Probing locus coeruleus functional network in healthy aging and its association with Alzheimer’s disease biomarkers using pupillometry

Alzheimer s Research & Therapy, Journal Year: 2025, Volume and Issue: 17(1)

Published: Feb. 27, 2025

Abstract Background Alzheimer’s disease (AD) is the leading cause of dementia, and early detection disease-associated changes allows interventions. The locus coeruleus (LC) has been reported to be first brain region develop tau pathology in AD. However, functional network LC both healthy aging AD largely unknown due technical difficulties associated with small size LC. In this study, we used measurement spontaneous pupil constriction/dilation as a surrogate for activity study during aging. Methods Thirty-seven younger thirty-nine older adults were included from Emory Healthy Brain Study underwent resting-state MRI while simultaneously tracking diameter. measurements diameter dynamics reference signals connectivity analysis. identified networks was then compared between participants. Correlations regions neuropsychological assessments cerebrospinal fluid (CSF) biomarkers also evaluated. Results A 20 clusters identified, including well functionally connected found positively correlate salience negatively central executive network. Functional decreased within memory, executive, visuospatial functioning. CSF total closely correlated Conclusions Pupil provide valuable insights into LC-related processes. While they are not solely influenced by activity, constrictor/dilatory shows promise non-invasive approach probe warrants further studies evaluate its value an biomarker

Language: Английский

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Revisiting the intersection of amyloid, pathologically modified tau and iron in Alzheimer’s disease from a ferroptosis perspective

Progress in Neurobiology, Journal Year: 2019, Volume and Issue: 184, P. 101716 - 101716

Published: Oct. 8, 2019

Language: Английский

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Noradrenergic modulation of rhythmic neural activity shapes selective attention

Trends in Cognitive Sciences, Journal Year: 2021, Volume and Issue: 26(1), P. 38 - 52

Published: Nov. 16, 2021

Language: Английский

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Network structure of the mouse brain connectome with voxel resolution

Science Advances, Journal Year: 2020, Volume and Issue: 6(51)

Published: Dec. 18, 2020

High-resolution mapping of the mouse axonal connectome reveals new foundational wiring principles mammalian brain.

Language: Английский

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The Role of the Locus Coeruleus in Pain and Associated Stress-Related Disorders

Biological Psychiatry, Journal Year: 2021, Volume and Issue: 91(9), P. 786 - 797

Published: Dec. 16, 2021

The locus coeruleus (LC)-noradrenergic system is the main source of noradrenaline in central nervous and involved intensively modulating pain stress-related disorders (e.g., major depressive disorder anxiety) their comorbidity. However, mechanisms involving LC that underlie these effects have not been fully elucidated, part owing to technical difficulties inherent exploring such a tiny nucleus. novel research tools are now available helped redefine system, moving away from traditional view as homogeneous structure exerts uniform influence on neural activity. Indeed, innovative techniques DREADDs (designer receptors exclusively activated by designer drugs) optogenetics demonstrated functional heterogeneity LC, magnetic resonance imaging applications combined with pupillometry opened way evaluate activity vivo. This review aims bring together data efferent LC-noradrenergic relation its comorbidity anxiodepressive disorders. Acute triggers robust stress response, producing spinal cord-mediated endogenous analgesia while promoting aversion, vigilance, threat detection through ascending efferents. this protective biological fails chronic pain, produces facilitation, anxiety, increased aversive memory, behavioral despair, acting at medulla, prefrontal cortex, amygdala levels. Thus, activation/deactivation specific projections contributes different outcomes shift acute pain.

Language: Английский

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Norepinephrine metabolite DOPEGAL activates AEP and pathological Tau aggregation in locus coeruleus

Journal of Clinical Investigation, Journal Year: 2019, Volume and Issue: 130(1), P. 422 - 437

Published: Dec. 2, 2019

Aberrant Tau inclusions in the locus coeruleus (LC) are earliest detectable Alzheimer's disease-like (AD-like) neuropathology human brain. However, why LC neurons selectively vulnerable to developing early pathology and degenerating later disease whether might seed stereotypical spread of rest brain remain unclear. Here, we show that 3,4-dihydroxyphenylglycolaldehyde, which is produced exclusively noradrenergic by monoamine oxidase A metabolism norepinephrine, activated asparagine endopeptidase cleaved at residue N368 into aggregation- propagation-prone forms, thus leading degeneration pathology. Activation endopeptidase-cleaved aggregation vitro intact cells was triggered resulting neurotoxicity propagation forebrain. Thus, our findings reveal norepinephrine cleavage represent specific molecular mechanism underlying selective vulnerability AD.

Language: Английский

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Locus coeruleus integrity is related to tau burden and memory loss in autosomal-dominant Alzheimer's disease

Neurobiology of Aging, Journal Year: 2021, Volume and Issue: 112, P. 39 - 54

Published: Dec. 8, 2021

Abnormally phosphorylated tau, an indicator of Alzheimer's disease, accumulates in the first decades life locus coeruleus (LC), brain's main noradrenaline supply. However, technical challenges in-vivo assessments have impeded research into role LC disease. We studied participants with or known to be at-risk for mutations genes causing autosomal-dominant disease (ADAD) early onset, providing a unique window pathogenesis largely disentangled from age-related factors. Using high-resolution MRI and tau PET, we found lower rostral integrity symptomatic participants. was associated individual differences burden memory decline. Post-mortem analyses separate set carriers same mutation confirmed substantial neuronal loss LC. Our findings link degeneration Alzheimer's, highlight noradrenergic system this neurodegenerative

Language: Английский

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Alzheimer’s disease pathology: pathways between central norepinephrine activity, memory, and neuropsychiatric symptoms

Molecular Psychiatry, Journal Year: 2019, Volume and Issue: 26(3), P. 897 - 906

Published: May 28, 2019

Language: Английский

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Locus Coeruleus Phasic, But Not Tonic, Activation Initiates Global Remapping in a Familiar Environment

Journal of Neuroscience, Journal Year: 2018, Volume and Issue: 39(3), P. 445 - 455

Published: Nov. 26, 2018

Locus coeruleus (LC) neurons, the source of hippocampal norepinephrine (NE), are activated by novelty and changes in environmental contingencies. Based on role monoamines reconfiguring invertebrate networks, data from mammalian systems, a network reset hypothesis for effects LC activation has been proposed. We used cellular compartmental analysis temporal FISH technique based distribution immediate early genes to examine effect inactivation, regional maps male rats, when activity was manipulated just before placement second familiar (A/A) and/or novel environment (A/B). found that bilateral phasic, but not tonic, A/A condition, whereas silencing with clonidine A/B condition blocked map emerged dentate gyrus, proximal distal CA1, CA3c. However, CA3a CA3b encoded environment. These results support phasic responses generating sequences during memory encoding and, potentially, updating. The experiments suggest environments may be recognized as different gyrus CA1 without input. functional distinction between tonic argues these parameters critical determining changes. consistent hippocampus activating internal representations encode experiential episodes input is this role. SIGNIFICANCE STATEMENT Burst broadly projecting signaling system locus initiates new throughout despite unchanged external environments. Tonic does alter same condition. This suggests differences neuromodulator function. Silencing prevented appearance Instead, were expressed subset areas, another “being two places at once” independent regions within hippocampus. strengthen view states major determinants brain's construction representations.

Language: Английский

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Locus coeruleus integrity and the effect of atomoxetine on response inhibition in Parkinson’s disease

Brain, Journal Year: 2021, Volume and Issue: 144(8), P. 2513 - 2526

Published: March 29, 2021

Cognitive decline is a common feature of Parkinson's disease, and many these cognitive deficits fail to respond 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 noradrenergic reuptake inhibitor atomoxetine can improve some patients with but there considerable heterogeneity treatment response. Accurately predicting who would benefit from therapies this neurotransmitter remains critical goal, order design necessary clinical trials stratified patient selection establish potential atomoxetine. Here, we test hypothesis that integrity coeruleus explains variation improvement following In double-blind placebo-controlled randomized crossover design, 19 disease completed acute psychopharmacological challenge 40 mg oral or placebo. A stop-signal task was used measure inhibition, reaction times obtained through hierarchical Bayesian estimation ex-Gaussian race model. Twenty-six control subjects same without undergoing drug manipulation. separate session, controls underwent ultra-high field 7 T imaging neuromelanin-sensitive magnetization transfer sequence. The principal result improved those lower integrity. This context general impairment as on placebo had longer compared controls. We also found caudal portion showed largest neuromelanin signal decrease Our results highlight link between disease. Furthermore, they demonstrate importance baseline state determining suggest offers marker capacity could be stratify therapy ultimately inform personalized approaches.

Language: Английский

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