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Neuropathological consensus criteria for the evaluation of Lewy pathology in post-mortem brains: a multi-centre study

Lookup NU author(s): Professor Johannes Attems, Dr Lauren WalkerORCiD, Dr Kirsty McAleese, Dr Tuomo Polvikoski, Professor Ian McKeith

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© 2021, The Author(s). Currently, the neuropathological diagnosis of Lewy body disease (LBD) may be stated according to several staging systems, which include the Braak Lewy body stages (Braak), the consensus criteria by McKeith and colleagues (McKeith), the modified McKeith system by Leverenz and colleagues (Leverenz), and the Unified Staging System by Beach and colleagues (Beach). All of these systems use semi-quantitative scoring (4- or 5-tier scales) of Lewy pathology (LP; i.e., Lewy bodies and Lewy neurites) in defined cortical and subcortical areas. While these systems are widely used, some suffer from low inter-rater reliability and/or an inability to unequivocally classify all cases with LP. To address these limitations, we devised a new system, the LP consensus criteria (LPC), which is based on the McKeith system, but applies a dichotomous approach for the scoring of LP (i.e., “absent” vs. “present”) and includes amygdala-predominant and olfactory-only stages. α-Synuclein-stained slides from brainstem, limbic system, neocortex, and olfactory bulb from a total of 34 cases with LP provided by the Newcastle Brain Tissue Resource (NBTR) and the University of Pennsylvania brain bank (UPBB) were scanned and assessed by 16 raters, who provided diagnostic categories for each case according to Braak, McKeith, Leverenz, Beach, and LPC systems. In addition, using LP scores available from neuropathological reports of LP cases from UPBB (n = 202) and NBTR (n = 134), JT (UPBB) and JA (NBTR) assigned categories according to all staging systems to these cases. McKeith, Leverenz, and LPC systems reached good (Krippendorff’s α ≈ 0.6), while both Braak and Beach systems had lower (Krippendorff’s α ≈ 0.4) inter-rater reliability, respectively. Using the LPC system, all cases could be unequivocally classified by the majority of raters, which was also seen for 97.1% when the Beach system was used. However, a considerable proportion of cases could not be classified when using Leverenz (11.8%), McKeith (26.5%), or Braak (29.4%) systems. The category of neocortical LP according to the LPC system was associated with a 5.9 OR (p < 0.0001) of dementia in the 134 NBTR cases and a 3.14 OR (p = 0.0001) in the 202 UPBB cases. We established that the LPC system has good reproducibility and allows classification of all cases into distinct categories. We expect that it will be reliable and useful in routine diagnostic practice and, therefore, suggest that it should be the standard future approach for the basic post-mortem evaluation of LP.


Publication metadata

Author(s): Attems J, Toledo JB, Walker L, Gelpi E, Gentleman S, Halliday G, Hortobagyi T, Jellinger K, Kovacs GG, Lee EB, Love S, McAleese KE, Nelson PT, Neumann M, Parkkinen L, Polvikoski T, Sikorska B, Smith C, Grinberg LT, Thal DR, Trojanowski JQ, McKeith IG

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica

Year: 2021

Volume: 141

Issue: 2

Pages: 159-172

Print publication date: 01/02/2021

Online publication date: 05/01/2021

Acceptance date: 16/12/2020

Date deposited: 26/07/2021

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer Nature

URL: https://doi.org/10.1007/s00401-020-02255-2

DOI: 10.1007/s00401-020-02255-2

PubMed id: 33399945


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Funding

Funder referenceFunder name
Alzheimer's Research UK
Alzheimer's Society
G0400074

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