LAUSR

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder associated with neuroglial accumulation of 4-repeat tau protein [2]. Kovacs et al. [1] have recently proposed a new semi-quantitative six-stage system to categorise the severity of PSP pathology. Importantly, the system reduces reliance on regions with high risk of concomitant pathology and focusses on cell type-specific tau-pathology. Here, we test the new PSP pathology staging system in an independent series of 35 PSP cases 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; Movement Disorder Society 2017 criteria; Supplementary table 1, online resource). 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). The left brain hemisphere was available for pathological evaluation (Supplementary methods, online resource) and following the guidelines from Kovacs et al. we rated regional tau cytopathology focussing on astrocytic tau inclusions in striatum (STR), frontal and occipital cortices, and neuronal and oligodendroglia tau inclusions in globus pallidus (GP), subthalamic nucleus (STN), and cerebellum. First, 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]. The raters were in agreement in just 45/60 regions (75%). Pallidum, cerebellum and occipital lobe had high agreement (≥ 8/10), STN and frontal cortex intermediate (7/10), while STR had low agreement (4/10). This discrepancy was attributed to the lack of operational criteria and individual interpretations of the staging system ratings for each area, confounded by marked differences between regions in the absolute numbers of immunoreactive cells per field. We therefore formulated operational criteria with region-specific thresholds see Fig. 1c and Supplementary Fig. 1 (online resource) for a visual guide. With the new operational criteria the interrater agreement increased to 88% (52/59 regions), with high agreement for GP, STR, frontal cortex, occipital and cerebellum (9/10) and intermediate for STN (7/9). Integrating these operational criteria to the new staging system, 91% (32/35) of cases fitted readily into one of the six stages (Fig. 1a), including 9/10 of the cases with non-Richardson’s phenotype (Fig. 1d and e). We then tested whether the pathology staging was associated with demographic, age and clinical severity. There was no significant association between the pathological stages and age or symptom duration (Kruskal Wallis, p > 0.05). The interval between death and last assessment of disease severity (PSPRS and ACE-R) varied from 24 days to 35 months. To account for the differences in interval between testing and death we took two approaches (1) weighting the analysis for this time interval (Clinical score ~ PSP pathology stage|weight = 1/interval between assessment and death; Fig. 1b) and, (2) imputing the PSPRS and ACE-R scores at death from longitudinal assessments (imputed score ~ PSP * Sanne Simone Kaalund [email protected]