Validation of the new pathology staging system for progressive supranuclear palsy

Mayen Briggs,James Benedict Rowe,Kieren Simon James Allinson,Maura Malpetti,Sanne Simone Kaalund,Maria Grazia Spillantini

doi:10.1007/s00401-021-02298-z

Abstract

Abstract Progressive supranuclear palsy (PSP) is a neurodegenerative disorder associated with neuroglial accumulation of 4-repeat tau protein. Kovacs et al. have recently proposed a new semi-quantitative staging system to categorise the severity of PSP pathology, using the distribution of tau aggregates as it progresses from subcortical to cerebellar and cortical regions. Here, we test the new PSP pathology staging system in an independent series of PSP, and test the potential association between pathology stage and clinical severity at death. We include tissue from 35 people with a clinical diagnosis of PSP (including N=25 with Richardson’s syndrome and N=10 with other phenotypes). Donors had attended longitudinal clinical studies at the Cambridge Centre Parkinson-plus including assessment of clinical severity by the PSP rating scale (PSPRS) and cognitive performance by the revised Addenbrooke’s Cognitive Examination (ACE-R). We rated tau pathology from none-to-severe in six regions. We focused on (I) astrocytic tau inclusions in striatum, frontal and occipital regions, and (II) neuronal and oligodendroglia tau inclusions in globus pallidus, subthalamic nucleus, and cerebellum. Thirty-two cases (91%) readily conformed to the new staging system, ranging from stage 2 to 6. Staging system applied to brains from people with different clinical phenotypes of PSP. Neuropathology stages correlated with clinical severity at death using both PSPRS and ACE-R, weighted for the interval between last assessment and donation. Our study supports the proposed sequential distribution of tau aggregates in PSP pathology, and the hypothesised relationship between clinical and neuropathological severity. For future studies, in order to standardise rating between centres, we propose a set of operational criteria for region-specific thresholds or tau burden, and a visual guide.

Highlights

We selected ten random cases and, in each area, two authors independently rated tau pathology following the new staging system as described by Kovacs et al [1]
With the new operational criteria the interrater agreement increased to 88% (52/59 regions), with high agreement for globus pallidus (GP), STR, frontal cortex, occipital and cerebellum (9/10) and intermediate for subthalamic nucleus (STN) (7/9)
Our study supports the validity of the proposed Progressive supranuclear palsy (PSP) pathology staging system proposed by Kovacs et al [1], being easy to implement in the day-to-day neuropathological evaluation as the regions required are routinely sampled for the pathological diagnosis of neurodegenerative disease

Summary

Introduction

We selected ten random cases and, in each area, two authors independently rated tau pathology following the new staging system as described by Kovacs et al [1]. 2 Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge CB2 0SZ, UK 4 Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Clifford Allbutt Building, Hills Road, Cambridge CB2 0AH, UK

Results

Conclusion