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The Lancet. Neurology Jun 2024Sleep disorders are common in people with Parkinson's disease. These disorders, which increase in frequency throughout the course of the neurodegenerative disease and... (Review)
Review
Sleep disorders are common in people with Parkinson's disease. These disorders, which increase in frequency throughout the course of the neurodegenerative disease and impair quality of life, include insomnia, excessive daytime sleepiness, circadian disorders, obstructive sleep apnoea, restless legs syndrome, and rapid eye movement (REM) sleep behaviour disorder. The causes of these sleep disorders are complex and multifactorial, including the degeneration of the neural structures that modulate sleep, the detrimental effect of some medications on sleep, the parkinsonian symptoms that interfere with mobility and comfort in bed, and comorbidities that disrupt sleep quality and quantity. The clinical evaluation of sleep disorders include both subjective (eg, questionnaires or diaries) and objective (eg, actigraphy or video polysomnography) assessments. The management of patients with Parkinson's disease and a sleep disorder is challenging and should be individualised. Treatment can include education aiming at changes in behaviour (ie, sleep hygiene), cognitive behavioural therapy, continuous dopaminergic stimulation at night, and specific medications. REM sleep behaviour disorder can occur several years before the onset of parkinsonism, suggesting that the implementation of trials of neuroprotective therapies should focus on people with this sleep disorder.
PubMed: 38942041
DOI: 10.1016/S1474-4422(24)00170-4 -
Clinical Neurophysiology : Official... Jun 2024Parkinsonian motor symptoms are linked to pathologically increased beta oscillations in the basal ganglia. Studies with externalised deep brain stimulation electrodes...
OBJECTIVE
Parkinsonian motor symptoms are linked to pathologically increased beta oscillations in the basal ganglia. Studies with externalised deep brain stimulation electrodes showed that Parkinson patients were able to rapidly gain control over these pathological basal ganglia signals through neurofeedback. Studies with fully implanted deep brain stimulation systems duplicating these promising results are required to grant transferability to daily application.
METHODS
In this study, seven patients with idiopathic Parkinson's disease and one with familial Parkinson's disease were included. In a postoperative setting, beta oscillations from the subthalamic nucleus were recorded with a fully implanted deep brain stimulation system and converted to a real-time visual feedback signal. Participants were instructed to perform bidirectional neurofeedback tasks with the aim to modulate these oscillations.
RESULTS
While receiving regular medication and deep brain stimulation, participants were able to significantly improve their neurofeedback ability and achieved a significant decrease of subthalamic beta power (median reduction of 31% in the final neurofeedback block).
CONCLUSION
We could demonstrate that a fully implanted deep brain stimulation system can provide visual neurofeedback enabling patients with Parkinson's disease to rapidly control pathological subthalamic beta oscillations.
SIGNIFICANCE
Fully-implanted DBS electrode-guided neurofeedback is feasible and can now be explored over extended timespans.
PubMed: 38941959
DOI: 10.1016/j.clinph.2024.06.001 -
Bioorganic Chemistry Jun 2024Molecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new...
Molecular hybridization between structural fragments from the structures of curcumin (1) and resveratrol (2) was used as a designing tool to generate a new N-acyl-cinnamoyl-hydrazone hybrid molecular architecture. Twenty-eight new compounds were synthesized and evaluated for multifunctional activities related to Parkinson's disease (PD), including neuroprotection, antioxidant, metal chelating ability, and Keap1/Nrf2 pathway activation. Compounds 3b (PQM-161) and 3e (PQM-164) were highlighted for their significant antioxidant profile, acting directly as induced free radical stabilizers by DPPH and indirectly by modulating intracellular inhibition of t-BOOH-induced ROS formation in neuronal cells. The mechanism of action was determined as a result of Keap1/Nrf2 pathway activation by both compounds and confirmed by different experiments. Furthermore, compound 3e (PQM-164) exhibited a significant effect on the accumulation of α-synuclein and anti-inflammatory activity, leading to an expressive decrease in gene expression of iNOS, IL-1β, and TNF-α. Overall, these results highlighted compound 3e as a promising and innovative multifunctional drug prototype candidate for PD treatment.
PubMed: 38941700
DOI: 10.1016/j.bioorg.2024.107587 -
Brain : a Journal of Neurology Jun 2024The relative inability to produce effortful movements is the most specific motor sign of Parkinson's disease, which is primarily characterized by loss of dopaminergic...
The relative inability to produce effortful movements is the most specific motor sign of Parkinson's disease, which is primarily characterized by loss of dopaminergic terminals in the putamen. The motor motivation hypothesis suggests that this motor deficit may not reflect a deficiency in motor control per se, but a deficiency in cost-benefit considerations for motor effort. For the first time, we investigated the quantitative effect of dopamine depletion on the motivation of motor effort in Parkinson's disease. A total of 21 early-stage, unmedicated patients with Parkinson's disease and 26 healthy controls were included. An incentivized force task was used to capture the amount of effort participants were willing to invest for different monetary incentive levels and dopamine transporter depletion in the bilateral putamen was assessed. Our results demonstrate that patients with Parkinson's disease applied significantly less grip force than healthy controls, especially for low incentive levels. Congruously, decrease of motor effort with greater loss of putaminal dopaminergic terminals was most pronounced for low incentive levels. This signifies that putaminal dopamine is most critical to motor effort when the trade-off with the benefit is poor. Taken together, we provide direct evidence that the reduction of effortful movements in Parkinson's disease depends on motivation and that this effect is associated with putaminal dopaminergic degeneration.
PubMed: 38941444
DOI: 10.1093/brain/awae214 -
The Journal of Physical Chemistry. B Jun 2024In recent work we proposed that interdiction in the earliest contact-formation events along the folding pathway of key viral proteins could provide a novel avenue for... (Review)
Review
A Perspective on Interdicting in Protein Misfolding for Therapeutic Drug Design: Modulating the Formation of Nonlocal Contacts in α-Synuclein as a Strategy against Parkinson's Disease.
In recent work we proposed that interdiction in the earliest contact-formation events along the folding pathway of key viral proteins could provide a novel avenue for therapeutic drug design. In this Perspective we explore the potential applicability of the protein folding interdiction strategy in the realm of neurodegenerative diseases with a specific focus on synucleinopathies. In order to fulfill this goal we review the interdiction proposal and its practical challenges, and we present new results concerning design strategies for possible peptide drugs that could be useful in preventing α-synuclein aggregation.
PubMed: 38940731
DOI: 10.1021/acs.jpcb.3c07519 -
Applied and Environmental Microbiology Jun 2024Farnesol salvage, a two-step pathway converting farnesol to farnesyl pyrophosphate (FPP), occurs in bacteria, plants, and animals. This paper investigates the presence...
UNLABELLED
Farnesol salvage, a two-step pathway converting farnesol to farnesyl pyrophosphate (FPP), occurs in bacteria, plants, and animals. This paper investigates the presence of this pathway in fungi. Through bioinformatics, biochemistry, and physiological analyses, we demonstrate its absence in the yeasts and , suggesting a likely absence across fungi. We screened 1,053 fungal genomes, including 34 from , for potential homologs to four genes (, , , and ) known to accomplish farnesol/prenol salvage in other organisms. Additionally, we showed that H-farnesol was not converted to FPP or any other phosphorylated prenol, and exogenous farnesol was not metabolized within 90 minutes at any phase of growth and did not rescue cells from the toxic effects of atorvastatin, but it did elevate the levels of intracellular farnesol (F). All these experiments were conducted with . In sum, we found no evidence for farnesol salvage in fungi.
IMPORTANCE
The absence of farnesol salvage constitutes a major difference in the metabolic capabilities of fungi. In terms of fungal physiology, the lack of farnesol salvage pathways relates to how farnesol acts as a quorum-sensing molecule in and why farnesol should be investigated for use in combination with other known antifungal antibiotics. Its absence is essential for a model (K. W. Nickerson et al., Microbiol Mol Biol Rev 88:e00081-22, 2024), wherein protein farnesylation, protein chaperones, and the unfolded protein response are combined under the unifying umbrella of a cell's intracellular farnesol (F). In terms of human health, farnesol should have at least two different modes of action depending on whether those cells have farnesol salvage. Because animals have farnesol salvage, we can now see the importance of dietary prenols as well as the potential importance of farnesol in treating neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis.
PubMed: 38940563
DOI: 10.1128/aem.00874-24 -
Movement Disorders : Official Journal... Jun 2024
PubMed: 38940474
DOI: 10.1002/mds.29892 -
ELife Jun 2024Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these...
Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor comorbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and in a PD model, following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline (NA) reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both NA and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry.
Topics: Animals; Dopaminergic Neurons; Serotonergic Neurons; Dorsal Raphe Nucleus; Mice; Disease Models, Animal; Oxidopamine; Parkinsonian Disorders; Male; Mice, Inbred C57BL; Desipramine; Norepinephrine
PubMed: 38940422
DOI: 10.7554/eLife.90278 -
Epigenomics Jun 2024
PubMed: 38940212
DOI: 10.1080/17501911.2024.2365615 -
Journal of Integrative Neuroscience May 2024The objective of this study is to compare the differences in effective connectivity within the default mode network (DMN) subsystems between patients with Parkinson's...
OBJECTIVE
The objective of this study is to compare the differences in effective connectivity within the default mode network (DMN) subsystems between patients with Parkinson's disease with mild cognitive impairment (PD-MCI) and patients with Parkinson's disease with normal cognition (PD-CN). The mechanisms underlying DMN dysfunction in PD-MCI patients and its association with clinical cognitive function in PD-MCI are aimed to be investigated.
METHODS
The spectral dynamic causal model (spDCM) was employed to analyze the effective connectivity of functional magnetic resonance imaging (fMRI) data in the resting state for the DMN subsystems, which include the medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), left and right angular gyrus (LAG, RAG) in 23 PD-MCI and 22 PD-CN patients, respectively. The effective connectivity values of DMN subsystems in the two groups were statistically analyzed using a two-sample -test. The Spearman correlation analysis was used to test the correlation between the effective connectivity values of the subsystems with significant differences between the two groups and the clinical cognitive function (as measured by Montreal Cognitive Assessment Scale (MoCA) score).
RESULTS
Statistical analysis revealed significant differences in the effective connections of MPFC-LAG and LAG-PCC between the two patient groups (MPFC-LAG: t = -2.993, < 0.05; LAG-PCC: t = 2.174, < 0.05).
CONCLUSIONS
The study findings suggest that abnormal strength and direction of effective connections between DMN subsystems are found in PD-MCI patients.
Topics: Humans; Parkinson Disease; Cognitive Dysfunction; Male; Female; Default Mode Network; Magnetic Resonance Imaging; Aged; Middle Aged; Prefrontal Cortex; Gyrus Cinguli; Connectome; Nerve Net
PubMed: 38940086
DOI: 10.31083/j.jin2306110