Objective:

To examine spectrum of neocortical tau burden using digital histological methods in Alzheimer’s disease (AD) and Lewy Body Disease (dementia with Lewy bodies and Parkinson’s disease) with AD co-pathology (LBD+AD) with high Braak tau stages.

Background:

Neuropathological assessment remains gold-standard for diagnosing and staging neurodegenerative diseases. Digital histological assessment may capture a spectrum of pathological burden not easily demonstrated by traditional methods.

Design/Methods:

Cases from UC-San Diego (UCSD) and University of Pennsylvania (UPenn) with AD (UCSD:15, UPenn:33) and LBD+AD (UCSD:7, UPenn:10) with Braak tau stages V and VI (B3) had middle frontal cortex (MFC), superior temporal cortex (STC), and angular gyrus (ANG) immunohistochemically stained for pathological tau inclusions (AT8) and whole-slide images analyzed for tau %area occupied (tau%AO) using QuPath image analysis software. Natural-log tau%AO values were compared between ordinal severity scores (0-3), Braak stages, and between AD and LBD+AD in each region using ANOVA and t-tests.

Results:

In both cohorts, here were significant increases in tau%AO across blinded regional ordinal severity scores (UCSD F=28.4, p<0.001, UPenn F=236, p<0.001). All regions had higher tau%AO in Braak VI cases than Braak V in the UCSD cohort (p<0.02). The STC harbored the highest tau%AO values in AD and LBD+AD. AD had higher tau%AO than LBD+AD in every region (MFC, STC, ANG, neocortical average: t=2.2-4.3, p<0.03).

Conclusions:

Digital histological measurements recapitulate aspects of known patterns of AD-related tau pathology but reveal a range of pathological burden within current grading and staging systems. These methods may have relevance for ongoing biomarker development and modeling disease using human histology.