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The locus coeruleus (LC), the origin of noradrenergic modulation of cognitive and behavioral function, may play an important role healthy ageing and in neurodegenerative conditions. We investigated the functional significance of age-related differences in mean normalized LC signal intensity values (LC-CR) in magnetization-transfer (MT) images from the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) cohort - an open-access, population-based dataset. Using structural equation modelling, we tested the pre-registered hypothesis that putatively noradrenergic (NA)-dependent functions would be more strongly associated with LC-CR in older versus younger adults. A unidimensional model (within which LC-CR related to a single factor representing all cognitive and behavioral measures) was a better fit with the data than the a priori two-factor model (within which LC-CR related to separate NA-dependent and NA-independent factors). Our findings support the concept that age-related reduction of LC structural integrity is associated with impaired cognitive and behavioral function.

BackgroundThe Locus Coeruleus (LC) may play an important role in the pathogenesis of Alzheimer’s disease (AD). Neuromelanin-sensitive Magnetic Resonance Imaging (MRI) permits the visualization of the LC in vivo. Previously, we proposed an automatic, deep learning-based approach to segmenting the LC in a cohort of 82 healthy young and older adults (82 HC; Dünnwald et al. 2021). Here, we applied the same automatic segmentation method to baseline data from the DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study comprising 42 healthy elderly adults (HEA), 18 participants with subjective cognitive decline (SCD), 25 participants with mild cognitive impairment (MCI) and 11 participants with AD.MethodThe LC was visualized using 3T T1-weighted Fast Low Angle Shot (FLASH) MRI acquired at 0.75mm isotropic resolution. Prior to processing, the data was sinc-interpolated to a resolution of 0.375mm³. The automated segmentation pipeline comprises two consecutive Convolutional Neural Networks (CNNs), which perform LC centerpoint regression and segmentation (see Fig. 1). The networks were trained only on the 82 HC dataset using a cross-validation scheme. We applied the networks to the unseen DELCODE data and assessed their performance with respect to manually delineated masks from two trained raters using Dice similarity coefficient (DSC) and intraclass correlation coefficient (ICC) of contrast ratios (CRs).ResultIn HEA, the networks showed similar agreement (DSC, ICC) compared to that observed between two independent raters. Using DSC, automated segmentation of SCD, MCI and AD groups showed less agreement than in the HEA group with 66.67%, 64.86%, 59.77% and 67.06% on average respectively (see Fig. 2). However, good reliability between automated and manually delineated masks for all groups using LC MRI contrast was observed (see Tab. 1) indicating that CRs may be relatively robust wrt. mask differences (see Fig. 3 and 4 for qualitative comparisons).ConclusionThe results demonstrate good reliability between manual and automatically generated LC segmentations with respect to LC MRI contrast using networks trained on healthy older adults. Additional fine-tuning of the networks to account for the variance in AD should be explored as a means to further improve reliability.

Older adults struggle in dealing with changeable and uncertain environments across several cognitive domains. This has been attributed to difficulties in forming adequate task representations that help navigate uncertain environments. Here, we investigate how, in older adults, inadequate task representations impact on model-based reversal learning. We combined computational modeling and pupillometry during a novel model-based reversal learning task, which allowed us to isolate the relevance of task representations at feedback evaluation. We find that older adults overestimate the changeability of task states and consequently are less able to converge on unequivocal task representations through learning. Pupillometric measures and behavioral data show that these unreliable task representations in older adults manifest as a reduced ability to focus on feedback that is relevant for updating task representations, and as a reduced metacognitive awareness in the accuracy of their actions. Instead, the data suggested older adults' choice behavior was more consistent with a guidance by uninformative feedback properties such as outcome valence. Our study highlights that an inability to form adequate task representations may be a crucial factor underlying older adults' impaired model-based inference. (VLID)3132503

The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, may play an important role in neuropsychiatric disorders including Parkinson's disease and Alzheimer's disease. The pattern of age-related change of the LC across the life span is unclear. We obtained normalized, mean LC signal intensity values, that is, contrast ratios (CRs), from magnetization transfer–weighted images to investigate the relationship between LC CR and age in cognitively normal healthy adults (N = 605, age range 18–88 years). Study participants were part of the Cambridge Centre for Ageing and Neuroscience—an open-access, population-based data set. We found a quadratic relationship between LC CR and age, the peak occurring around 60 years, with no differences between males and females. Subregional analyses revealed that age-related decline in LC CR was confined to the rostral portion of the LC. Older adults showed greater variance in overall LC CR than younger adults, and the functional and clinical implications of these observed age-related differences require further investigation. Visualization of the LC in this study may inform how future scanning parameters can be optimized, and provides insight into how LC integrity changes across the life span., Highlights • A quadratic relationship between locus coeruleus signal intensity and age was found. • No differences between males and females were observed. • Older adults had higher variance than younger adults. • The functional and clinical implications of these changes require further research.

The locus coeruleus (LC), the major origin of noradrenergic modulation of the central nervous system, may play an important role in neuropsychiatric disorders including Parkinson's disease and Alzheimer's disease. The pattern of age-related change of the LC across the life span is unclear. We obtained normalized, mean LC signal intensity values, that is, contrast ratios (CRs), from magnetization transfer-weighted images to investigate the relationship between LC CR and age in cognitively normal healthy adults (N = 605, age range 18-88 years). Study participants were part of the Cambridge Centre for Ageing and Neuroscience-an open-access, population-based data set. We found a quadratic relationship between LC CR and age, the peak occurring around 60 years, with no differences between males and females. Subregional analyses revealed that age-related decline in LC CR was confined to the rostral portion of the LC. Older adults showed greater variance in overall LC CR than younger adults, and the functional and clinical implications of these observed age-related differences require further investigation. Visualization of the LC in this study may inform how future scanning parameters can be optimized, and provides insight into how LC integrity changes across the life span.

Maximizing gains during probabilistic reinforcement learning requires the updating of choice - outcome expectations at the time when the feedback about a specific choice or action is given. Extant theories and evidence suggest that dopaminergic modulation plays a crucial role in reinforcement learning and the updating of choice - outcome expectations. Furthermore, recently a positive component of the event-related potential about 200 ms (P2) after feedback has been suggested to reflect such updating. The efficacy of dopaminergic modulation changes across the life span. However, to date investigations of age-related differences in feedback-related P2 during reinforcement learning are still scarce. The present study thus aims to investigate whether individual differences in the feedback-related P2 would be associated with polymorphic variations in a dopamine relevant gene PPP1R1B (also known as DARPP-32) and whether the genetic effect may differ between age groups. We observed larger P2 amplitudes in individuals carrying the genotype associated with higher dopamine receptor efficacy, i.e., a allele homozygotes of a single nucleotide polymorphism (rs907094) of the PPP1R1B gene. Moreover, this effect was more pronounced in children and older adults in comparison to adolescents and younger adults. Together, our findings indicate that polymorphic variations in a dopamine relevant gene are associated with individual differences in brain-evoked potentials of outcome updating and hint at the possibility that genotype effects on neurocognitive phenotypes may vary as a function of brain maturation and aging.