The locus coeruleus: In‐vivo characterization with advanced MRI methods and associations with memory in older adults at risk for Alzheimer’s disease

Abstract

AbstractBackgroundThe locus coeruleus (LC) is the brain’s main source of norepinephrine and plays a key role in modulating attention and memory processes. In Alzheimer’s disease (AD), the LC has been identified as an early site of tau accumulation and this tau pathology may spread via its connections to the transentorhinal cortex (TEC). Historically, this region has been nearly impossible to study in vivo. However, recent advances in structural magnetic resonance imaging (MRI) have provided opportunities to capture the integrity of LC neurons and their projections. We utilized a combination of neuromelanin‐sensitive and diffusion tensor MRI to examine LC integrity and its role in memory.Method31 older adults (26 cognitively normal; 5 MCI) underwent T1 fast spin echo and diffusion MRI scans as well as neuropsychological testing. Bilateral LC contrast ratios (CRs) were calculated as neuromelanin‐related signal intensities relative to a reference region. In a subset of participants (n=12; 10 cognitively normal, 2 MCI) LC‐TEC white matter pathways were reconstructed using probabilistic tractography in FSL and average fractional anisotropy (FA) was extracted. Logical Memory and CVLT‐2 were used to assess verbal learning and memory.ResultResults revealed lower bilateral LC‐CRs was associated with poorer performance on measures of story learning (LMI; r=0.425, p=.045) and word‐list recall (CVLT‐2 Short Delay Recall: r=.481, p=.006; CVLT‐2 Long Delay Recall: r=.375, p=.038). Tractography analyses indicated that higher FA of the left LC‐TEC tract was associated with poorer story learning (LM1: r=‐.651, p=.02), whereas higher FA of the right LC‐TEC tract was associated with poorer word‐list recall (CVLT‐2 Short Delay Recall: r=‐.599, p=.039; CVLT‐2 Short Delay Cued Recall, r=‐.705, p=.01).ConclusionPreliminary results indicate that neuromelanin and tractography MRI methods can be utilized for in vivo characterization of the human LC. Lower neuromelanin signal, but higher FA is associated with poorer memory performance in a sample of cognitively normal and MCI adults. Greater tau pathology may alter the LC signal and encroaching tau accumulation in the LC‐TEC pathway may initiate neuroinflammatory processes reflected by increased FA. Future work is needed to understand the temporal course and nature of LC changes across the aging‐MCI‐AD continuum.