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:ObjectivesAbnormal tau, a hallmark Alzheimer's disease (AD) pathology, may appear in the locus coeruleus (LC) decades before AD symptom onset. Reports of subjective cognitive decline are also often present prior to formal diagnosis. Yet, the relationship between LC structural integrity and subjective cognitive decline has remained unexplored. Here, we aimed to explore these potential associations.MethodsWe examined 381 community-dwelling men (mean age = 67.58; SD = 2.62) in the Vietnam Era Twin Study of Aging who underwent LC-sensitive magnetic resonance imaging and completed the Everyday Cognition scale to measure subjective cognitive decline along with their selected informants. Mixed models examined the associations between rostral-middle and caudal LC integrity and subjective cognitive decline after adjusting for depressive symptoms, physical morbidities, and family. Models also adjusted for current objective cognitive performance and objective cognitive decline to explore attenuation.ResultsFor participant ratings, lower rostral-middle LC contrast to noise ratio (LCCNR) was associated with significantly greater subjective decline in memory, executive function, and visuospatial abilities. For informant ratings, lower rostral-middle LCCNR was associated with significantly greater subjective decline in memory only. Associations remained after adjusting for current objective cognition and objective cognitive decline in respective domains.ConclusionsLower rostral-middle LC integrity is associated with greater subjective cognitive decline. Although not explained by objective cognitive performance, such a relationship may explain increased AD risk in people with subjective cognitive decline as the LC is an important neural substrate important for higher order cognitive processing, attention, and arousal and one of the first sites of AD pathology.
| S-EPMC10272292 | biostudies-literature
Project description:Dementia as one of the most prevalent diseases urges for a better understanding of the central mechanisms responsible for clinical symptoms, and necessitates improvement of actual diagnostic capabilities. The brainstem nucleus locus coeruleus (LC) is a promising target for early diagnosis because of its early structural alterations and its relationship to the functional disturbances in the patients. In this study, we applied our improved method of localisation-based LC resting-state fMRI to investigate the differences in central sensory signal processing when comparing functional connectivity (fc) of a patient group with mild cognitive impairment (MCI, n = 28) and an age-matched healthy control group (n = 29). MCI and control participants could be differentiated in their Mini-Mental-State-Examination (MMSE) scores (p < .001) and LC intensity ratio (p = .010). In the fMRI, LC fc to anterior cingulate cortex (FDR p < .001) and left anterior insula (FDR p = .012) was elevated, and LC fc to right temporoparietal junction (rTPJ, FDR p = .012) and posterior cingulate cortex (PCC, FDR p = .021) was decreased in the patient group. Importantly, LC to rTPJ connectivity was also positively correlated to MMSE scores in MCI patients (p = .017). Furthermore, we found a hyperactivation of the left-insula salience network in the MCI patients. Our results and our proposed disease model shed new light on the functional pathogenesis of MCI by directing to attentional network disturbances, which could aid new therapeutic strategies and provide a marker for diagnosis and prediction of disease progression.
| S-EPMC9704796 | biostudies-literature
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.
| S-EPMC7894108 | biostudies-literature
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.
| S-EPMC8810611 | biostudies-literature
Project description:Late-life depression (LLD) is a risk factor for age-dependent cognitive deterioration. Norepinephrine-related degeneration in the locus coeruleus (LC) may explain this link. To examine the LC norepinephrine system in vivo, we acquired neuromelanin-sensitive MRI (NM-MRI) in a sample of 48 participants, including 25 with LLD (18 women, age 68.08 ± 5.41) and 23 never-depressed comparison participants (ND, 12 women, age 70 ± 8.02), matched on age and cognitive status. We employed a semi-automated procedure to segment the LC into three bilateral sections along its rostro-caudal extent, and calculated relative contrast as a proxy of integrity. Then, we examined associations between integrity and LLD diagnosis, age, and cognition, as measured via the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and the Delis-Kaplan Executive Function System (D-KEFS). We did not identify an effect of LLD diagnosis nor age on LC integrity, but exploratory canonical correlation analysis across the combined participant sample revealed a strong (Rc = 0.853) and significant multivariate relationship between integrity and cognition (Wilks' λ = 0.03, F(84, 162.44) = 1.66, p = <.01). The first and only significant variate explained 72.83% model variance, and linked better attention and delayed memory performance, faster processing speed, and lower verbal fluency performance with higher integrity in the right rostral but lower integrity in the left caudal LC. Our results complement prior evidence of LC involvement in cognition in healthy older adults, and extend this association to individuals with LLD.
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