Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy

Shanu F Roemer^#¹, Lea T Grinberg^#^{2

3

4}, John F Crary⁵, William W Seeley^{2

3}, Ann C McKee⁶, Gabor G Kovacs^{7

8}, Thomas G Beach⁹, Charles Duyckaerts¹⁰, Isidro A Ferrer¹¹, Ellen Gelpi¹², Edward B Lee¹³, Tamas Revesz¹⁴, Charles L White 3rd¹⁵, Mari Yoshida¹⁶, Felipe L Pereira², Kristen Whitney⁵, Nikhil B Ghayal¹, Dennis W Dickson¹⁷

Affiliations

¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
² Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
³ Department of Pathology, University of California, San Francisco, CA, USA.
⁴ Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
⁵ Departments of Pathology, Nash Family Department of Neuroscience, Artificial Intelligence and Human Health, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, Friedman Brain Institute, Neuropathology Brain Bank and Research CoRE, New York, NY, USA.
⁶ Department of Pathology, Boston University School of Medicine, Boston, MA, USA.
⁷ Tanz Centre for Research in Neurodegenerative Disease and Department of Laboratory Medicine and Pathobiology and Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁸ Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
⁹ Banner Sun Health Research Institute, Sun City, AZ, USA.
¹⁰ Department of Neuropathology, Sorbonne Université, Hôpital de La Pitié-Salpêtrière, Paris, France.
¹¹ Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain.
¹² Department of Neuropathology and Neurochemistry, Medical University of Vienna, Vienna, Austria.
¹³ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Department of Neurodegenerative Diseases, Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, University College London, Queen Square, London, UK.
¹⁵ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁶ Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.
¹⁷ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. dickson.dennis@mayo.edu.

^# Contributed equally.

PMID: 35947184
PMCID: PMC9468104
DOI: 10.1007/s00401-022-02479-4

Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy

Shanu F Roemer et al. Acta Neuropathol. 2022 Oct.

. 2022 Oct;144(4):603-614.

doi: 10.1007/s00401-022-02479-4. Epub 2022 Aug 10.

Authors

Affiliations

¹ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
² Department of Neurology, Memory and Aging Center, University of California San Francisco, San Francisco, CA, USA.
³ Department of Pathology, University of California, San Francisco, CA, USA.
⁴ Department of Pathology, LIM-22, University of São Paulo Medical School, São Paulo, Brazil.
⁵ Departments of Pathology, Nash Family Department of Neuroscience, Artificial Intelligence and Human Health, Ronald M. Loeb Center for Alzheimer's Disease, Icahn School of Medicine at Mount Sinai, Friedman Brain Institute, Neuropathology Brain Bank and Research CoRE, New York, NY, USA.
⁶ Department of Pathology, Boston University School of Medicine, Boston, MA, USA.
⁷ Tanz Centre for Research in Neurodegenerative Disease and Department of Laboratory Medicine and Pathobiology and Department of Medicine, University of Toronto, Toronto, ON, Canada.
⁸ Laboratory Medicine Program and Krembil Brain Institute, University Health Network, Toronto, ON, Canada.
⁹ Banner Sun Health Research Institute, Sun City, AZ, USA.
¹⁰ Department of Neuropathology, Sorbonne Université, Hôpital de La Pitié-Salpêtrière, Paris, France.
¹¹ Department of Pathology and Experimental Therapeutics, University of Barcelona, Hospitalet de Llobregat, Spain.
¹² Department of Neuropathology and Neurochemistry, Medical University of Vienna, Vienna, Austria.
¹³ Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
¹⁴ Department of Neurodegenerative Diseases, Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, University College London, Queen Square, London, UK.
¹⁵ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁶ Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.
¹⁷ Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA. dickson.dennis@mayo.edu.

^# Contributed equally.

PMID: 35947184
PMCID: PMC9468104
DOI: 10.1007/s00401-022-02479-4

Abstract

Neuropathologic criteria for progressive supranuclear palsy (PSP) proposed by a National Institute of Neurological Disorders and Stroke (NINDS) working group were published in 1994 and based on the presence of neurofibrillary tangles in basal ganglia and brainstem. These criteria did not stipulate detection methods or incorporate glial tau pathology. In this study, a group of 14 expert neuropathologists scored digital slides from 10 brain regions stained with hematoxylin and eosin (H&E) and phosphorylated tau (AT8) immunohistochemistry. The cases included 15 typical and atypical PSP cases and 10 other tauopathies. Blinded to clinical and neuropathological information, raters provided a categorical diagnosis (PSP or not-PSP) based upon provisional criteria that required neurofibrillary tangles or pretangles in two of three regions (substantia nigra, subthalamic nucleus, globus pallidus) and tufted astrocytes in one of two regions (peri-Rolandic cortices, putamen). The criteria showed high sensitivity (0.97) and specificity (0.91), as well as almost perfect inter-rater reliability for diagnosing PSP and differentiating it from other tauopathies (Fleiss kappa 0.826). Most cases (17/25) had 100% agreement across all 14 raters. The Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of PSP feature a simplified diagnostic algorithm based on phosphorylated tau immunohistochemistry and incorporate tufted astrocytes as an essential diagnostic feature.

Keywords: Autopsy cohort; Criteria; Human; Neurofibrillary tangles; Neuropathology; Oligodendroglia; Phosphorylated tau; Progressive supranuclear palsy (PSP); Threads; Tufted astrocytes.

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Figures

**Fig. 1**
A schematic representation of tau lesions included in the Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of PSP (green shading = tufted astrocytes, blue shading = tangles or pretangles). To fulfill a PSP diagnosis, tufted astrocytes need to be present in a minimum of one of two regions (green shading) AND neurofibrillary tangles need to be present in a minimum of two of three regions (blue shading) B based upon tau immunohistochemistry. Scale bar = 20 µm. All images were captured at 60 × magnification on an Olympus BX41 microscope, using digital the camera DP22

See this image and copyright information in PMC

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Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy

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Rainwater Charitable Foundation criteria for the neuropathologic diagnosis of progressive supranuclear palsy

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