Examining the relationship between in vivo cholinergic integrity and cortical structure and function in healthy postmenopausal women using FEOBV PET

Introduction Compared to men, women have a higher risk of developing Alzheimer's disease (AD) in later life. A hypothesized reason for this increased risk may be the change in hormone levels following menopause. Estrogen is important for neurotransmitter systems, such as the cholinergic system, and the loss of estrogen post-menopause may accelerate cholinergic and cognitive decline in some women. Previous studies have examined the effect of cholinergic decline in postmenopausal women, but only in an indirect fashion, often through the use of cholinergic antagonists. The investigational radiotracer [18F]-fluoroethoxybenzovesamicol radiotracer (FEOBV) offers a way to assess cholinergic integrity more directly, as the tracer binds to the presynaptic vesicular cholinergic transporter. Previous studies have shown that FEOBV can quantify cholinergic system decline in AD patients compared to cognitively unimpaired older adults. The present study is an investigation of cholinergic system integrity in a sample of cognitively unimpaired postmenopausal women, who were part of a larger study examining cholinergic compensation following the menopause transition. To explore the effectiveness of using FEOBV to assess in vivo cholinergic activity, we assessed whether higher FEOBV standardized uptake value ratios (SUVR) would be associated with other markers of cholinergic integrity, such as basal forebrain volumes, as well as other risk factors including age and cognitive performance Methods Sixteen healthy postmenopausal women aged 50-70 years completed an FEOBV PET scan (6.5 mCi dose), in addition to structural MRI, EEG recording and cognitive assessments. Co-registration of the FEOBV PET images to the participant's structural MRI data before the SUVR was normalized in reference to the supraventricular white matter. This mask was used as a reference to avoid any partial volume effects from the ventricular tissue. Preliminary analyses focused on associations between FEOBV SUVR and the key outcome variables. Results Preliminary analyses showed a positive relationship between global FEOBV SUVR and the gray-matter volume of the basal forebrain of both hemispheres. A negative relationship was found between age and FEOBV SUVR, with older adults showing reduced SUVR. Finally, a positive relationship was also seen between global FEOBV SUVR and global cognition, with higher SUVR associated with better cognitive performance. Conclusions Greater FEOBV SUVR was associated with both basal forebrain volume and cognitive performance in this pilot sample of cognitively unimpaired postmenopausal women. These results highlight the role of cholinergic compensation in postmenopausal women as a potential risk factor for future cognitive decline. This research was funded by Funding Information: This research was supported by NIA grant R01 AG066159, a CTSA award UL1TR000445 from the National Center for Advancing Translational Sciences and funding from the Vanderbilt Trans-Institutional Partnership.