Neuropathologic basis of frontotemporal dementia in progressive supranuclear palsy

Abstract

Background: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia.

Methods: In this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods.

Results: We found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia.

Conclusions: The results confirm the subset of cognitive-predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Keywords: behavioral variant frontotemporal dementia; immunohistochemistry, image analysis; progressive supranuclear palsy; tau.

Figure 1

Macroscopic and phospho‐tau immunohistochemistry in PSP‐FTD. Cerebral atrophy is marked in frontal cortex (A). Pigmentation of substantia nigra is preserved (B).The superior cerebellar peduncle has no atrophy (C). Representative phospho‐tau immunohistochemistry of superior frontal cortex in PSP. Phospho‐tau pathology is present in both gray matter and white matter in PSP‐FTD and PSP‐RS. In gray matter, NFTs (D), threads (E), and tufted astrocytes (F) are illustrated, whereas coiled bodies are seen in the white matter (G). Scale bar: 20 μm

Figure 2

Image analysis of phospho‐tau in PSP‐FTD and PSP‐RS. Representative images of phospho‐tau immunohistochemistry in superior frontal cortex of PSP. Phospho‐tau pathology is present in both gray matter and white matter in PSP‐FTD (A), but much less in PSP‐RS (B). Tufted astrocytes are more frequent in PSP‐FTD than PSP‐RS (arrow). Dashed line indicates junction between gray matter and white matter. Scale bar: 200 μm. Digital image analysis of phospho‐tau immunohistochemistry in the superior frontal cortex of PSP‐FTD (C) and PSP‐RS (D). Higher magnification image of PSP‐FTD (E, G) and higher magnification image of digital analysis of PSP‐FTD (F, H). Application of the image analysis color deconvolution algorithm shows strong positive pixels as red. A positive pixel count algorithm was customized to quantify immunoreactive pixels (red), subtracting inverse pixels (blue), and background pixels (yellow). The analysis does not discriminate between NFTs, neuropil threads, coiled bodies, and tufted astrocytes. Dashed line indicates junction of gray matter and white matter. Scale bar: 150 μm (A–D). Scale bar: 30 μm (E–H).