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

Abstract

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.

Keywords: Diagnostic neuropathology; Lewy body disease.

Fig. 1

The new Lewy pathology consensus criteria (LPC). Yellow colour, LP can be absent ( −) or present ( +); red colour, LP must be present ( +). Of note: while presence ( +) of LP in the amygdala and in medial–temporal lobe or cingulate cortex is not mandatory for assigning a category of limbic and neocortical LP, respectively, we emphasise that it is highly unlikely that LP will be absent ( −) in the amygdala of limbic LP and in the medial–temporal lobe or cingulate cortex of neocortical LP. LP Lewy-related pathology; OB olfactory bulb/tract; dmX dorsal motor nucleus of vagal nerve/ medulla; SN substantia nigra; Amy amygdala; MTL medial–temporal cortex; Cing cingulate cortex; Fr. or Pa. ctx, frontal or parietal cortex

Fig. 2

Photomicrographs of α-synuclein stained slides showing dot like, artefactual positivity that should not be considered positive for scoring (encircled in a and b) and single α-synuclein-positive Lewy neurites (arrows in c and d) that would yield a score of “positive”. Scale bar in a: 70 μm, in b, c, and d: 50 μm

Fig. 3

Inter-rater reliability (Krippendorff’s α) for semi-quantitative scores (a) and diagnostic categories assigned using the different staging systems (b). Percentages of cases that were deemed non-classifiable by the majority of raters (median and 25th and 75% percentiles) (c)

Fig. 4

Percentages of assigned diagnostic categories according to Braak (a), McKeith (b), Leverenz (c), Beach (d) and LPC (e) systems. X-axis shows individual case numbers

Fig. 5

Diagnostic categories for archival cases of the University of Pennsylvania brain bank (UPBB; (a) and Newcastle Brain Tissue Resource (NBTR; b), stratified by their clinical diagnoses

Fig. 5

Diagnostic categories for archival cases of the University of Pennsylvania brain bank (UPBB; (a) and Newcastle Brain Tissue Resource (NBTR; b), stratified by their clinical diagnoses