Age, Gender, and Ethnicity Effects on NET Availability in Humans using [¹¹C]MRB

Objectives: Alzheimer’s disease (AD) is a major health challenge in our aging society. An improved understanding of its underlying pathological mechanisms is urgently needed to enable the development of effective treatments. Postmortem findings indicate that tau pathology emerges decades before amyloid pathology, appearing first in the brainstem; in particular in the locus coeruleus (LC), a small nucleus that is the source of most of the brain’s norepinephrine (NE). Although very little is known about how the NE system changes during normal aging and its potential role in progression of preclinical stages of AD, our preliminary data using (S,S)-[¹¹C]MRB ([¹¹C]MRB) have documented an age-related decline in NE transporters (NET) availability starting in middle age, suggesting in vivo NET availability is a sensitive biomarker for aging and for changes during the preclinical stages of AD. In addition to the age effect, this report investigated the potential gender and ethnicity effects on NET availability.

Methods: Dynamic [¹¹C]MRB images of healthy subjects were acquired for 120 min and individual structure MRI images were acquired for co-registration purposes. The segmentation of cortical and subcortical ROIs was automatically established via FreeSurfer (https://surfer.nmr.mgh.harvard.edu/) based on the template MRI atlas (FS2005). Left and right olfactory (Ofac) regions were also generated using the Destrieux Atlas. With Firevoxel developed at NYU (https://wp.nyu.edu/Firevoxel), PET, MRI, and the FS atlas images of each individual were coregistered using a mutual information algorithm with autofocus transformation that was tested and validated. Dynamic regional time-activity curves (TAC) were generated and MRTM2 was selected as the modeling method. Binding potential (BP_ND, a measure of specific binding with respect to non-displaceable uptake) values were automatically calculated, and tested by various starting time, parameter k2’ and using two potential reference regions (caudate & occipital, low NET regions), for comparison and validation purposes. Annual percent change (APC) of regional BP_ND values was calculated based on linear regression (APC = 100 × (e^m - 1), m is the slope) and effects of age, gender and ethnicity on the NET-MRB binding were evaluated.

Results: Data presented here were based on t2* 20 min and k2’ 0.021 min^-1 with occi as the reference region. For all HC (N=31), with both genders and all race included, the NET availability decline can be observed; e.g., -0.4%/yr for BS & ROfac. However, in gender-separated group analysis [M (N=19, age range: 23-55, avg=36.2±9.9) and F (N=12, age range 25-54, avg= 36.6±9.0)], while BP_ND values were not significantly different, there was a significant gender effect for APC (P <0.01) with decline rates faster for M (e.g., -0.8, -0.6, -0.5, & -0.4%/yr for TH, RAmyg, ROfac, & Hip, respectively), and significant decline starting from mid 30 (p<0.001). Gender effects were also observed in the group-level analyses in all white (N=16, 11M) and in all AA subgroups (N=14, 7M) with the decline rate faster for M than F, but APC difference did not reach significance (may be due to sample size and age range not completely matched). Interestingly, out of all investigated brain ROIs (16), avg BP_ND values of each ROI from AA (N=14, avg age 34±7) were consistently higher than those from white subjects (N=12, avg age 35±8)(P<0.000). However, the decline rate was consistently higher for AA than for white subjects (P<0.00001), e.g., the decline rate for AA-M: -3%/yr in LTH & RAmyg and over -1%/yr in BS & ROfac, and for AA-F: -2%/yr in BS & Ofac.

Conclusions: Compared to our previous age-related study of dopamine transporter (DAT), NET exhibited a faster decline rate than DAT. In addition to our previously determined age effect on MRB-NET binding, this report further reveals the role of gender and ethnicity effects on NET availability. A bigger sample size is warranted to investigate their effects on the NET availability.