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 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. . 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 inter-rater 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 pathology stage; Supplementary Fig. 2a, b and 3, 4, online resource). There was a significant association between pathology stage and PSPRS, both when weighting for time between last testing and death (F(4,25) = 30.0, p = 0.036) and using imputed PSPRS scores (F(4,27) = 2.8, p = 0.045). There was a significant association between pathology stage and cognitive deficit, when weighting the analysis for time between testing and death (F(4,27) = 5.09, p = 0.0035), but not using imputed ACE-R scores (F(4, 27) = 2.43, p = 0.07). Given the small group sizes for stages 2, 3 and 6, post hoc analysis were not performed.
Overall, our study supports the validity of the proposed PSP pathology staging system proposed by Kovacs et al. , being easy to implement in the day-to-day neuropathological evaluation (and retrospectively) as the regions required are routinely sampled for the pathological diagnosis of neurodegenerative disease. The proposed PSP staging schema is applicable across the spectrum of clinical PSP subtypes with > 90% of cases fulfilling staging criteria. In addition to the written description provided by Kovacs et al. we provide region-specific quantitative criteria along with a visual guide for the rating of tau pathology. Together with high compliance with the staging scheme, our findings suggest that the sequential distribution of tau pathology is associated with progressive clinical severity in PSP.
The datasets used are available from the corresponding author on reasonable request.
Kovacs GG, Lukic MJ, Irwin DJ et al (2020) Distribution patterns of tau pathology in progressive supranuclear palsy. Acta Neuropathol 140:99–119. https://doi.org/10.1007/s00401-020-02158-2
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The authors would like to thank the research participants and caregivers, and the staff at the Cambridge Centre for Parkinson-Plus and the Department of Histopathology and Cytology at the Cambridge Brain Bank.
This work was funded by the Cambridge Brain Bank, Wellcome Trust (103838); Medical Research Council (146281), and the Cambridge Centre for Parkinson-plus (RG95450). The Cambridge Brain Bank is supported by the NIHR Cambridge Biomedical Research Centre. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care.
Conflict of interests
The authors declare that they have no conflict of interest.
The study ethics was approved by the Health Research Authority, NHS, England (IRAS- 202 802, “Neurodegeneration Research in Dementia”). The PiPPIN (Pick's Disease and Progressive Supranuclear Palsy: Prevalence and Incidence) Study was approved by Cambridge's research ethics committee. The study was conducted in accordance with the 1964 Helsinki declaration.
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Briggs, M., Allinson, K.S.J., Malpetti, M. et al. Validation of the new pathology staging system for progressive supranuclear palsy. Acta Neuropathol 141, 787–789 (2021). https://doi.org/10.1007/s00401-021-02298-z