Noradrenergic modulation of saccades in Parkinson’s disease DOI Creative Commons
Isabella F. Orlando, Frank H. Hezemans, Rong Ye

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Jan. 5, 2024

Abstract Noradrenaline is a powerful modulator of cognitive processes, including action-decisions underlying saccadic control. Changes in eye movements are common across neurodegenerative diseases ageing, Parkinson’s disease. With growing interest noradrenergic treatment potential for non-motor symptoms disease, the temporal precision oculomotor function advantageous to assess effects this modulation. Here we studied effect 40 mg atomoxetine, noradrenaline reuptake inhibitor, nineteen people with idiopathic disease using single dose, randomised double-blind crossover placebo-controlled design. Twenty-five healthy adult participants completed assessments provide normative data. Participants performed prosaccade and antisaccade tasks. The latency, velocity accuracy saccades, resting pupil diameter, were measured. Increased diameter on drug confirmed its expected locus coeruleus ascending arousal system. Atomoxetine improved key aspects saccade performance: latencies faster main sequence was normalised. These improvements accompanied by increased error rates drug. Together these findings suggest shift speed-accuracy trade-off visuo-motor decisions response treatment. Our results new evidence substantiate role modulation based known circuitry advance hypothesis that reflects at level coeruleus–superior colliculus pathway. Given related conditions, system can support assessment without limb-motor confounds task performance.

Language: Английский

Differential senolytic inhibition of normal versus Aβ-associated cholinesterases: implications in aging and Alzheimer’s disease DOI Creative Commons
Sultan Darvesh, Meghan K. Cash,

Katrina Forrestall

et al.

Aging, Journal Year: 2025, Volume and Issue: unknown

Published: March 29, 2025

Cellular senescence is a hallmark of aging and the age-related condition, Alzheimer's disease (AD). How contributes to cholinergic neuropathologic changes in AD remains uncertain. Furthermore, little known about relationship between cholinesterases (ChEs). Acetylcholinesterase (AChE) butyrylcholinesterase (BChE) are important neurotransmission, cell cycle regulation, amyloid-β (Aβ) pathology. Senolytic agents have shown therapeutic promise models. Therefore, we evaluated vitro silico activity senolytics, dasatinib (1), nintedanib (2), fisetin (3), quercetin (4), GW2580 (5), nootropic, meclofenoxate hydrochloride (6), toward AChE BChE. As ChEs associated with pathology altered biochemical properties, also 1-6 brain tissues. Enzyme kinetics showed 1, 3, 4, 6 inhibited both ChEs, while 2 5 only AChE. Histochemistry inhibition Aβ plaque-associated (1 2: ChEs; 5: BChE; 6: AChE), but not normal neural-associated ChEs. Modeling studies interacted same five binding locations some which may be allosteric sites. These exert their beneficial effects, part, by inhibiting provide new avenues for development next-generation inhibitors targeting pathology-associated

Language: Английский

Citations

0
The Role of α7-Nicotinic Acetylcholine Receptors in the Pathophysiology and Treatment of Parkinson’s Disease DOI Open Access
Eslam El Nebrisi, Yosra Lozon, Murat Öz

et al.

International Journal of Molecular Sciences, Journal Year: 2025, Volume and Issue: 26(7), P. 3210 - 3210

Published: March 30, 2025

The α7 nicotinic acetylcholine receptor (α7-nAChR) is a pivotal regulator of neurotransmission, neuroprotection, and immune modulation in the central nervous system. This review explores its structural functional attributes, highlighting therapeutic potential neurodegenerative disorders, particularly Parkinson’s disease (PD). α7-nAChRs mediate synaptic plasticity, modulate inflammatory responses, influence dopamine release, positioning them as promising pharmacological target. Positive allosteric modulators (PAMs) enhance α7-nAChR activity mainly by reducing desensitization, offering superior approach compared with direct agonists. Emerging preclinical studies suggest that activation mitigates dopaminergic neurodegeneration, improves L-dopa-induced dyskinesia, reduces neuroinflammation. Despite findings, clinical trials have yielded mixed results, necessitating further research into optimizing α7-targeted therapies. underscores significance PD pathophysiology highlights future directions for their translational neuroprotection symptomatic relief.

Language: Английский

Citations

0
Nature’s Remedies: Exploring the Potential of Propolis to Alleviate Non-Motor Manifestations of Parkinson’s Disease DOI Creative Commons
Kételin Vitória Matias, V Gonçalves,

Fulvio Alexandre Scorza

et al.

Molecules, Journal Year: 2025, Volume and Issue: 30(8), P. 1672 - 1672

Published: April 8, 2025

Parkinson’s disease (PD) is a complex neurodegenerative disorder with debilitating non-motor symptoms, including gastrointestinal dysfunction, cardiovascular abnormalities, mood and anxiety disorders, cognitive decline, sleep disturbances, respiratory pain. Despite their significant impact on quality of life, these symptoms are often inadequately addressed. Propolis natural bee-derived product, rich in bioactive compounds anti-inflammatory, antioxidant, immunomodulatory, neuroprotective properties, which holds potential PD due to its multitarget multipathway actions, addressing various underlying mechanisms symptom diseases. Preclinical clinical studies suggest that propolis may influence key pathological PD’s symptoms. Evidence points benefits improving cognition, health, alleviating sleep-related issues. Although research remains scarce, findings from related conditions ability associated This review underscores the underexplored therapeutic PD, drawing existing evidence advocating for further fully assess role patient outcomes.

Language: Английский

Citations

0
Normative modelling of molecular-based functional circuits captures clinical heterogeneity transdiagnostically in psychiatric patients DOI Creative Commons
Timothy Lawn, Alessio Giacomel, Daniel Martins

et al.

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

Published: June 5, 2024

Abstract Advanced methods such as REACT have allowed the integration of fMRI with brain’s receptor landscape, providing novel insights transcending multiscale organisation brain. Similarly, normative modelling has translational neuroscience to move beyond group-average differences and characterise deviations from health at an individual level. Here, we bring these together for first time. We used create functional networks enriched main modulatory, inhibitory, excitatory neurotransmitter systems generated models capture connectivity in patients schizophrenia, bipolar disorder (BPD), ADHD. Substantial overlap was seen symptomatology normality across groups, but could be mapped into a common space linking constellations symptoms through underlying neurobiology transdiagnostically. This work provides impetus developing biomarkers that molecular- systems-level dysfunction level, facilitating transition towards mechanistically targeted treatments.

Language: Английский

Citations

3
Locus coeruleus integrity and left frontoparietal connectivity provide resilience against attentional decline in preclinical alzheimer’s disease DOI Creative Commons

J. J. Pahl,

Prokopis C. Prokopiou, Elisenda Bueichekú

et al.

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

Citations

2
Noradrenergic modulation of saccades in Parkinson’s disease DOI Creative Commons
Isabella F. Orlando, Frank H. Hezemans, Rong Ye

et al.

Brain Communications, Journal Year: 2024, Volume and Issue: 6(5)

Published: Jan. 1, 2024

Noradrenaline is a powerful modulator of cognitive processes, including action decisions underlying saccadic control. Changes in eye movements are common across neurodegenerative diseases ageing, Parkinson's disease. With growing interest noradrenergic treatment potential for non-motor symptoms disease, the temporal precision oculomotor function advantageous to assess effects this modulation. Here, we studied effect 40 mg atomoxetine, noradrenaline reuptake inhibitor, 19 people with idiopathic disease using single dose, randomized double-blind, crossover, placebo-controlled design. Twenty-five healthy adult participants completed assessments provide normative data. Participants performed prosaccade and antisaccade tasks. The latency, velocity accuracy saccades, resting pupil diameter, were measured. Increased diameter on drug confirmed its expected locus coeruleus ascending arousal system. Atomoxetine altered key aspects saccade performance: latencies faster main sequence was normalized. These changes accompanied by increased error rates drug. Together, these findings suggest shift speed-accuracy trade-off visuomotor response treatment. Our results new evidence substantiate role modulation based known circuitry, advance hypothesis that reflects at level coeruleus-superior colliculus pathway. Given related conditions, system can support assessment without limb-motor confounds task performance.

Language: Английский

Citations

2
Cognition’s dependence on functional network integrity with age is conditional on structural network integrity DOI Creative Commons
Xulin Liu, Lorraine K. Tyler,

Cam‐CAN

et al.

Neurobiology of Aging, Journal Year: 2023, Volume and Issue: 129, P. 195 - 208

Published: June 6, 2023

Maintaining good cognitive function is crucial for well-being across the lifespan. We proposed that degree of maintenance determined by functional interactions within and between large-scale brain networks. Such connectivity can be represented white matter architecture structural networks shape intrinsic neuronal activity into integrated distributed explored how function-structure convergence, divergence from connectivity, contribute to adult Multivariate analyses were used investigate relationship convergence with multivariate profiles, respectively. Cognitive was increasingly dependent on as age increased. The dependency particularly strong high-order cortical subcortical results suggest network integrity sustains functions in old age, a brain's connectivity.

Language: Английский

Citations

6
Pharmacological and pupillary evidence for the noradrenergic contribution to reinforcement learning in Parkinson's disease DOI Creative Commons
Claire O’Callaghan, Frank H. Hezemans,

Naresh Subramaniam

et al.

Research Square (Research Square), Journal Year: 2024, Volume and Issue: unknown

Published: May 8, 2024

Abstract Noradrenaline plays an integral role in learning, by optimising behavioural strategies and facilitating choice execution. Testing the noradrenergic framework of learning context human diseases offers a test bed for current normative neuroscience theories may also indicate therapeutic potential. Parkinson's disease is often considered as model dopamine deficits, including dopamine’s reinforcement learning. However, function severely impaired disease, contributing to cognitive deficits. Using single dose noradrenaline reuptake inhibitor atomoxetine, people with (n=19, randomised double-blind placebo-controlled crossover design), we show improvements compared placebo. Computational modelling confirmed substantial shift decision noise parameter, indicative more exploitative choices. This response pattern closely resembled that age-matched controls (n=26) simulations optimal strategies. Pupillometry revealed increased baseline pupil diameter under which correlated improvements, heightened phasic pupillary feedback. Our findings confirm contribution doing so they challenge simple interpretation tonic-phasic locus coeruleus firing patterns based on pupillometry. Noradrenergic modulation potential treatment strategy symptoms related disorders.

Language: Английский

Citations

2
Dementia diagnostic and treatment services in the Western Pacific: challenges, preparedness and opportunities in the face of amyloid-targeting therapies DOI Creative Commons
Claire O’Callaghan, Johannes C. Michaelian, Yoko Aihara

et al.

The Lancet Regional Health - Western Pacific, Journal Year: 2024, Volume and Issue: 50, P. 101183 - 101183

Published: Sept. 1, 2024

Language: Английский

Citations

2
Sleep spindle architecture associated with distinct clinical phenotypes in older adults at risk for dementia DOI Creative Commons
Isabella F. Orlando, Claire O’Callaghan, Aaron Lam

et al.

Molecular Psychiatry, Journal Year: 2023, Volume and Issue: 29(2), P. 402 - 411

Published: Dec. 5, 2023

Sleep spindles are a hallmark of non-REM sleep and play fundamental role in memory consolidation. Alterations these emerging as sensitive biomarkers for neurodegenerative diseases ageing. Understanding the clinical presentations associated with spindle alterations may help to elucidate functional distinct electroencephalographic oscillations pathophysiology disorders. Here, we use data-driven approach examine sleep, default mode network connectivity phenotypes architecture older adults (mean age = 66 years). Participants were recruited from specialist clinic early diagnosis intervention cognitive decline, proportion showing mild deficits on neuropsychological testing. In sample 88 people who underwent assessment, overnight polysomnography resting-state fMRI, k-means cluster analysis was applied measures interest: fast density, duration amplitude. This resulted three clusters, characterised by preserved higher density longer (Cluster 1), (Clusters 2 3). These clusters further reduced 3) nocturnal hypoxemia, apnea Resting-state fMRI confirmed that related architecture, although directionality this relationship differed across groups. Together, results confirm diversity adults, clinically meaningful phenotypes, including function apnea. They suggest during awake state can be architecture; however, is highly dependent phenotype. Establishing relationships between neuroimaging features will advance our understanding bidirectional changes

Language: Английский

Citations

6