Associations of 18F‐flortaucipir tau PET with quantitative tau histopathology in the medial temporal lobe

TL;DR

This study shows that 18F-flortaucipir PET imaging correlates with tau tangles in early Alzheimer's disease brain regions, supporting its use for tracking tau pathology.

Contribution

The study provides direct evidence linking PET imaging with tau tangles in early Braak stages, addressing concerns about its sensitivity and specificity.

Findings

18F-flortaucipir PET SUVRs correlated strongly with tau tangles in the entorhinal cortex and hippocampus.

PET imaging was not associated with TDP-43 pathology, indicating specificity for tau.

Most intermediate-high AD cases showed PET positivity above the established cutoff.

Abstract

18F‐Flortaucipir is widely used for positron emission tomography (PET) imaging of Alzheimer's disease (AD)‐type tau, but its sensitivity in early Braak stages has been questioned, and hippocampal uptake is at least partially confounded by off‐target binding. We investigated associations between antemortem PET uptake and digitally‐quantified tau and TDP‐43 neuropathology.

Participants (n = 14, Figure 1) included 5 people with no/low AD neuropathologic change (ADNC) at autopsy, 2 intermediate, and 7 high. Clinical diagnoses included normal cognition (n = 2), AD (n = 5), dementia with Lewy bodies (n = 2), Parkinson's disease dementia (n = 1), corticobasal syndrome (n = 2), and posterior cortical atrophy (n = 2). We used the Automated Segmentation of Hippocampal Subfields T1 MRI pipeline to segment anterior and posterior hippocampus, Brodmann's areas (BA) 35 (transentorhinal cortex) & 36, and entorhinal cortex. 18F‐Flortaucipir standardized uptake value ratios (SUVRs) were computed relative to inferior cerebellar grey matter and averaged across hemispheres. Postmortem sampling comprised hippocampal subiculum, CA1, CA2, CA3, and dentate gyrus; BA35 and BA36; and entorhinal cortex. FFPE‐brain tissue was immunostained using PHF1 and phospho‐specific TDP‐43 antibodies and digitally imaged. Two different weakly supervised learning algorithms, Wildcat, were trained to identify tau tangles and threads; or somatic and neuritic phosphorylated TDP‐43 (pTDP‐43) inclusions. Each pathology type was quantified by summary statistics on Wildcat heatmaps, averaged over hippocampal subfields; and over BA35/entorhinal cortex (Denning et al., 2024). We computed non‐parametric correlations between SUVRs and pathology measures at a=0.05 with false discovery rate correction.

Tangles were associated with SUVRs in BA35/entorhinal cortex (Spearman's r=0.59, p = 0.029; Figure 2A). The mean hippocampal tangle measure was associated with SUVRs in both anterior (r=0.77, p = 0.002) and posterior (r=0.77, p = 0.002) hippocampus (Figure 2B‐C). Associations between SUVR and tau threads were marginally significant (Figure 2D‐F). In BA35/entorhinal cortex, 9/9 intermediate‐high ADNC cases had SUVRs above an established positivity cutoff of 1.23 (Figure 3). PET SUVRs were not associated with somatic or neuritic pTDP‐43 measures.

Results suggest 18F‐flortaucipir is sensitive to tau burden in early Braak‐stage regions and primarily reflects neurofibrillary tangles rather than thread‐like tau inclusions.

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