HAI Book 2025 - Flipbook - Page 347
Heuer, Lauren
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MK-6240 off-target binding patterns in relation to microglia density,
measured through TSPO PET
Lauren Heuer1, Aubrey Johnson1, Anna Smith1, Diana Guzman1, Hannah Houlihan1,
Amarachukwu Okafor1, Thairi Sanchez1, Daniel Talmasov1, Dina Dass1, Nbdusi Chikwem1, Frank
Provenzano1, William Kreisl1, James Noble1, Scott Small1, Patrick Lao1
1
Columbia University Medical Center, New York, NY, US
Background: Tau PET tracers have distinct off-target binding profiles, which may confound quantification.
Microglia and border macrophages are involved in blood-brain-barrier permeability and glymphatic clearance
mechanisms. We investigated patterns (not magnitude) of off-target leptomeningeal binding profiles of MK-6240
in relation to microglia density, as measured by translocator protein (TSPO) PET signal, across Alzheimer9s disease
and related dementias.
Methods: Participants (n=35; age=70±8 years, 49% female, BMI=25±4, education=17±3, 83% White, 94% NonHispanic, 19% low TSPO affinity, 35% APOE4) from the Longitudinal Imaging of Microglial Activation in Different
Clinical Variants of Alzheimer9s Disease study completed baseline amyloid PET (Florbetaben), tau PET (MK-6240),
and TSPO PET (ER176). Amyloid positivity was determined by visual read (26%), tau positivity as >2SD+mean in
controls for early Braak regions (31%), and TSPO positivity as >mean in controls for a global composite (69%).
Clinical groups were determined by case consensus (19 controls, 4 aMCI/MCI, 5 AD, 1 LATE, 1 FTD, 1 lvPPA, 4 PCA).
Low (29%), variable (11%), and high (60%) extent of MK-6240 off-target binding was visual assessed (fixed range
and colorbar across scans; minimal adjustments as necessary). We compared regional ER176 SUVR across MK6240 off-target binding patterns, adjusting for TSPO affinity and diagnosis [yes/no].
Results: Notably, MK-6240 off-target binding was present in a range of participants including amyloid-negative,
tau-negative, TSPO-negative, and individuals with cognitive impairment beyond MCI/AD. Across MK-6240 offtarget binding patterns, there was no difference by demographic characteristics (Figure 1A). ER176 was greater in
the striatum and prefrontal cortex for the variable MK-6240 off-target binding pattern (Figure 1B).
Conclusion: TSPO PET may capture aspects of regional blood-brain-barrier permeability and/or glymphatic
clearance related to the pattern, not necessarily the magnitude, of incomplete (i.e., variable) off-target signal in
the leptomeninges. Larger, longitudinal studies with more direct measures of underlying biological mechanisms
of off-target binding are needed.
HAI2025 - 347
