Locus coeruleus hyperactivity in middle age may be associated with better cognitive performance

Abstract

AbstractBackgroundMeasuring the health of the locus coeruleus (LC), the brainstem site of the first cellular damage in Alzheimer’s Disease (AD) pathogenesis, is of particular interest for early diagnosis. In both rodents and humans (Elman 2017; Kelberman 2023; Malatt 2022; Weinshenker 2008), increased tonic firing rates have been noted in middle age. This occurs prior to the hypoactivity and reduced functional and structural connectivity associated with cognitive aging (Jacobs 2015; Kelberman 2022; Langley 2022; Prokopiou 2022) . Understanding the mechanism or function behind LC hyperactivity in middle age may be key to identifying individuals on pathological aging trajectories.MethodParticipants (29 younger, 18 middle‐aged, 24 older) performed a dual attention task in the scanner with multi‐echo fMRI and concurrent pupillometry. Cognition was assessed with NIH Toolbox Cognitive Battery (Fluid Composite) and sorted into high (>50th percentile) or low (<50th) categories. Age groupings were determined by a pupillary behavior data analysis.Results Pupil (Fig. 1): using a linear mixed effects model to predict the dynamic range‐normalized pupillary response area under the curve (AUC) from age group and trial type, there was a significant effect of age and significant age*trial type interactions. Middle‐aged adults had larger responses than other groups. Using a model to predict AUC from cognitive category and trial type, there was a significant interaction between cognitive category and trial type, with the high cognitive group having larger target and distractor responses. Blood‐Oxygen‐Level‐Dependent (BOLD) (Fig. 2): using a linear mixed effects model to predict LC BOLD response from age group and trial type, there was no significant effect of age but a significant age*trial type interaction. Middle‐aged adults had larger distractor responses and older adults had smaller target responses. Using a model to predict BOLD response from cognitive category and trial type, there was no significant effect of category, but there was a significant interaction between category and trial type, with the high cognitive group having larger target and distractor responses.ConclusionsElevated LC BOLD and pupillary responses to target trials in middle age are associated with better cognitive performance. LC hyperactivity may be adaptive in middle age.