Effects of melatonin prolonged-release on both sleep and motor symptoms in Parkinson's disease: a preliminary evidence

background sleep-related symptoms, especially insomnia, are frequently reported by patients with parkinson's disease (PD) and can markedly affect motor symptoms and impair patients' quality of life. melatonin has been shown to improve sleep in PD patients. this pilot study aimed at evaluating the effects of a 3-month treatment with 2 mg melatonin prolonged-release (PR) on sleep and motor disability in PD patients. materials and methods twelve PD patients under stable antiparkinsonian treatment were enrolled in the study. before treatment (T0), motor dysfunction was assessed with unified parkinson's disease rating scale (UPDRS-III) and sleep architecture with polysomnography. subjective sleep quality was also assessed through pittsburgh sleep quality Index (PSQI) and daytime somnolence with epworth sleepiness Scale (ESS). patients then started melatonin PR and all measures were repeated at the end of treatment after 3 months (T1). results sleep latency significantly decreased from T0 to T1, but no other significant differences were found in PSG parameters. melatonin PR treatment significantly reduced the ESS scores from T0 to T1, while the PSQI scores presented a trend of improvement from T0 to T1. motor dysfunction was not improved by melatonin PR, although there was a trend in decreasing UPDRS-III. both clinical global improvement and patient clinical global impression documented an improvement in insomnia symptoms at T1. conclusions these findings suggest that melatonin may improve sleep symptoms in PD patients, although further evidence is needed in larger controlled studies to confirm these results and explore the possible direct and indirect influence of sleep improvement on motor dysfunction

Differences in CSF Biomarkers Profile of Patients with Parkinson's Disease Treated with MAO-B Inhibitors in Add-On

Monoamine oxidase type B inhibitors (iMAO-Bs) are a class of largely-used antiparkinsonian agents that, based on experimental evidence, are supposed to exert different degrees of neuroprotection in Parkinson's disease (PD). However, clinical proofs on this regard are very scarce. Since cerebrospinal fluid (CSF) reflects pathological changes occurring at brain level, we examined the neurodegeneration-related CSF biomarkers profile of PD patients under chronic treatment with different iMAO-Bs to identify biochemical signatures suggestive for differential neurobiological effects.Thirty-five PD patients under chronic treatment with different iMAO-Bs in add-on to levodopa were enrolled and grouped in rasagiline (n = 13), selegiline (n = 9), safinamide (n = 13). Respective standard clinical scores for motor and non-motor disturbances, together with CSF biomarkers of neurodegeneration levels (amyloid- β -42, amyloid- β -40, total and 181-phosphorylated tau, and lactate) were collected and compared among the three iMAO-B groups.No significant clinical differences emerged among the iMAO-B groups. CSF levels of tau proteins and lactate were instead different, resulting higher in patients under selegiline than in those under rasagiline and safinamide.Although preliminary and limited, this study indicates that patients under different iMAO-Bs may present distinct profiles of CSF neurodegeneration-related biomarkers, probably because of the differential neurobiological effects of the drugs. Larger studies are now needed to confirm and extend these initial observations

In vivo mapping of brainstem nuclei functional connectivity disruption in Alzheimer's disease

We assessed here functional connectivity changes in the locus coeruleus (LC) and ventral tegmental area (VTA) of patients with Alzheimer's disease (AD). We recruited 169 patients with either AD or amnestic mild cognitive impairment due to AD and 37 elderly controls who underwent cognitive and neuropsychiatric assessments and resting-state functional magnetic resonance imaging at 3T. Connectivity was assessed between LC and VTA and the rest of the brain. In amnestic mild cognitive impairment patients, VTA disconnection was predominant with parietal regions, while in AD patients, it involved the posterior nodes of the default-mode network. We also looked at the association between neuropsychiatric symptoms (assessed by the neuropsychiatric inventory) and VTA connectivity. Symptoms such as agitation, irritability, and disinhibition were associated with VTA connectivity with the parahippocampal gyrus and cerebellar vermis, while sleep and eating disorders were associated with VTA connectivity to the striatum and the insular cortex. This suggests a contribution of VTA degeneration to AD pathophysiology and to the occurrence of neuropsychiatric symptoms. We did not find evidence of LC disconnection, but this could be explained by the size of this nucleus, which makes it difficult to isolate. These results are consistent with animal findings and have potential implications for AD prognosis and therapies

Non-motor symptoms burden in motor-fluctuating patients with Parkinson's disease may be alleviated by safinamide: the VALE-SAFI study

parkinson's disease (PD) is characterized by motor symptoms often experienced in concomitance with non-motor symptoms (NMS), such as depression, apathy, pain, sleep disorders, and urinary dysfunction. the present study aimed to explore the effect of safinamide treatment on NMS and quality of life in motor-fluctuating PD patients. VALE-SAFI is an observational single-centre study performed in fluctuating PD patients starting safinamide treatment and followed for 6 months. the effects of safinamide on NMS, sleep, fatigue, depression and pain were assessed through validated sales. changes in the scales from baseline to the 6-month follow-up visit were analysed. 60 PD patients (66.67% males) were enrolled at baseline, and 45 patients completed the 6-month follow-up. PD patients improved motor symptoms at follow-up, with the significant reduction of motor fluctuations. the global score of the NMS Scale significantly decreased between baseline and the follow-up. regarding pain domains, patients reported a significant improvement in discolouration and oedema/swelling. further, a significant improvement was observed from baseline to follow-up in sleep quality measured through the pittsburgh sleep quality Index, while no changes were documented in daytime sleepiness. no differences were found in depression and fatigue between baseline and follow-up. finally, the patient's perception of the impact of PD on functioning and well-being decreased from baseline to follow-up. the present findings confirmed the beneficial effect of safinamide on both motor and non-motor symptoms, also improving the quality of life of PD patients. furthermore, these data support the positive effects of safinamide on pain and mood, as well as on sleep quality and continuity

Optogenetic Activation of Striatopallidal Neurons Reveals Altered HCN Gating in DYT1 Dystonia

Summary: Firing activity of external globus pallidus (GPe) is crucial for motor control and is severely perturbed in dystonia, a movement disorder characterized by involuntary, repetitive muscle contractions. Here, we show that GPe projection neurons exhibit a reduction of firing frequency and an irregular pattern in a DYT1 dystonia model. Optogenetic activation of the striatopallidal pathway fails to reset pacemaking activity of GPe neurons in mutant mice. Abnormal firing is paralleled by alterations in motor learning. We find that loss of dopamine D2 receptor-dependent inhibition causes increased GABA input at striatopallidal synapses, with subsequent downregulation of hyperpolarization-activated, cyclic nucleotide-gated cation (HCN) channels. Accordingly, enhancing in vivo HCN channel activity or blocking GABA release restores both the ability of striatopallidal inputs to pause ongoing GPe activity and motor coordination deficits. Our findings demonstrate an impaired striatopallidal connectivity, supporting the central role of GPe in motor control and, more importantly, identifying potential pharmacological targets for dystonia

Parkinson's disease motor progression in relation to the timing of REM sleep behavior disorder presentation: an exploratory retrospective study

REM sleep behavior disorder (RBD) is a frequent non-motor symptom of parkinson's disease (PD), and the timing of its presentation might have a role in the underlying neurodegenerative process. Here, we aimed to define the potential impact of probable RBD (pRBD) on PD motor progression. we conducted a longitudinal retrospective study on 66 PD patients followed up at the university hospital of rome tor vergata. patients were divided into three groups: with post-motor pRBD (pRBD(post), n = 25), without pRBD (pRBD(wo), n = 20), and with pre-motor pRBD (pRBD(pre), n = 21). Hoehn and Yahr (H&Y) scores, unified PD rating scale (UPDRS) motor scores, and levodopa equivalent daily dose were collected at two follow-up visits conducted in a 5-year interval (T0 and T1). pRBD(post )patients had a greater rate of motor progression in terms of the H&Y scale compared to pRBD(pre) and pRBD(wo) patients, without the influence of anti-parkinsonian treatment. these preliminary findings suggest that the post-motor occurrence of pRBD can be associated with an acceleration in PD motor progression

Persistent elevation of D-Aspartate enhances NMDA receptor-mediated responses in mouse substantia nigra pars compacta dopamine neurons

Dopamine neurons in the substantia nigra pars compacta regulate not only motor but also cognitive functions. NMDA receptors play a crucial role in modulating the activity of these cells. Considering that the amino-acid D-Aspartate has been recently shown to be an endogenous NMDA receptor agonist, the aim of the present study was to examine the effects of D-Aspartate on the functional properties of nigral dopamine neurons. We compared the electrophysiological actions of D-Aspartate in control and D-aspartate oxidase gene (Ddo(-/-)) knock-out mice that show a concomitant increase in brain D-Aspartate levels, improved synaptic plasticity and cognition. Finally, we analyzed the effects of L-Aspartate, a known dopamine neuron endogenous agonist in control and Ddo(-/-) mice. We show that D- and L-Aspartate excite dopamine neurons by activating NMDA, AMPA and metabotropic glutamate receptors. Ddo deletion did not alter the intrinsic properties or dopamine sensitivity of dopamine neurons. However, NMDA-induced currents were enhanced and membrane levels of the NMDA receptor GluN1 and GluN2A subunits were increased. Inhibition of excitatory amino-acid transporters caused a marked potentiation of D-Aspartate, but not L-Aspartate currents, in Ddo(-/-) neurons. This is the first study to show the actions of D-Aspartate on midbrain dopamine neurons, activating not only NMDA but also non-NMDA receptors. Our data suggest that dopamine neurons, under conditions of high D-Aspartate levels, build a protective uptake mechanism to compensate for increased NMDA receptor numbers and cell hyper-excitation, which could prevent the consequent hyper-dopaminergia in target zones that can lead to neuronal degeneration, motor and cognitive alterations

Dietary Vitamin E as a Protective Factor for Parkinson's Disease: Clinical and Experimental Evidence

Effective disease-modifying treatments are an urgent need for Parkinson's disease (PD). A putative successful strategy is to counteract oxidative stress, not only with synthetic compounds, but also with natural agents or dietary choices. Vitamin E, in particular, is a powerful antioxidant, commonly found in vegetables and other components of the diet. In this work, we performed a questionnaire based case-control study on 100 PD patients and 100 healthy controls. The analysis showed that a higher dietary intake of Vitamin E was inversely associated with PD occurrence independently from age and gender (OR = 1.022; 95% CI = 0.999–1.045; p < 0.05), though unrelated to clinical severity. Then, in order to provide a mechanistic explanation for such observation, we tested the effects of Vitamin E and other alimentary antioxidants in vitro, by utilizing the homozygous PTEN-induced kinase 1 knockout (PINK1−/−) mouse model of PD. PINK1−/− mice exhibit peculiar alterations of synaptic plasticity at corticostriatal synapses, consisting in the loss of both long-term potentiation (LTP) and long-term depression (LTD), in the absence of overt neurodegeneration. Chronic administration of Vitamin E (alpha-tocopherol and the water-soluble analog trolox) fully restored corticostriatal synaptic plasticity in PINK1−/− mice, suggestive of a specific protective action. Vitamin E might indeed compensate PINK1 haploinsufficiency and mitochondrial impairment, reverting some central steps of the pathogenic process. Altogether, both clinical and experimental findings suggest that Vitamin E could be a potential, useful agent for PD patients. These data, although preliminary, may encourage future confirmatory trials

N-Glycans mutations rule oligomeric assembly and functional expression of P2X3 receptor for extracellular ATP

N-Glycosylation affects the function of ion channels at the level of multisubunit assembly, protein trafficking, ligand binding and channel opening. Like the majority of membrane proteins, ionotropic P2X receptors for extracellular ATP are glycosylated in their extracellular moiety. Here, we used site-directed mutagenesis to the four predicted N-glycosylation sites of P2X3 receptor (Asn139, Asn170, Asn194 and Asn290) and performed comparative analysis of the role of N-glycans on protein stability, plasma membrane delivery, trimer formation and inward currents. We have found that in transiently transfected HEK293 cells, Asn170 is apparently the most important site for receptor stability, since its mutation causes a primary loss in protein content and indirect failure in membrane expression, oligomeric association and inward current responses. Even stronger effects are obtained when mutating Thr172 in the same glycosylation consensus. Asn194 and Asn290 are the most dispensable, since even their simultaneous mutation does not affect any tested receptor feature. All double mutants containing Asn170 mutation or the Asn139/Asn290 double mutant are instead almost unable to assemble into a functional trimeric structure. The main emerging finding is that the inability to assemble into trimers might account for the impaired function in P2X3 mutants where residue Asn170 is replaced. These results improve our knowledge about the role of N-glycosylation in proper folding and oligomeric association of P2X3 recepto

Effects of Ultramicronized Palmitoylethanolamide (um-PEA) in COVID-19 Early Stages: A Case-Control Study

Ultramicronized palmitoylethanolamide (um-PEA), a compound with antioxidant, anti-inflammatory and neuroprotective properties, appears to be a potential adjuvant treatment for early stages of Coronavirus disease 2019 (COVID-19). In our study, we enrolled 90 patients with confirmed diagnosis of COVID-19 that were randomized into two groups, homogeneous for age, gender and BMI. The first group received oral supplementation based on um-PEA at a dose of 1800 mg/day for a total of 28 days; the second group was the control group (R.S. 73.20). At baseline (T0) and after 28 days of um-PEA treatment (T1), we monitored: routine laboratory parameters, inflammatory and oxidative stress (OS) biomarkers, lymphocytes subpopulation and COVID-19 serological response. At T1, the um-PEA-treated group presented a significant reduction in inflammation compared to the control group (CRP p = 0.007; IL-6 p = 0.0001; neutrophils to lymphocytes ratio p = 0.044). At T1, the controls showed a significant increase in OS compared to the treated group (FORT p = 0.05). At T1, the um-PEA group exhibited a significant decrease in D-dimer levels (p = 0.0001) and higher levels of IgG against SARS-CoV-2 (p = 0.0001) compared to the controls. Our data demonstrated, in a randomized clinical trial, the beneficial effects of um-PEA in both asymptomatic and mild-symptomatic patients related to reductions in inflammatory state, OS and coagulative cascade alterations