Importance of the locus coeruleus-norepinephrine system in sleep-wake regulation: Implications for aging and Alzheimer's disease

Sleep Medicine Reviews, Journal Year: 2022, Volume and Issue: 62, P. 101592 - 101592

Published: Jan. 21, 2022

Five decades ago, seminal studies positioned the brainstem locus coeruleus (LC) norepinephrine (NE) system as a key substrate for regulation of wakefulness and sleep, this picture has recently been elaborated thanks to methodological advances in precise investigation experimental modulation LC structure functions. This review presents discusses findings that support major role LC-NE at different levels sleep-wake organization, ranging from its involvement overall architecture cycle associations with sleep microstructure, while accounting intricate neuroanatomy surrounding LC. Given particular position held by being intersection dysregulation initial pathophysiological processes Alzheimer's disease (AD), we conclude examining emerging opportunities investigate mediated relationships between alteration AD human aging. We further propose several research perspectives could promising target identification at-risk individuals preclinical stages AD, development novel preventive interventions.

Language: Английский

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Neurobehavioral meaning of pupil size

Neuron, Journal Year: 2024, Volume and Issue: 112(20), P. 3381 - 3395

Published: June 25, 2024

Pupil size is a widely used metric of brain state. It one the few signals originating from that can be readily monitored with low-cost devices in basic science, clinical, and home settings. is, therefore, important to investigate generate well-defined theories related specific interpretations this metric. What exactly does it tell us about brain? Pupils constrict response light dilate during darkness, but also controls pupil irrespective luminosity. fluctuations resulting ongoing "brain states" are as arousal, what pupil-linked arousal how should interpreted neural, cognitive, computational terms? Here, we discuss some recent findings these issues. We identify open questions propose answer them through combination tasks, neurocomputational models, neurophysiological probing interconnected loops causes consequences size.

Language: Английский

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Microstructural integrity of the locus coeruleus and its tracts reflect noradrenergic degeneration in Alzheimer’s disease and Parkinson’s disease

Translational Neurodegeneration, Journal Year: 2024, Volume and Issue: 13(1)

Published: Feb. 9, 2024

Abstract Background Degeneration of the locus coeruleus (LC) noradrenergic system contributes to clinical symptoms in Alzheimer’s disease (AD) and Parkinson’s (PD). Diffusion magnetic resonance imaging (MRI) has potential evaluate integrity LC system. The aim current study was determine whether diffusion MRI-measured its tracts are sensitive degeneration AD PD. Methods Post-mortem situ T1-weighted multi-shell MRI performed for 9 AD, 14 PD, 8 control brain donors. Fractional anisotropy (FA) mean diffusivity were derived from LC, between anterior cingulate cortex, dorsolateral prefrontal cortex (DLPFC), primary motor (M1) or hippocampus. Brain tissue sections cortical regions obtained immunostained dopamine-beta hydroxylase (DBH) quantify cell density fiber load. Group comparisons correlations outcome measures using linear regression partial correlations. Results PD cases showed loss cells fibers. In increased DBH + immunoreactivity DLPFC compared controls, while reduced M1 controls. Higher FA within found which correlated with fibers LC. Increased LC-DLPFC tract combined group, whereas LC-M1 neuronal group. alterations not immunoreactivity. Conclusions MRI-detected associated local rather than changes cortex.

Language: Английский

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MicroRNAs as Potential Orchestrators of Alzheimer's Disease-Related Pathologies: Insights on Current Status and Future Possibilities

Frontiers in Aging Neuroscience, Journal Year: 2021, Volume and Issue: 13

Published: Oct. 12, 2021

Alzheimer's disease (AD) is a progressive and deleterious neurodegenerative disease, strongly affecting the cognitive functions memory of seniors worldwide. Around 58% affected patients live in low middle-income countries, with estimates increasing deaths caused by AD coming decade. multifactor pathology. Mitochondrial function declines brain currently emerging as hallmark this disease. It has been considered one intracellular processes severely compromised AD. Many mitochondrial parameters decline already during aging; efficiency for energy production, reactive oxygen species (ROS) metabolism de novo synthesis pyrimidines, to reach an extensive functional failure, concomitant onset conditions. Besides its impact on functions, characterized loss synapses, extracellular amyloid plaques composed amyloid-β peptide (Aβ), aggregates hyperphosphorylated Tau protein, accompanied drastic sleep disorders, sensory alterations pain sensitization. Unfortunately, till date, effective management AD-related disorders early, non-invasive diagnostic markers are yet be found. MicroRNAs (miRNAs) small non-coding nucleic acids that regulate key signaling pathway(s) various About 70% experimentally detectable miRNAs expressed where they neurite outgrowth, dendritic spine morphology, synaptic plasticity. Increasing studies suggest intimately involved specific signals formation. This pivotal considering crucial molecules studied dysfunctions increasingly acknowledged contributor via deregulating genes pathogenesis. Moreover, have proved control sensitization circadian clock system affects process. Interestingly, differential expression miRNA panels implies their potential biomarkers. In review, we will present updated analysis role regulating pathologies. We discuss current challenges against wider use future promising capabilities therapeutic means better

Language: Английский

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Spatiotemporal characterization of cellular tau pathology in the human locus coeruleus–pericoerulear complex by three-dimensional imaging

Acta Neuropathologica, Journal Year: 2022, Volume and Issue: 144(4), P. 651 - 676

Published: Aug. 30, 2022

Abstract Tau pathology of the noradrenergic locus coeruleus (LC) is a hallmark several age-related neurodegenerative disorders, including Alzheimer’s disease. However, comprehensive neuropathological examination LC difficult due to its small size and rod-like shape. To investigate cytoarchitecture tau cytoskeletal in relation possible propagation patterns disease-associated an unprecedented large-scale three-dimensional view, we utilized volume immunostaining optical clearing technology combined with light sheet fluorescence microscopy. We examined AT8 + pathological LC/pericoerulear region 20 brains from Braak neurofibrillary tangle (NFT) stage 0–6. demonstrate intriguing morphological complexity heterogeneity cellular structures LC, representing various intracellular stages NFT maturation their diverse transition forms. describe novel morphologies neuronal such as cells fine filamentous somatic protrusions or disintegrating soma. show that gradual dendritic atrophy first sign degeneration tangle-bearing neurons, even preceding axonal lesions. Interestingly, irrespective stage, more advanced dorsal preferentially projects vulnerable forebrain regions disease, like hippocampus neocortical areas, compared ventral projecting cerebellum medulla. Moreover, already precortical 0 3D analysis reveals clustering tendency dendro-dendritic close appositions long axons NFT-bearing join ascending bundle after leaving well processes neurons target 4th ventricle wall. Our study suggests unique cytoarchitecture, comprised densely packed dendritically extensively interconnected network projections, makes human be ideal anatomical template for early accumulation trans-neuronal spreading hyperphosphorylated tau.

Language: Английский

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Neuromelanin-sensitive MRI as a promising biomarker of catecholamine function

Brain, Journal Year: 2023, Volume and Issue: unknown

Published: Sept. 5, 2023

Abstract Disruptions to dopamine and noradrenergic neurotransmission are noted in several neurodegenerative psychiatric disorders. Neuromelanin-sensitive (NM)-MRI offers a non-invasive approach visualize quantify the structural functional integrity of substantia nigra locus coeruleus. This method may aid diagnosis quantification longitudinal changes disease could provide stratification tool for predicting treatment success pharmacological interventions targeting dopaminergic systems. Given growing clinical interest NM-MRI, understanding contrast mechanisms that generate this signal is crucial appropriate interpretation NM-MRI outcomes continued development quantitative MRI biomarkers assess severity progression. To date, most studies associate measurements content neuromelanin pigment and/or density neuromelanin-containing neurons, while recent suggest main source not presence but high-water neurons. In review, we consider biological physical basis discuss wide range interpretations NM-MRI. We describe different acquisition image processing approaches how these methods be improved standardized facilitate large-scale multisite translation into use. review potential applications neurological disorders promise as biomarker disease, finally, current limitations need addressed before technique can utilized translated practice offer suggestions future research.

Language: Английский

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The gene expression landscape of the human locus coeruleus revealed by single-nucleus and spatially-resolved transcriptomics

eLife, Journal Year: 2024, Volume and Issue: 12

Published: Jan. 24, 2024

Norepinephrine (NE) neurons in the locus coeruleus (LC) make long-range projections throughout central nervous system, playing critical roles arousal and mood, as well various components of cognition including attention, learning, memory. The LC-NE system is also implicated multiple neurological neuropsychiatric disorders. Importantly, are highly sensitive to degeneration both Alzheimer’s Parkinson’s disease. Despite clinical importance brain region prominent role a variety behavioral functions, detailed molecular characterization LC lacking. Here, we used combination spatially-resolved transcriptomics single-nucleus RNA-sequencing characterize landscape transcriptomic profile human brain. We provide freely accessible resource these data web-accessible downloadable formats.

Language: Английский

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Racial Discrimination, Neural Connectivity, and Epigenetic Aging Among Black Women

JAMA Network Open, Journal Year: 2024, Volume and Issue: 7(6), P. e2416588 - e2416588

Published: June 13, 2024

Racial discrimination increases the risk of adverse brain health outcomes, potentially via neuroplastic changes in emotion processing networks. The involvement deep regions (brainstem and midbrain) these responses is unknown. Potential associations racial with alterations functional connectivity accelerated epigenetic aging, a process that substantially vulnerability to problems, are also

Language: Английский

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Ageing-Related Neurodegeneration and Cognitive Decline

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(7), P. 4065 - 4065

Published: April 5, 2024

Neuropathological assessment was conducted on 1630 subjects, representing 5% of all the deceased that had been sent to morgue Uppsala University Hospital during a 15-year-long period. Among 1610 were ≥41 years age (range 41 102 years). Overall, hyperphosphorylated (HP) τ observed in brains 98% and amyloid β-protein (Aβ) 64%. The most common alteration Alzheimer disease neuropathologic change (ADNC) (56%), followed by primary age-related tauopathy (PART) 26% subjects. In 16% HPτ limited locus coeruleus. 14 subjects (<1%), no altered proteins observed. 3 only Aβ observed, 17, distribution other than seen ADNC/PART. transactive DNA-binding protein 43 (TDP43) associated with limbic-predominant TDP encephalopathy (LATE) 565 (35%) α-synuclein (αS) pathology, i.e., Lewy body (LBD) or multi system atrophy (MSA) 21% A total 39% ADNC, 59% PART, 81% coeruleus lacked concomitant pathologies, LATE-NC LBD-NC. Of 293 (18% subjects) dementia, exhibited high intermediate level ADNC. 84% individuals various degrees alterations observed; MIXED-NC cause dementia. PART 10 dementia (3%), tangle-predominant No vascular NC (VNC), but 17 severe VNC might have contributed cognitive decline. Age-related tau astrogliopathy (ARTAG) 37% 53% those

Language: Английский

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Neuromodulatory subcortical nucleus integrity is associated with white matter microstructure, tauopathy and APOE status

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: June 3, 2024

Abstract The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are earliest sites of tauopathy in Alzheimer’s disease (AD). They project broadly throughout brain’s white matter. We investigated relationship between IdC microstructure and whole-brain matter to better understand early neuropathological changes AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for integrity related 1) neurite density, 2) orientation dispersion tracts known be affected Pattern 2 was associated CSF concentration phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both more strongly than non-carriers. variation is reflected matter, particularly AD-affected tracts, highlighting an mechanism pathological development.

Language: Английский

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