were most frequently aggregated into clusters, the clusters being regularly distributed parallel to the pia mater. In many regions, the regularly distributed clusters of NCI were in the size range 400 – 800 m, approximating to the dimension of cell columns associated with the cortico-cortical pathways. Conclusion: The presence of regularly distributed clusters of NCI in the cortex of all eight tauopathies suggests an association between the pathology and the cortico-cortical pathways and is consistent with the pathogenic spread of tau along these connections. Hence, treatments designed to protect the cortex from this spread may be applicable across many tauopathies.