Locus coeruleus integrity and left frontoparietal connectivity provide resilience against attentional decline in preclinical alzheimer’s disease

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: May 31, 2024

Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline dementia. Recent neuroimaging and pharmacological studies left frontoparietal network functional connectivity (LFPN-FC) confers resilience beta-amyloid (Aβ)-related preclinical sporadic autosomal dominant Alzheimer's disease (AD), as well LC-related changes. Given LFPN LC play important roles attention, attention deficits have been observed early process, we examined whether LFPN-FC structural health attenuate attentional context of AD pathology. 142 participants from Harvard Aging Brain Study who underwent resting-state MRI, imaging, PiB(Aβ)-PET, up to 5 years follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated integrity (measured average five continuous voxels with highest intensities images) or Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal mixed effect analyses associations between DSST (i) two-way interactions baseline (or LFPN-FC) PiB (ii) three-way interaction integrity, LFPN-FC, PiB. Baseline age, sex, education covariates. At baseline, lower but not was related worse performance. Longitudinally, a faster decline, especially > 10.38 CL. Lower steeper on independent elevated levels (> 46 CL), higher an attenuated DSST, despite presence integrity. Our findings demonstrate can provide Aβ-related decline. However, when Aβ accumulates LC's resources may be depleted, functioning cortical target regions LC, such additional sustain AD. These results critical insights into correlates contributing individual variability risk versus

Language: Английский

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Implication of tau propagation on neurodegeneration in Alzheimer’s disease

Frontiers in Neuroscience, Journal Year: 2023, Volume and Issue: 17

Published: July 7, 2023

Propagation of tau fibrils correlate closely with neurodegeneration and memory deficits seen during the progression Alzheimer’s disease (AD). Although it is not well-established what drives or attenuates spreading, new studies on human brain using positron emission tomography (PET) have shed light how phosphorylation, genetic factors, initial epicenter accumulation influence propagation throughout brain. Here, we review latest PET performed across entire AD continuum looking at impact amyloid load pathology. We also explore effects structural, functional, proximity connectivity spreading in a stereotypical manner patients. Since can be quite heterogenous between individuals, then consider speed pattern are influenced by starting localization connected regions. provide an overview some variants that were shown to accelerate slow down spreading. Finally, discuss phosphorylation certain epitopes affect fibrils. pathology early event pathogenesis one best predictors impairments, understanding process which spread from region another could pave way novel therapeutic avenues efficient stages disease, before induces permanent damage severe loss.

Language: Английский

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Damage to the Locus Coeruleus Alters the Expression of Key Proteins in Limbic Neurodegeneration

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3159 - 3159

Published: March 9, 2024

The present investigation was designed based on the evidence that, in neurodegenerative disorders, such as Alzheimer’s dementia (AD) and Parkinson’s disease (PD), damage to locus coeruleus (LC) arising norepinephrine (NE) axons (LC-NE) is documented hypothesized foster onset progression of neurodegeneration within target regions. Specifically, experiments were assess whether selective LC-NE may alter key proteins involved specific limbic regions, hippocampus piriform cortex, compared with dorsal striatum. To achieve this, a loss induced by neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) C57 Black mice, assessed NE dopamine-beta-hydroxylase In these experimental conditions, amount alpha-synuclein (alpha-syn) protein levels increased along alpha-syn expressing neurons cortex. Similar findings obtained concerning phospho-Tau immunoblotting. contrast, decrease inducible HSP70-expressing sequestosome (p62)-expressing cells, at immunoblotting, reported. data provide further understand why AD engagement during PD.

Language: Английский

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Early and selective localization of tau filaments to glutamatergic subcellular domains within the human anterodorsal thalamus

Acta Neuropathologica, Journal Year: 2024, Volume and Issue: 147(1)

Published: June 1, 2024

Abstract Widespread cortical accumulation of misfolded pathological tau proteins (ptau) in the form paired helical filaments is a major hallmark Alzheimer’s disease. Subcellular localization ptau at various stages disease progression likely to be informative cellular mechanisms involving its spread. Here, we found that density within several distinct rostral thalamic nuclei post-mortem human tissue ( n = 25 cases) increased with stage, anterodorsal nucleus (ADn) consistently being most affected. In ADn, ptau-positive elements were present already pre-cortical (Braak 0) stage. Tau pathology preferentially affected calretinin-expressing subpopulation glutamatergic neurons ADn. At subcellular level, detected immunoreactivity ADn cell bodies, dendrites, and specialized type presynaptic terminal expresses vesicular glutamate transporter 2 (vGLUT2) originates from mammillary body. The ptau-containing terminals displayed signs degeneration, including endosomal/lysosomal organelles. contrast, corticothalamic axon lacked ptau. data demonstrate involvement specific population onset presence subcortical supports hypotheses about transsynaptic spread selectively affecting axonal pathways.

Language: Английский

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Microstructural assessment of the locus coeruleus–entorhinal cortex pathway and association with ATN markers in cognitive impairment

Alzheimer s & Dementia, Journal Year: 2025, Volume and Issue: 21(4)

Published: April 1, 2025

Abstract INTRODUCTION Whether Alzheimer's disease pathology involves white matter pathways connecting the locus coeruleus (LC) to entorhinal cortex (EC) is unclear. In this cross‐sectional observational study, we investigated microstructural integrity of LC–EC pathway in relation amyloid, tau, and neurodegeneration (ATN) biomarkers along cognitive spectrum from normal cognition dementia. METHODS One hundred twenty‐four participants underwent clinical assessment, diffusion‐weighted imaging, structural magnetic resonance imaging (N), amyloid (A), tau (T) positron emission tomography. Diffusivity indices were assessed tract using a probabilistic atlas, linear models used assess associations with ATN markers cognition. RESULTS Differences parameters observed Braak stage > I versus 0 ( p < 0.020), N+ N− 0.001), cognitively impaired unimpaired 0.019). mean diffusivity was associated Mini‐Mental State Examination score even after accounting for = 0.015). DISCUSSION Our results suggest that provides complementary information over explaining impairment. Highlights Locus coeruleus–entorhinal (LC–EC) microstructure especially markers. more sensitive than tracts commonly affected disease. measures provide biomarkers.

Language: Английский

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Tyrosinase-induced neuromelanin accumulation triggers rapid dysregulation and degeneration of the mouse locus coeruleus

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: March 10, 2023

Abstract The locus coeruleus (LC), the major source of norepinephrine (NE) in brain, is an early site pathology both Alzheimer’s disease (AD) and Parkinson’s (PD), it undergoes catastrophic degeneration later disorders. Dysregulation LC thought to contribute prodromal symptoms AD PD such as anxiety sleep disturbances, while frank LC-NE loss promotes cognitive decline. However, mechanisms responsible for its selective vulnerability are unknown. among only structures brain that produces appreciable amounts neuromelanin (NM), a dark cytoplasmic pigment. It has been proposed NM initially plays protective role by sequestering toxic catecholamine metabolites heavy metals, but may become harmful during aging overwhelms cellular machinery released neurodegeneration. Rodents do not naturally produce NM, limiting study causal relationships between pathology. Adapting viral-mediated approach expression human tyrosinase, enzyme peripheral melanin production, we successfully promoted pigmentation mouse neurons recapitulates key ultrastructural features endogenous found primates. Pigment results neuron hyperactivity, reduced tissue NE levels, transcriptional changes, novelty-induced phenotypes 1-week post-injection. By 6-10 weeks, accumulation associated with severe neurodegeneration microglial engulfment pigment granules, anxiety-like behavior abated. These reminiscent dysfunction cell death PD, validating this model studying consequences relates neurodegenerative disease.

Language: Английский

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Atrophy links lower novelty‐related locus coeruleus connectivity to cognitive decline in preclinical AD

Alzheimer s & Dementia, Journal Year: 2024, Volume and Issue: 20(6), P. 3958 - 3971

Published: April 27, 2024

Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated contribution of LC-MTL functional connectivity (FC

Language: Английский

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Spatial characterization of tangle-bearing neurons and ghost tangles in the human inferior temporal gyrus with three-dimensional imaging

Brain Communications, Journal Year: 2023, Volume and Issue: 5(3)

Published: Jan. 1, 2023

Abstract Studies of post-mortem human tissue provide insight into pathological processes, but are inherently limited by practical considerations that limit the scale at which can be examined, and obvious issue reflects only one time point in a continuous disease process. We approached this problem adapting new clearance techniques to an entire cortical area brain, allows surveillance hundreds thousands neurons throughout depth thickness. This approach detection ‘rare’ events may difficult detect standard 5 micrometre-thick paraffin sections. For example, it is well established neurofibrillary tangles begin within neuron, ultimately, least some instances, persist brain even after neuron has died. These referred as ‘ghost tangles’, term appropriately implies their ‘difficult see’ ephemeral qualities. set out find ghost example power clearance/image analysis rare events, learn what happens end-point tangle’s life history. were able identify 8103 tau tangles, 132 465 299 640 nuclei samples from three subjects with severe Alzheimer’s (Braak V–VI) 4 200 447 462 715 no significant pathology 0–I). Among these data, we located 57 makes them 0.7% total observed. found more likely layers 3 (49/57), select few scattered across other 1, 2, 6. ability such large enough quantities statistically test distribution exemplifies how clearing used powerful tool for studying selective vulnerability or resilience regions.

Language: Английский

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Effective connectivity of the locus coeruleus in patients with late-life Major Depressive Disorder or mild cognitive impairment

Spanish Journal of Psychiatry and Mental Health, Journal Year: 2024, Volume and Issue: unknown

Published: March 1, 2024

Introduction: We compared effective connectivity from the locus coeruleus (LC) during resting-state in patients with late-life Major Depressive Disorder (MDD), individuals amnestic Mild Cognitive Impairment (aMCI), and Healthy Controls (HCs). Participants: 23 MDD, 22 aMCI, 28 HCs. Material methods: Participants were assessed two time-points, 2 years apart. They underwent a functional magnetic resonance imaging high-resolution anatomical acquisition, as well clinical assessments. Functional data analyzed dynamic causal modeling, parametric empirical Bayes model was used to map between 7 distinct nodes: 4 3 regions displaying gray matter decreases two-year follow-up period. Results: Longitudinal analysis of structural identified three clusters larger over-time volume reduction (MDD + aMCI vs. HCs): right precuneus, visual association parahippocampal cortices. showed decreased left rostral caudal portions LC, while LC cortex increased. In there decline across seeds, increased seed over time. Connectivity alterations cortical involved cross-hemisphere increases same-hemisphere decreases. Conclusions: Our discoveries provide insight into changes MDD also shedding light on mechanisms potentially contributing onset neurodegenerative disorders.

Language: Английский

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Cardiovascular risk of dementia is associated with brain–behaviour changes in cognitively healthy, middle-aged individuals

Neurobiology of Aging, Journal Year: 2024, Volume and Issue: 144, P. 78 - 92

Published: Sept. 13, 2024

Language: Английский

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