HAI Book 2025 - Flipbook - Page 271
Ikonomovic, Milos
Binding of [3H]MK-6240 to different tau lesions: a brain autopsy study
Eric Abrahamson1,2, Tobey Betthauser3,4,5, M Shahriar Salamat3,6, Lan Shao1, Victor
Villemagne7, Milos Ikonomovic1,2,7
1
Department of Neurology, University of Pittsburgh, Pittsburgh, PA, US
Geriatric Research Education and Clinical Center, VA Pittsburgh HS, Pittsburgh, PA, US
3
Wisconsin Alzheimer’s Disease Research Center, University of Wisconsin-Madison, Madison, WI, US
4
Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, US
5
Department of Medical Physics, School of Medicine and Public Health, University of Wisconsin-Madison, Madison,
WI, US
6
Department of Pathology, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, US
7
Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, US
2
Introduction: Monoclonal anti-A´ antibody treatment reduces brain A´ deposits in AD, but reductions in tau-PET
were also reported. We tested the hypothesis that tau lesions most closely involved with A´ plaques are an
important binding substrate of tau-PET ligands.
Methods: We combined l3H]MK-6240 autoradiography (ARG) with dual immunofluorescence for p-tau (AT8) and A´
(NAB228) in same tissue sections from autopsy AD brains. We then assessed localization and intensity of l3H]MK6240 ARG signal relative to tau pathology subtypes including neurofibrillary tangles (NFT), dystrophic neurites in
neuritic plaques (DN/NP), and neuropil threads (NT), as well as A´ plaques using semi-quantitative methods. We
also correlated p-tau immunolabeled NFT, DN/NP, and NT load (percent area coverage) with l3H]MK-6240 ARG
binding in 10 brain regions from a typical AD case.
Results: The most intense l3H]MK-6240 ARG signal corresponded to AT8-positive DN/NP. No ARG signal was
detected in A´ plaques without AT8-labeled DN. Semi-quantitative rating of ARG signal intensity showed that
DN/NP >> NFT > NT, with DN/NP yielding significant ARG signal even at low densities. High densities of NFT and
NT also produced significant ARG signal. l3H]MK-6240 ARG correlated with total tau pathology percent area
coverage (R=0.69, p=0.035), with trends for NFT (R=0.59, p=0.08) and NT (R=0.53, p=0.12) but not DN/NP (R=0.12,
p=0.76).
Conclusion: Tau in DN/NP is a robust binding substrate of MK-6240. However, across brain regions, NFT and NT
had greater areal coverage than DN/NP likely driving their better correlations with l3H]MK-6240 ARG. DN/NP
densities showed regional variability, with inferior temporal cortex 2-3 times higher than other regions. Thus, both
type and regional density of tau lesions contribute to MK-6240 PET signal. Reductions in tau PET seen after A´
monoclonal antibody treatment could involve DN/NP removal especially in brain regions where their percent area
coverage exceeds that of NFT and NT.
Keywords: Alzheimer’s disease, autoradiography, neuritic plaques, neurofibrillary tangles, tau
HAI2025 - 271
