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5 Associations Between Regional Perfusion and Locus Coeruleus MRI Contrast are Moderated by Plasma Alzheimer’s Disease Biomarkers in Older Adults

Published online by Cambridge University Press:  21 December 2023

Shubir Dutt*
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Shelby L Bachman
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Yanrong Li
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Belinda Yew
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Jung Y Jang
Affiliation:
University of California, Irvine, Irvine, CA, USA
Jean K Ho
Affiliation:
University of California, Irvine, Irvine, CA, USA
Kaoru Nashiro
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Jungwon Min
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Hyun Joo Yoo
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Aimee Gaubert
Affiliation:
University of California, Irvine, Irvine, CA, USA
Amy Nguyen
Affiliation:
University of California, Irvine, Irvine, CA, USA
Isabel J Sible
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Anna E Blanken
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Anisa J Marshall
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Arunima Kapoor
Affiliation:
University of California, Irvine, Irvine, CA, USA
John P Alitin
Affiliation:
University of California, Irvine, Irvine, CA, USA
Kim Hoang
Affiliation:
University of California, Irvine, Irvine, CA, USA
Alessandra C Martini
Affiliation:
University of California, Irvine, Irvine, CA, USA
Elizabeth Head
Affiliation:
University of California, Irvine, Irvine, CA, USA
Xingfeng Shao
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Danny J J Wang
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Mara Mather
Affiliation:
University of Southern California, Los Angeles, CA, USA.
Daniel A Nation
Affiliation:
University of California, Irvine, Irvine, CA, USA
*
Correspondence: Shubir Dutt, University of Southern California, shubirdu@usc.edu
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Abstract

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Objective:

The locus coeruleus (LC) innervates the cerebrovasculature and plays a crucial role in optimal regulation of cerebral blood flow. However, no human studies to date have examined links between these systems with widely available neuroimaging methods. We quantified associations between LC structural integrity and regional cortical perfusion and probed whether varying levels of plasma Alzheimer’s disease (AD) biomarkers (Aß42/40 ratio and ptau181) moderated these relationships.

Participants and Methods:

64 dementia-free community-dwelling older adults (ages 55-87) recruited across two studies underwent structural and functional neuroimaging on the same MRI scanner. 3D-pCASL MRI measured regional cerebral blood flow in limbic and frontal cortical regions, while T1-FSE MRI quantified rostral LC-MRI contrast, a well-established proxy measure of LC structural integrity. A subset of participants underwent fasting blood draw to measure plasma AD biomarker concentrations (Aß42/40 ratio and ptau181). Multiple linear regression models examined associations between perfusion and LC integrity, with rostral LC-MRI contrast as predictor, regional CBF as outcome, and age and study as covariates. Moderation analyses included additional terms for plasma AD biomarker concentration and plasma x LC interaction.

Results:

Greater rostral LC-MRI contrast was linked to lower regional perfusion in limbic regions, such as the amygdala (ß = -0.25, p = 0.049) and entorhinal cortex (ß = -0.20, p = 0.042), but was linked to higher regional perfusion in frontal cortical regions, such as the lateral (ß = 0.28, p = 0.003) and medial (ß = 0.24, p = 0.05) orbitofrontal (OFC) cortices. Plasma amyloid levels moderated the relationship between rostral LC and amygdala CBF (Aß42/40 ratio x rostral LC interaction term ß = -0.31, p = 0.021), such that as plasma Aß42/40 ratio decreased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and amygdala perfusion decreased. Plasma ptau181levels moderated the relationship between rostral LC and entorhinal CBF (ptau181 x rostral LC interaction term ß = 0.64, p = 0.001), such that as ptau181 increased (i.e., greater pathology), the strength of the negative relationship between rostral LC integrity and entorhinal perfusion decreased. For frontal cortical regions, ptau181 levels moderated the relationship between rostral LC and lateral OFC perfusion (ptau181 x rostral LC interaction term ß = -0.54, p = .004), as well as between rostral LC and medial OFC perfusion (ptau181 x rostral LC interaction term ß = -0.53, p = .005), such that as ptau181 increased (i.e., greater pathology), the strength of the positive relationship between rostral LC integrity and frontal perfusion decreased.

Conclusions:

LC integrity is linked to regional cortical perfusion in non-demented older adults, and these relationships are moderated by plasma AD biomarker concentrations. Variable directionality of the associations between the LC and frontal versus limbic perfusion, as well as the differential moderating effects of plasma AD biomarkers, may signify a compensatory mechanism and a shifting pattern of hyperemia in the presence of aggregating AD pathology. Linking LC integrity and cerebrovascular regulation may represent an important understudied pathway of dementia risk and may help to bridge competing theories of dementia progression in preclinical AD studies.

Type
Poster Session 01: Medical | Neurological Disorders | Neuropsychiatry | Psychopharmacology
Copyright
Copyright © INS. Published by Cambridge University Press, 2023