Sex differences in off-target binding using tau positron emission tomography.

Area of Science:

• Neuroimaging
• Radiochemistry
• Biomarkers

Background:

• Off-target binding in the skull and meninges can affect tau positron emission tomography (PET) imaging accuracy.
• Potential sex differences in tau off-target binding warrant investigation for improved diagnostic interpretation.
• Understanding these variations is critical for sex-specific analysis in neurodegenerative disease research.

Purpose of the Study:

• To investigate and elucidate sex differences in tau off-target binding within the skull and meninges.
• To compare off-target binding patterns across three distinct tau PET tracers: [18F]flortaucipir, [18F]RO948, and [18F]MK6240.

Main Methods:

• 541 cognitively unimpaired, amyloid-β negative participants underwent tau PET imaging using [18F]flortaucipir, [18F]RO948, or [18F]MK6240.
• Baseline Standardized Uptake Value Ratio (SUVR) values were compared between sexes at voxel and region-of-interest (ROI) levels, specifically targeting the skull/meninges.
• Cross-sectional relationships between skull/meningeal SUVR and age, as well as longitudinal changes in SUVR, were assessed.

Main Results:

• Voxel-wise analysis revealed significantly higher meningeal off-target binding in females compared to males across all three tau PET tracers.
• Skull/meningeal ROI retention was highest for [18F]RO948, followed by [18F]MK6240 and [18F]flortaucipir.
• Females consistently exhibited higher mean skull/meningeal SUVR values than males for all tracers; off-target binding decreased with age for [18F]flortaucipir and [18F]RO948.

Conclusions:

• Significant sex-based differences exist in off-target retention within the meninges and skull for [18F]flortaucipir, [18F]RO948, and [18F]MK6240 tau PET tracers.
• These findings highlight the importance of considering sex as a biological variable in the interpretation of tau PET imaging data.
• The observed differences may necessitate sex-specific analytical approaches or reference ranges for accurate clinical application.