In vivo imaging of LC‐NE Integrity: Mechanism for racial/ethnic disparity in preclinical AD

Abstract

AbstractBackgroundDespite studies suggesting that blacks may be at greater risk of developing AD, there have been few studies investigating health disparities, and blacks have been underrepresented in many prominent AD biomarker studies and clinical trials. The current ATN biomarker classification system may not fully account for health disparities and can’t explain the increased prevalence among blacks for both AD and AD vascular risks of diabetes and hypertension when compared to whites. Research on cognitive aging has traditionally focused on how decline in various cortical and hippocampal (Hip) regions influences cognition. However, tau pathology emerges decades before amyloid pathology, appearing first in the brainstem (BS); particularly in the locus coeruleus (LC), the source of brain’s norepinephrine (NE). Our decade‐long studies in humans using a norepinephrine transporter (NET)‐selective radiotracer ([11C]MRB) have demonstrated a special vulnerability of LC to aging and stress.MethodCo‐registration of PET (dynamic [11C]MRB), MRI and the FreeSurfer (FS) atlas images of each individual was used to generate regional time‐activity curves using Firevoxel. Binding potential (BPND) values were determined using MRTM2 with occipital as the reference region. Annual percent change (APC) of BPND was calculated based on linear regression (APC = 100 × (em – 1), m: slope) and effects of age, gender and ethnicity on tracer binding were evaluated.ResultFor all HC (N=31), with both genders and all races included, age‐sensitive decline of NET availability was observed; e.g., 0.3‐0.5%/yr for Hip, BS and olfactory. However, our data reveals that the decline rate of NET is much faster among blacks starting in the mid‐30s, particularly in black males; e.g., 2‐3%/yr vs. 0.14‐0.23%/yr in thalamus and brainstem for black males vs. white males (p<0.00001).ConclusionIn addition to our previously determined age effect on MRB‐NET binding, this report further reveals the role of ethnicity effects on NET availability. Our study showed that a faster decline of LC‐NE function occurs in blacks, possibly caused by cumulative stress to socioeconomic disadvantage and racial discrimination, and may be responsible for the different disease expression among blacks. Thus, NET availability imaging represents a novel biomarker approach to racial‐dependent strategies for diagnosis and assessment of therapeutic interventions.