MRI-assessed locus coeruleus integrity is heritable and associated with multiple cognitive domains, mild cognitive impairment, and daytime dysfunction.
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ABSTRACT: Introduction
The locus coeruleus (LC) undergoes extensive neurodegeneration in early Alzheimer's disease (AD). The LC is implicated in regulating the sleep-wake cycle, modulating cognitive function, and AD progression.Methods
Participants were 481 men (ages 62 to 71.7) from the Vietnam Era Twin Study of Aging. LC structural integrity was indexed by neuromelanin-sensitive magnetic resonance imaging (MRI) contrast-to-noise ratio (LCCNR ). We examined LCCNR , cognition, amnestic mild cognitive impairment (aMCI), and daytime dysfunction.Results
Heritability of LCCNR was .48. Participants with aMCI showed greater daytime dysfunction. Lower LCCNR was associated with poorer episodic memory, general verbal fluency, semantic fluency, and processing speed, as well as increased odds of aMCI and greater daytime dysfunction.Discussion
Reduced LC integrity is associated with widespread differences across cognitive domains, daytime sleep-related dysfunction, and risk for aMCI. These findings in late-middle-aged adults highlight the potential of MRI-based measures of LC integrity in early identification of AD risk.
SUBMITTER: Elman JA
PROVIDER: S-EPMC8248066 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundThe brainstem locus coeruleus (LC) constitutes the intersection of the initial pathophysiological processes of Alzheimer's disease (AD) and sleep-wake dysregulation in the preclinical stages of the disease. However, the interplay between in vivo assessment of LC degeneration and AD-related sleep alterations remains unknown. Here, we sought to investigate whether MRI-assessed LC structural integrity relates to subjective sleep-wake measures in the context of AD plasma biomarkers, in cognitively unimpaired older individuals.MethodsSeventy-two cognitively unimpaired older individuals aged 50-85 years (mean age = 65.2 ± 8.2 years, 37 women, 21 APOE ε4 carriers) underwent high-resolution imaging of the LC at 7 Tesla, and LC structural integrity was quantified using a data-driven approach. Reports on habitual sleep quality and nocturnal awakenings were collected using sleep questionnaires. Plasma levels of total tau, p-tau181, Aβ40, and Aβ42 were measured using single-molecule array technology.ResultsIntensity-based cluster analyses indicated two distinct LC segments, with one covering the middle-to-caudal LC and displaying lower intensity compared to the middle-to-rostral cluster (t70 = -5.12, p < 0.0001). After correction for age, sex, depression, and APOE status, lower MRI signal intensity within the middle-to-caudal LC was associated with a higher number of self-reported nocturnal awakenings (F1,63 = 6.73, pFDR = 0.03). Furthermore, this association was mostly evident in individuals with elevated levels of total tau in the plasma (F1,61 = 4.26, p = 0.04).ConclusionOur findings provide in vivo evidence that worse LC structural integrity is associated with more frequent nocturnal awakenings in the context of neurodegeneration, in cognitively unimpaired older individuals. These results support the critical role of the LC for sleep-wake regulation in the preclinical stages of AD and hold promises for the identification of at-risk populations for preventive interventions.
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Project description:Mild cognitive impairment (MCI) is a common global health problem. Recently, the potential of mind-body intervention for MCI has drawn the interest of investigators. This study aims to comparatively explore the modulation effect of Baduanjin, a popular mind-body exercise, and physical exercise on the cognitive function, as well as the norepinephrine and dopamine systems using the resting state functional connectivity (rsFC) method in patients with MCI. 69 patients were randomized to the Baduanjin, brisk walking, or healthy education control group for 6 months. The Montreal Cognitive Assessment (MoCA) and magnetic resonance imaging (MRI) scans were applied at baseline and at the end of the experiment. Results showed that (1) compared to the brisk walking, the Baduanjin significantly increased MoCA scores; (2) Baduanjin significantly increased the right locus coeruleus (LC) and left ventral tegmental area (VTA) rsFC with the right insula and right amygdala compared to that of the control group; and the right anterior cingulate cortex (ACC) compared to that of the brisk walking group; (3) the increased right LC-right insula rsFC and right LC-right ACC rsFC were significantly associated with the corresponding MoCA score after 6-months of intervention; (4) both exercise groups experienced an increased effective connectivity from the right ACC to the left VTA compared to the control group; and (5) Baduanjin group experienced an increase in gray matter volume in the right ACC compared to the control group. Our results suggest that Baduanjin can significantly modulate intrinsic functional connectivity and the influence of the norepinephrine (LC) and dopamine (VTA) systems. These findings may shed light on the mechanisms of mind-body intervention and aid the development of new treatments for MCI.
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Project description:For decades, research into memory decline in human cognitive ageing has focused on neocortical regions, the hippocampus and dopaminergic neuromodulation. Recent findings indicate that the locus coeruleus (LC) and noradrenergic neuromodulation may also play an important role in shaping memory development in later life. However, technical challenges in quantification of LC integrity have hindered the study of LC-cognition associations in humans. Using high-resolution, neuromelanin-sensitive magnetic resonance imaging, we found that individual differences in learning and memory were positively associated with LC integrity across a variety of memory tasks in both younger (n?=?66) and older adults (n?=?228). Moreover, we observed functionally relevant age differences confined to rostral LC. Older adults with a more 'youth-like' rostral LC also showed higher memory performance. These findings link non-invasive, in vivo indices of LC integrity to memory in ageing and highlight the role of the LC norepinephrine system in the decline of cognition.
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Project description:BackgroundThe locus coeruleus (LC) is the major noradrenergic source in the central nervous system. Structural alterations in the LC contribute to the pathophysiology of different neuropsychiatric disorders, which may increase to a variable extent the likelihood of developing neurodegenerative conditions. The characterization of such alterations may therefore help to predict progression to neurodegenerative disorders. Despite the LC cannot be visualized with conventional magnetic resonance imaging (MRI), specific MRI sequences have been developed to infer its structural integrity.MethodsWe quantified LC signal Contrast Ratios (LCCRs) in late-life major depressive disorder (MDD) (n = 37, 9 with comorbid aMCI), amnestic Mild Cognitive Impairment (aMCI) (n = 21, without comorbid MDD), and healthy controls (HCs) (n = 31), and also assessed the putative modulatory effects of comorbidities and other clinical variables.ResultsLCCRs were lower in MDD compared to aMCI and HCs. While no effects of aMCI comorbidity were observed, lower LCCRs were specifically observed in patients taking serotonin/norepinephrine reuptake inhibitors (SNRIs).ConclusionOur results do not support the hypothesis that lower LCCRs characterize the different clinical groups that may eventually develop a neurodegenerative disorder. Conversely, our results were specifically observed in patients with late-life MDD taking SNRIs. Further research with larger samples is warranted to ascertain whether medication or particular clinical features of patients taking SNRIs are associated with changes in LC neurons.
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Project description:There is growing evidence that neuronal integrity of the noradrenergic locus coeruleus (LC) is important for later-life cognition. Less understood is how LC integrity relates to brain correlates of cognition, such as brain structure. Here, we examined the relationship between cortical thickness and a measure reflecting LC integrity in 229 older and 67 younger adults. Using a magnetic resonance imaging sequence which yields high signal intensity in the LC, we assessed the contrast between signal intensity of the LC and that of neighboring pontine reference tissue. The FreeSurfer software suite was used to quantify cortical thickness. LC contrast was positively related to cortical thickness in older adults, and this association was prominent in parietal, frontal, and occipital regions. Brain regions where LC contrast was related to cortical thickness include portions of the frontoparietal network which have been implicated in noradrenergically modulated cognitive functions. These findings provide novel evidence for a link between LC structure and cortical brain structure in later adulthood.
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Project description:Cognitive decline is a common feature of Parkinson's disease, and many of these cognitive deficits fail to respond to dopaminergic therapy. Therefore, targeting other neuromodulatory systems represents an important therapeutic strategy. Among these, the locus coeruleus-noradrenaline system has been extensively implicated in response inhibition deficits. Restoring noradrenaline levels using the noradrenergic reuptake inhibitor atomoxetine can improve response inhibition in some patients with Parkinson's disease, but there is considerable heterogeneity in treatment response. Accurately predicting the patients who would benefit from therapies targeting this neurotransmitter system remains a critical goal, in order to design the necessary clinical trials with stratified patient selection to establish the therapeutic potential of atomoxetine. Here, we test the hypothesis that integrity of the noradrenergic locus coeruleus explains the variation in improvement of response inhibition following atomoxetine. In a double-blind placebo-controlled randomized crossover design, 19 patients with Parkinson's disease completed an acute psychopharmacological challenge with 40 mg of oral atomoxetine or placebo. A stop-signal task was used to measure response inhibition, with stop-signal reaction times obtained through hierarchical Bayesian estimation of an ex-Gaussian race model. Twenty-six control subjects completed the same task without undergoing the drug manipulation. In a separate session, patients and controls underwent ultra-high field 7 T imaging of the locus coeruleus using a neuromelanin-sensitive magnetization transfer sequence. The principal result was that atomoxetine improved stop-signal reaction times in those patients with lower locus coeruleus integrity. This was in the context of a general impairment in response inhibition, as patients on placebo had longer stop-signal reaction times compared to controls. We also found that the caudal portion of the locus coeruleus showed the largest neuromelanin signal decrease in the patients compared to controls. Our results highlight a link between the integrity of the noradrenergic locus coeruleus and response inhibition in patients with Parkinson's disease. Furthermore, they demonstrate the importance of baseline noradrenergic state in determining the response to atomoxetine. We suggest that locus coeruleus neuromelanin imaging offers a marker of noradrenergic capacity that could be used to stratify patients in trials of noradrenergic therapy and to ultimately inform personalized treatment approaches.
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Project description:PurposeThe locus coeruleus (LC) is implicated as an early site of protein pathogenesis in Alzheimer's disease (AD). Tau pathology is hypothesized to propagate in a prion-like manner along the LC-transentorhinal cortex (TEC) white matter (WM) pathway, leading to atrophy of the entorhinal cortex and adjacent cortical regions in a progressive and stereotypical manner. However, WM damage along the LC-TEC pathway may be an earlier observable change that can improve detection of preclinical AD.Theory and methodsDiffusion-weighted MRI (dMRI) allows reconstruction of WM pathways in vivo, offering promising potential to examine this pathway and enhance our understanding of neural mechanisms underlying the preclinical phase of AD. However, standard dMRI analysis tools have generally been unable to reliably reconstruct this pathway. We apply a novel method, geometric-optics based entropy spectrum pathways (GO-ESP) and produce a new measure of connectivity: the equilibrium probability (EP).ResultsWe demonstrated reliable reconstruction of LC-TEC pathways in 50 cognitively normal older adults and showed a negative association between LC-TEC EP and cerebrospinal fluid tau. Using Human Connectome Project data, we demonstrated replicability of the method across acquisition schemes and scanners. Finally, we compared our findings with the only other existing LC-TEC tractography template, and replicated their pathway as well as investigated the source of these discrepant findings.ConclusionsAD-related tau pathology may be detectable within GO-ESP-identified LC-TEC pathways. Furthermore, there may be multiple possible routes from LC to TEC, raising important questions for future research on the LC-TEC connectome and its role in AD pathogenesis.
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Project description:The locus coeruleus (LC) is involved in numerous crucial brain functions and several disorders like depression and Alzheimer's disease. Recently, the LC resting-state functional connectivity (rs-fc) has been investigated in functional MRI by calculating the blood oxygen level-dependent (BOLD) response extracted using Montreal Neurological Institute (MNI) space masks. To corroborate these results, we aimed to investigate the LC rs-fc at native space by improving the identification of the LC location using a neuromelanin sensitive sequence. Twenty-five healthy male participants (mean age 24.8 ± 4.2) were examined in a Siemens MAGNETOM Prisma 3 T MRT applying a neuromelanin sensitive T1TSE sequence and functional MRI. We compared the rs-fc of LC calculated by a MNI-based approach with extraction of the BOLD signal at the exact individual location of the LC after applying CompCor and field map correction. As a measure of advance, a marked increase of regional homogeneity (ReHo) of time series within LC could be achieved with the subject-specific approach. Furthermore, the methods differed in the rs-fc to the right temporoparietal junction, which showed stronger connectivity to the LC in the MNI-based method. Nevertheless, both methods comparably revealed LC rs-fc to multiple brain regions including ACC, bilateral thalamus, and cerebellum. Our results are relevant for further research assessing and interpreting LC function, especially in patient populations examined at 3 T MRI.
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Project description:The locus coeruleus is a small brainstem nucleus which contains neuromelanin cells and is involved in a number of cognitive functions such as attention, arousal and stress, as well as several neurological and psychiatric disorders. Locus coeruleus imaging in vivo is generally performed using a T1-weighted turbo spin echo MRI sequence at 3 Tesla (T). However, imaging at high magnetic field strength can increase the signal-to-noise ratio and offers the possibility of imaging at higher spatial resolution. Therefore, in the present study we explored the possibility of visualizing the locus coeruleus at 7T. To this end, twelve healthy volunteers participated in three scanning sessions: two with 3T MRI and one with 7T MRI. The volumes of the first 3T session were used to segment the locus coeruleus, whereas the volumes of the second 3T and the 7T session were used to quantify the contrast of the locus coeruleus with several reference regions across eight different structural sequences. The results indicate that several of the 7T sequences provide detectable contrast between the locus coeruleus and surrounding tissue. Of the tested sequences, a T1-weighted sequence with spectral presaturation inversion recovery (SPIR) seems the most promising method for visualizing the locus coeruleus at ultra-high field MRI. While there is insufficient evidence to prefer the 7T SPIR sequence over the 3T TSE sequence, the isotropic voxels at 7T are an important advantage when visualizing small structures such as the locus coeruleus.
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Project description:The locus coeruleus (LC) in the pons is the major source of noradrenaline (NA) in the brain. Two modes of LC firing have been associated with distinct cognitive states: changes in tonic rates of firing are correlated with global levels of arousal and behavioural flexibility, whilst phasic LC responses are evoked by salient stimuli. Here, we unify these two modes of firing by modelling the response of the LC as a correlate of a prediction error when inferring states for action planning under Active Inference (AI). We simulate a classic Go/No-go reward learning task and a three-arm 'explore/exploit' task and show that, if LC activity is considered to reflect the magnitude of high level 'state-action' prediction errors, then both tonic and phasic modes of firing are emergent features of belief updating. We also demonstrate that when contingencies change, AI agents can update their internal models more quickly by feeding back this state-action prediction error-reflected in LC firing and noradrenaline release-to optimise learning rate, enabling large adjustments over short timescales. We propose that such prediction errors are mediated by cortico-LC connections, whilst ascending input from LC to cortex modulates belief updating in anterior cingulate cortex (ACC). In short, we characterise the LC/ NA system within a general theory of brain function. In doing so, we show that contrasting, behaviour-dependent firing patterns are an emergent property of the LC that translates state-action prediction errors into an optimal balance between plasticity and stability.
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