Locus coeruleus signal intensity and emotion regulation in agitation in Alzheimer’s disease DOI Creative Commons
Kathy Liu, Matthew J. Betts,

Dorothea Hämmerer

et al.

Brain Communications, Journal Year: 2024, Volume and Issue: 7(1)

Published: Dec. 17, 2024

Abstract Hyperphosphorylated tau accumulation is seen in the noradrenergic locus coeruleus from earliest stages of Alzheimer’s disease onwards and has been associated with symptoms agitation. It hypothesized that compensatory coeruleus-noradrenaline system overactivity impaired emotion regulation could underlie agitation propensity, but to our knowledge this not previously investigated. A better understanding neurobiological underpinnings would help development targeted prevention treatment strategies. Using a sample individuals amnestic mild cognitive impairment probable dementia German Center for Neurodegenerative Diseases (DZNE)-Longitudinal Cognitive Impairment Dementia (DELCODE) study cohort (N = 309, aged 67–96 years, 51% female), we assessed cross-sectional relationships between latent factor representing functional integrity an affect-related executive network point prevalence severity scores. In subsample MRI imaging data 37, 68–93 49% also investigated preliminary associations contrast ratios (a measure structural integrity, whole or divided into rostral, middle, caudal thirds) individual scores measures. Regression models controlled effects age clinical and, including resting-state connectivity variables, grey matter volume education years. Agitation showed positive relationship (and negative corresponding measure) network. Locus were positively (but only rostral third, N 13) negatively Resting-state medial prefrontal cortex region left amygdala was related ratios. These findings implicate involvement dysregulation support presence potential processes. At neural level, there may be dissociation mechanisms underlying risk per se symptom severity. Further studies are needed replicate extend these findings, incorporating longitudinal designs, measures autonomic function non-linear modelling approaches explore causal context-dependent across stages.

Language: Английский

Loss of excitatory inputs and decreased tonic and evoked activity of locus coeruleus neurons in aged P301S mice DOI Creative Commons
Anthony M. Downs,

Gracianne Kmiec,

Christina M. Catavero

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 17, 2025

Abstract Tau pathology in the locus coeruleus (LC) is associated with several neurodegenerative conditions including Alzheimer’s disease and frontotemporal dementia. Phosphorylated tau accumulates LC results inflammation, synaptic loss, eventually cell death as progresses. Loss of neurons noradrenergic innervation thought to contribute symptoms cognitive decline later disease. While loss degeneration has been well studied, less known about changes physiology at advanced stages that precedes neurodegeneration. In this study, we investigated ex vivo electrophysiological properties male female mice from P301S mouse model tauopathy 9 months age, a time-point when significant accumulation, death, impairments are observed. We found reduction excitatory inputs post-synaptic current kinetics P301S. There was also decrease spontaneous discharge an increase AP threshold both sexes. Finally, observed excitability rheobase mice. Despite activity slice, did not identify differences total tissue norepinephrine (NE) or NE metabolites prefrontal cortex hippocampus. Together these findings demonstrate reductions late accumulation. However, compensatory mechanisms may maintain normal levels projection regions vivo.

Language: Английский

Citations

0
Locus coeruleus tau validates and informs high-resolution MRI in aging and at earliest Alzheimer’s pathology stages DOI Creative Commons

Alexander T. Hary,

Sarabjit Chadha,

Nathaniel D. Mercaldo

et al.

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: Feb. 28, 2025

The locus coeruleus (LC) has been identified as a site that develops phosphorylated tau pathology earlier than cerebral cortex. We present data using high-resolution postmortem MRI and validated histopathology in controls the earliest Braak (BB) stages (BBI-BBII) LC. ex vivo provides 3D volume (quantitative), while histology reveals specificity severity burden (semi-quantitative). mapped our highly regionally specific LC onto reconstructions of same samples used (n = 11). noted significant structural subatrophy between BB 0 II (30.0% smaller volumes, p 0.0381), trend which primarily affected rostral-most (49.2% average volume, 0.0381). show on both neighboring dorsal raphe caudal (DRc), were assessed at multiple rostrocaudal levels with sensitive spatial matrices. observed accumulation I (37.6% increase, < 0.0001), may reflect change prior to presumptive cognitive impairment III. Tau was most severe middle portion (11.3% greater compared rostral LC, 0.0289) when including gradient DRc (58.2% decrease DRc, suggesting selective regional vulnerabilities nuclei. Our study represents rigorous approach investigating pathology, having sections per sublevel measure whole without missing slices histological only approach. Taken together, findings provide novel demonstrate occurring during preclinical AD stages, alongside will serve valuable references for imaging.

Language: Английский

Citations

0
Loss of excitatory inputs and decreased tonic and evoked activity of locus coeruleus neurons in aged P301S mice DOI Creative Commons
Anthony M. Downs,

Gracianne Kmiec,

Christina M. Catavero

et al.

Neurobiology of Disease, Journal Year: 2025, Volume and Issue: unknown, P. 106883 - 106883

Published: March 1, 2025

Tau pathology in the locus coeruleus (LC) is associated with several neurodegenerative conditions including Alzheimer's disease and frontotemporal dementia. Phosphorylated tau accumulates LC results inflammation, synaptic loss, eventually cell death as progresses. Loss of neurons noradrenergic innervation thought to contribute symptoms cognitive decline later disease. While loss degeneration has been well studied, less known about changes physiology at advanced stages that precedes neurodegeneration. In this study, we investigated ex vivo electrophysiological properties male female mice from P301S mouse model tauopathy 9 months age, a time-point when significant accumulation, death, impairments are observed. We found reduction excitatory inputs post-synaptic current kinetics P301S. There was also decrease spontaneous discharge an increase AP threshold both sexes. Finally, observed excitability rheobase mice. Despite activity slices, did not identify differences total tissue norepinephrine (NE) or NE metabolites prefrontal cortex hippocampus. Together these findings demonstrate reductions late accumulation. However, compensatory mechanisms may maintain normal levels projection regions vivo.

Language: Английский

Citations

0
Neuromelanin-sensitive MRI for mechanistic research and biomarker development in psychiatry DOI
Kenneth Wengler, Paula Trujillo, Clifford Cassidy

et al.

Neuropsychopharmacology, Journal Year: 2024, Volume and Issue: 50(1), P. 137 - 152

Published: Aug. 19, 2024

Language: Английский

Citations

3
Locus coeruleus signal intensity and emotion regulation in agitation in Alzheimer’s disease DOI Creative Commons
Kathy Liu, Matthew J. Betts,

Dorothea Hämmerer

et al.

Brain Communications, Journal Year: 2024, Volume and Issue: 7(1)

Published: Dec. 17, 2024

Abstract Hyperphosphorylated tau accumulation is seen in the noradrenergic locus coeruleus from earliest stages of Alzheimer’s disease onwards and has been associated with symptoms agitation. It hypothesized that compensatory coeruleus-noradrenaline system overactivity impaired emotion regulation could underlie agitation propensity, but to our knowledge this not previously investigated. A better understanding neurobiological underpinnings would help development targeted prevention treatment strategies. Using a sample individuals amnestic mild cognitive impairment probable dementia German Center for Neurodegenerative Diseases (DZNE)-Longitudinal Cognitive Impairment Dementia (DELCODE) study cohort (N = 309, aged 67–96 years, 51% female), we assessed cross-sectional relationships between latent factor representing functional integrity an affect-related executive network point prevalence severity scores. In subsample MRI imaging data 37, 68–93 49% also investigated preliminary associations contrast ratios (a measure structural integrity, whole or divided into rostral, middle, caudal thirds) individual scores measures. Regression models controlled effects age clinical and, including resting-state connectivity variables, grey matter volume education years. Agitation showed positive relationship (and negative corresponding measure) network. Locus were positively (but only rostral third, N 13) negatively Resting-state medial prefrontal cortex region left amygdala was related ratios. These findings implicate involvement dysregulation support presence potential processes. At neural level, there may be dissociation mechanisms underlying risk per se symptom severity. Further studies are needed replicate extend these findings, incorporating longitudinal designs, measures autonomic function non-linear modelling approaches explore causal context-dependent across stages.

Language: Английский

Citations

0