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In Parkinson's disease (PD), respiratory insufficiency (including functional and muscle disorders) can impact dysarthria and swallowing. Most studies of this topic have been performed retrospectively in populations of patients with advanced PD. The objective of the present study was to characterize lung function (under off-drug conditions) in early-stage PD patients at baseline and then again two years later. Forty-one early-stage PD patients (mean ± SD age: 61.7 ± 7.7; mean ± SD disease duration: 1.9 ± 1.7 years) were prospectively enrolled and compared with 36 age-matched healthy controls. Neurological evaluations and pulmonary function testing were performed in the off-drug condition at the inclusion visit and then two years later. Pulmonary function testing did not reveal any restrictive or obstructive disorders; at baseline, inspiratory muscle weakness was the only abnormality observed in the PD group (in 53.7% of the patients, vs. 25% in controls; p = 0.0105). The PD patients had a lower mean maximal inspiratory mouth pressure than controls and a lower sniff nasal inspiratory pressure. Two years after the initiation of chronic treatment with antiparkinsonian medications, the maximal inspiratory mouth pressure and the sniff nasal inspiratory pressure tended to be higher. Lastly, overall motor outcomes were not significantly worse in patients with inspiratory muscle weakness than in patients without inspiratory muscle weakness. Inspiratory muscle weakness seems to be common in patients with early-stage PD, and was seen to be stable over a two-year period. Additional long-term follow-up studies are required to specify the impact of this new feature of PD.

Parkinson's disease is a progressive neurodegenerative disease characterized by the loss of dopaminergic neurons of the nigrostriatal pathway and the formation of neuronal inclusions known as Lewy bodies. Chronic neuroinflammation, another hallmark of the disease, is thought to play an important role in the neurodegenerative process. Glycosphingolipids are a well-defined subclass of lipids that regulate crucial aspects of the brain function and recently emerged as potent regulators of the inflammatory process. Deregulation in glycosphingolipid metabolism has been reported in Parkinson’s disease. However, the interrelationship between glycosphingolipids and neuroinflammation in Parkinson’s disease is not well known. This review provides a thorough overview of the links between glycosphingolipid metabolism and immune-mediated mechanisms involved in neuroinflammation in Parkinson’s disease. After a brief presentation of the metabolism and function of glycosphingolipids in the brain, it summarizes the evidences supporting that glycosphingolipids (i.e. glucosylceramides or specific gangliosides) are deregulated in Parkinson’s disease. Then, the implications of these deregulations for neuroinflammation, based on data from human inherited lysosomal glycosphingolipid storage disorders and gene-engineered animal studies are outlined. Finally, the key molecular mechanisms by which glycosphingolipids could control neuroinflammation in Parkinson’s disease are highlighted. These include inflammasome activation and secretion of pro-inflammatory cytokines, altered calcium homeostasis, changes in the blood-brain barrier permeability, recruitment of peripheral immune cells or production of autoantibodies.

Parkinson’s disease (PD) is affecting about 1.2 million patients in Europe with a prevalence that is expected to have an exponential increment, in the next decades. This epidemiological evolution will be challenged by the low number of neurologists able to deliver expert care for PD. As PD is better recognized, there is an increasing demand from patients for rigorous control of their symptoms and for therapeutic education. In addition, the highly variable nature of symtoms between patients and the fluctuations within the same patient requires innovative tools to help doctors and patients monitor the disease in their usual living environment and adapt treatment in a more relevant way. Nowadays, there are various body-worn sensors (BWS) proposed to monitor parkinsonian clinical features, such as motor fluctuations, dyskinesia, tremor, bradykinesia, freezing of gait (FoG) or gait disturbances. BWS have been used as add-on tool for patients’ management or research purpose. Here, we propose a practical anthology, summarizing the characteristics of the most used BWS for PD patients in Europe, focusing on their role as tools to improve treatment management. Consideration regarding the use of technology to monitor non-motor features is also included. BWS obviously offer new opportunities for improving management strategy in PD but their precise scope of use in daily routine care should be clarified.

Injection of botulinum toxin into each splenius capitis muscle at baseline and week 12 was more effective than placebo in reducing the severity of essential head tremor over 18 weeks. Effects waned at 24 weeks.

There is an urgent and unmet need for accurate biomarkers in Amyotrophic Lateral Sclerosis. A pharmaco-metabolomics study was conducted using plasma samples from the TRO19622 (olesoxime) trial to assess the link between early metabolomic profiles and clinical outcomes. Patients included in this trial were randomized into either Group O receiving olesoxime (n = 38) or Group P receiving placebo (n = 36). The metabolomic profile was assessed at time-point one (V1) and 12 months (V12) after the initiation of the treatment. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites (Biocrates® commercial kit). Multivariate analysis based on machine learning approaches (i.e. Biosigner algorithm) was performed. Metabolomic profiles at V1 and V12 and changes in metabolomic profiles between V1 and V12 accurately discriminated between Groups O and P (p<5×10-6), and identified glycine, kynurenine and citrulline/arginine as the best predictors of group membership. Changes in metabolomic profiles were closely linked to clinical progression, and correlated with glutamine levels in Group P and amino acids, lipids and spermidine levels in Group O. Multivariate models accurately predicted disease progression and highlighted the discriminant role of sphingomyelins (SM C22:3, SM C24:1, SM OH C22:2, SM C16:1). To predict SVC from SM C24:1 in group O and SVC from SM OH C22:2 and SM C16:1 in group P+O, we noted a median sensitivity between 67% and 100%, a specificity between 66.7 and 71.4%, a positive predictive value between 66 and 75% and a negative predictive value between 70% and 100% in the test sets. This proof-of-concept study demonstrates that the metabolomics has a role in evaluating the biological effect of an investigational drug and may be a candidate biomarker as a secondary outcome measure in clinical trials.

Accurate patient stratification into prognostic categories and targeting Amyotrophic Lateral Sclerosis (ALS)-associated pathways may pave the way for promising trials. We evaluated blood-based prognostic indicators using an array of pathological markers. Plasma samples were collected as part of a large, phase III clinical trial (Mitotarget/TRO19622) at months 1, 6, 12 and 18. The ALSFRS-r score was used as a proxy of disease progression to assess the predictive value of candidate biological indicators. First, established clinical predictors were evaluated in all 512 patients. Subsequently, pathologic markers, such as proxies of neuronal integrity (Neurofilament light chain and phosphorylated heavy chain), DNA oxidation (8-oxo-2′-desoxyguanosine), lipid peroxidation (4-hydroxy-2-nonenal, isoprostane), inflammation (interleukin-6) and iron status (ferritin, hepcidin, transferrin) were assessed in a subset of 109 patients that represented the whole cohort. Markers of neuronal integrity, DNA and lipid oxidation, as well as iron status at baseline are accurate predictors of disability at 18-month follow-up. The composite scores of these markers in association with established clinical predictors enable the accurate forecasting of functional decline. The identified four biomarkers are all closely associated with ‘ferroptosis’, a recently discovered form of programmed cell death with promising therapeutic targets. The predictive potential of these pathophysiology-based indicators may offer superior patient stratification for future trials, individualised patient care and resource allocation.

Background The burgeoning field of regenerative medicine has significantly advanced with recent findings on biotherapies using human platelet lysates (HPLs), derived from clinical-grade platelet concentrates (PCs), for treating brain disorders. These developments have opened new translational research avenues to explore the neuroprotective effects of platelet-extracellular vesicles (PEVs). Their potential in managing neurodegenerative conditions like traumatic brain injury (TBI) and Parkinson’s disease (PD) warrants further exploration. We aimed here to characterize the composition of a PEV preparation isolated from platelet concentrate (PC) supernatant, and determine its neuroprotective potential and neurorestorative effects in cellular and animal models of TBI and PD. Methods We isolated PEVs from the supernatant of clinical-grade PC collected from healthy blood donors utilizing high-speed centrifugation. PEVs were characterized by biophysical, biochemical, microscopic, and LC–MS/MS proteomics methods to unveil biological functions. Their functionality was assessed in vitro using SH-SY5Y neuronal cells, LUHMES dopaminergic neurons, and BV-2 microglial cells, and in vivo by intranasal administration in a controlled cortical impact (CCI)-TBI model using 8-weeks-old male C57/BL6 mice, and in a PD model induced by MPTP in 5-month-old male C57/BL6 mice. Results PEVs varied in size from 50 to 350 nm, predominantly around 200 nm, with concentrations ranging between 10 10 and 10 11 /mL. They expressed specific platelet membrane markers, exhibited a lipid bilayer by cryo-electron microscopy and, importantly, showed low expression of pro-coagulant phosphatidylserine. LC–MS/MS indicated a rich composition of trophic factors, including neurotrophins, anti-inflammatory agents, neurotransmitters, and antioxidants, unveiling their multifaceted biological functions. PEVs aided in the restoration of neuronal functions in SH-SY5Y cells and demonstrated remarkable neuroprotective capabilities against erastin-induced ferroptosis in dopaminergic neurons. In microglial cells, they promoted anti-inflammatory responses, particularly under inflammatory conditions. In vivo , intranasally delivered PEVs showed strong anti-inflammatory effects in a TBI mouse model and conserved tyrosine hydroxylase expression of dopaminergic neurons of the substantia nigra in a PD model, leading to improved motor function. Conclusions The potential of PEV-based therapies in neuroprotection opens new therapeutic avenues for neurodegenerative disorders. The study advocates for clinical trials to establish the efficacy of PEV-based biotherapies in neuroregenerative medicine. Graphical Abstract

Neuroinflammation, as defined by the presence of classically activated microglia, is thought to play a key role in numerous neurodegenerative disorders such as Alzheimer’s disease. While modulating neuroinflammation could prove beneficial against neurodegeneration, identifying its most relevant biological processes and pharmacological targets remains highly challenging. In the present study, we combined text-mining, functional enrichment and protein-level functional interaction analyses to 1) identify the proteins significantly associated to neuroinflammation in Alzheimer’s disease over the scientific literature, 2) distinguish the key proteins most likely to control the neuroinflammatory processes significantly associated to Alzheimer's disease, 3) identify their regulatory microRNAs among those dysregulated in Alzheimer's disease and 4) assess their pharmacological targetability. 94 proteins were found to be significantly associated to neuroinflammation in Alzheimer’s disease over the scientific literature and IL4, IL10 and IL13 signaling as well as TLR-mediated MyD88- and TRAF6-dependent responses were their most significantly enriched biological processes. IL10, TLR4, IL6, AKT1, CRP, IL4, CXCL8, TNF-alpha, ITGAM, CCL2 and NOS3 were identified as the most potent regulators of the functional interaction network formed by these immune processes. These key proteins were indexed to be regulated by 63 microRNAs dysregulated in Alzheimer's disease, 13 long non-coding RNAs and targetable by 55 small molecules and 8 protein-based therapeutics. In conclusion, our study identifies eleven key proteins with the highest ability to control neuroinflammatory processes significantly associated to Alzheimer’s disease, as well as pharmacological compounds with single or pleiotropic actions acting on them. As such, it may facilitate the prioritization of diagnostic and target-engagement biomarkers as well as the development of effective therapeutic strategies against neuroinflammation in Alzheimer’s disease.

Background In many clinical applications, evolution of a longitudinal marker is censored by an event occurrence, and, symmetrically, event occurrence can be influenced by the longitudinal marker evolution. In such frameworks joint modeling is of high interest. The Joint Latent Class Model (JLCM) allows to stratify the population into groups (classes) of patients that are homogeneous both with respect to the evolution of a longitudinal marker and to the occurrence of an event; this model is widely employed in real-life applications. However, the finite sample-size properties of this model remain poorly explored. Methods In the present paper, a simulation study is carried out to assess the impact of the number of individuals, of the censoring rate and of the degree of class separation on the finite sample size properties of the JLCM. A real-life application from the neurology domain is also presented. This study assesses the precision of class membership prediction and the impact of covariates omission on the model parameter estimates. Results Simulation study reveals some departures from normality of the model for survival sub-model parameters. The censoring rate and the number of individuals impact the relative bias of parameters, especially when the classes are weakly distinguished. In real-data application the observed heterogeneity on individual profiles in terms of a longitudinal marker evolution and of the event occurrence remains after adjusting to clinically relevant and available covariates; Conclusion The JLCM properties have been evaluated. We have illustrated the discovery in practice and highlights the usefulness of the joint models with latent classes in this kind of data even with pre-specified factors. We made some recommendations for the use of this model and for future research.

Background: Pathophysiological mechanisms that contribute to neurodegeneration in Amyotrophic Lateral Sclerosis (ALS) include oxidative stress and inflammation. We conducted a preliminary study to explore these mechanisms, to discuss their link in ALS, and to determine the feasibility of incorporating this combined analysis into current biomarkers research. Methods: We enrolled 10 ALS patients and 10 controls. We measured the activities of glutathione peroxidase, glutathione reductase, superoxyde dismutase (SOD), and the levels of serum total antioxidant status (TAS), malondialdehyde (MDA), 8-hydroxy-2’-deoxyguanosine (8-OHdG), and glutathione status (e.g. glutathione disulfide, GSSG/reduced glutathione, GSH). We analysed the concentrations of homocysteine, several cytokines, vitamins and metals by standard methods used in routine practice. Results: There was a significant decrease in TAS levels (p=0.027) and increase in 8-OHdG (p=0.014) and MDA (p=0.011) levels in ALS patients. We also observed a significantly higher GSSG/GSH ratio (p=0.022), and IL-6 (p=0.0079) and IL-8 (p=0.009) concentrations in ALS patients. Correlations were found between biological and clinical markers (homosysteine vs. clinical status at diagnosis, p=0.02) and between some biological markers such as IL-6 vs. GSSG/GSH (p=0.045) or SOD activity (p=0.017). Conclusion: We confirmed the systemic alteration of both the redox and the inflammation status in ALS patients, and we observed a link with some clinical parameters. These promising results encourage us to pursue this study with collection of combined oxidative stress and inflammatory markers. Détermination d’un panel de biomarqueurs du stress oxydant et de l’inflammation dans la SLA: une étude pilote. Contexte: Parmi les mécanismes impliqués dans la physiopathologie de la Sclérose Latérale Amyotrophique (SLA), on note un stress oxydant et des mécanismes inflammatoires. Nous avons ainsi mené une étude préliminaire afin de 1) d’explorer ces mécanismes, 2) de discuter leur lien dans la SLA, 3) de déterminer la faisabilité d’une telle analyse combinée pour une utilisation courante en recherche de biomarqueurs. Méthodes: Nous avons inclus prospectivement 10 patients SLA et 10 contrôles. Nous avons mesuré l’activité des enzymes suivantes : glutathion peroxydase, glutathion réductase, superoxyde dismutase (SOD), et les concentrations sériques des paramètres suivants : statut antioxydant total (SAT), malondialdéhyde (MDA), 8-hydroxy-2’-déoxyguanosine (8-OHdG), et le statut en glutathion (e.g. glutathione oxydé, GSSG/glutathione réduit, GSH). Nous avons analysé les concentrations d’homocystéine, de plusieurs cytokines, de vitamines et de différents métaux par des méthodes validées en routine. Résultats: Nous avons montré une diminution significative du SAT (p=0.027) et une augmentation de la 8-OHdG (p=0.014) ainsi que du MDA (p=0.011) chez les patients SLA. Nous avons observé une augmentation du rapport GSSG/GSH (p=0.022), ainsi que des concentrations d’IL-6 (p=0.0079) et d’IL-8 (p=0.009) chez les patients SLA. Des corrélations ont été observées entre certains marqueurs biologiques et cliniques (homosysteine vs sévérité de la pathologie au diagnostic, p=0.02) mais également entre les marqueurs biologiques entre eux tels que l’IL-6 vs GSSG/GSH (p=0.045) ou vs l’activité de la SOD (p=0.017). Conclusion: Nous avons confirmé l’altération du statut redox et la composante inflammatoire importante dans la SLA, en dehors du SNC. Nous avons également observé un lien entre certains paramètres cliniques et biologiques, ce qui nous incite à poursuivre cette étude en analysant la combinaison de ces marqueurs de stress oxydant et d’inflammation.