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Background and purposeDespite enormous advances in identifying genetic variants responsible for many neurological diseases, access to genetic testing may be limited in clinical practice. The objective of this study was to assess worldwide access to genetic tests for movement disorders and factors impacting their utilization.MethodsThe Rare Movement Disorders Study Group of the International Parkinson and Movement Disorder Society designed an online survey electronically mailed to all 7815 members.ResultsSurvey data completed by 1269 participants from 109 countries were analysed. Limited access to geneticists and genetic counsellors was reported in many world regions compared to Europe and North America. Availability of genetic testing was limited, with rates of access lower than 50%. Genetic testing for chorea was the most commonly available. For parkinsonism, dystonia, ataxia, hereditary spastic paraplegias and metabolic disorders, there was limited access to genetic testing in all countries compared to Europe and North America, with significant differences found for Africa, Central/South America, Asia. In many regions, genetic testing was supported by either private or public funding. Genetic testing was free of charge in Europe according to 63.5% of respondents. In North America, Africa, Central/South America, Asia and the Middle East access to free of charge genetic testing was by far significantly lower compared to Europe.ConclusionsThis survey highlights difficulties in accessing genetic testing and individuals with expertise in genetics at the worldwide level. In addition, major disparities in genetic testing amongst world regions are highlighted, probably due to a variety of factors including financial barriers.

Background: Peripheral immune cells critically contribute to the clinical‐pathological progression of neurodegenerative diseases and also represent a reliable frame for translational applications. However, data on progressive supranuclear palsy (PSP) are almost scarce in this regard. Objective: Our goal is to provide a broad biological characterization of peripheral immune cells in a selected PSP cohort. Methods: Seventy‐one PSP patients scored on the PSP Rating Scale (PSPRS), and 59 controls were enrolled. The blood cell count was collected, together with the neutrophil‐to‐lymphocyte ratio (NLR) calculation. In a subgroup of patients and controls, the peripheral blood mononuclear cells (PBMCs) were analyzed by the mitochondrial bioenergetic performance and the western blot assay of the nuclear factor erythroid 2‐related factor (NRF2)/heme oxygenase 1 (HO‐1) pathway and the total tau (t‐tau) and phosphorylated tau (p‐tau) proteins. Case–control comparison and correlation analyses were performed. Results: PSP patients had a NLR higher than controls, with increased circulating neutrophils. The leukocyte metabolism was also globally increased and the NRF2/HO‐1 pathway activated in patients. P‐tau, but not t‐tau, significantly accumulated in PSP PBMCs and inversely correlated with the PSPRS. Conclusions: PSP displays a systemic inflammatory shift of the peripheral immunity, which may justify a metabolic reprogramming of the blood leukocytes. Consistently, the NRF2/HO‐1 pathway, a master regulator of inflammatory and metabolic response, was activated. PBMCs also engulf tau proteins, especially p‐tau, in a way inverse to the disease severity, allowing for a peripheral tracking of tauopathy in patients. Immunometabolic targets may, therefore, gain relevance to PSP in biomarker or therapeutic purposes. © 2024 International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]

Background/Objectives: Driving abilities require the synchronized activity of cerebral networks associated with sensorimotor integration, motricity, and executive functions. Drivers with Parkinson's disease (DwP) have impaired driving ability, but little is known about the impact of "wearing-off" and therapies in addition to L-DOPA on driving capacities. This study aimed to (i) compare driving performance between DwP during different motor states and healthy controls and (ii) assess the impact of add-on therapies on driving abilities. Methods: DwP (n = 26) were enrolled as individuals experiencing wearing-off symptoms and treated (within 6 months before the enrollment) with add-on therapies to L-DOPA, including MAO inhibitors for DwP-A (n = 12) or opicapone for DwP-B (n = 14). Age- and sex-matched controls (CON, n = 12) were also enrolled. DwP received two driving assessments in a driving simulator during their "best-on" time and during their wearing-off time on different days. An anamnestic driving questionnaire was collected with the assistance of partners. A Virtual Driving Rating Scale (VDRS) was calculated, as well as learning curves (LCs) for driving items calculated in minutes. Results: DwP reported worse driving performance than CON at the driving questionnaire. In line with this, DwP showed worse VDRS (p < 0.01) and LC (p = 0.021) than CON. Lower VDRS was associated with wearing-off (p < 0.01), but DwP-B had better driving performance while in their "best-on" time (p = 0.037) and more items improving with LCs (7 vs. 3) than DwP-A. Conclusions: DwP demonstrated impaired driving compared to controls. Wearing-off symptoms can also affect driving ability, but therapies (opicapone more so than MAO inhibitors) may play a role in preserving specific driving skills, possibly through maintaining learning abilities. [ABSTRACT FROM AUTHOR]

Heterozygous mutations or genetic variants in the GBA1 gene, which encodes for the β-glucocerebrosidase (GCase), a lysosomal hydrolase enzyme, may increase the risk of Parkinson's disease (PD) onset. The heterozygous E326K form is one of the most common genetic risk factors for PD worldwide, but, to date, the underlying molecular mechanisms remain unclear. Here, we investigate the effect of the E326K on the structure, stability, dimerization process, and interaction mode with some proteins of the interactome of GCase using multiple molecular dynamics (MD) simulations at pH 5.5 and pH 7.0 to mimic the lysosomal and endoplasmic reticulum environments, respectively. The analysis of the MD trajectories highlights that the E326K mutation did not significantly alter the structural conformation of the catalytic dyad but significantly makes the structure of the dimeric complexes unstable, especially at lysosomal pH, potentially impacting the organization of the quaternary structure. Furthermore, the E326K mutation significantly impacts protein interactions by altering the binding mode with the activator Saposin C (SapC), reducing the binding affinity with the inhibitor α-Synuclein (α-Syn), and increasing the affinity for the Lysosomal integral membrane protein-2 (LIMP-2) transporter. [ABSTRACT FROM AUTHOR]

Conformational changes in disease-associated or mutant proteins represent a key pathological aspect of Huntington's disease (HD) and other protein misfolding diseases. Using immunoassays and biophysical approaches, we and others have recently reported that polyglutamine expansion in purified or recombinantly expressed huntingtin (HTT) proteins affects their conformational properties in a manner dependent on both polyglutamine repeat length and temperature but independent of HTT protein fragment length. These findings are consistent with the HD mutation affecting structural aspects of the amino-terminal region of the protein, and support the concept that modulating mutant HTT conformation might provide novel therapeutic and diagnostic opportunities. We now report that the same conformational TR-FRET based immunoassay detects polyglutamine- and temperature-dependent changes on the endogenously expressed HTT protein in peripheral tissues and post-mortem HD brain tissue, as well as in tissues from HD animal models. We also find that these temperature- and polyglutamine-dependent conformational changes are sensitive to bona-fide phosphorylation on S13 and S16 within the N17 domain of HTT. These findings provide key clinical and preclinical relevance to the conformational immunoassay, and provide supportive evidence for its application in the development of therapeutics aimed at correcting the conformation of polyglutamine-expanded proteins as well as the pharmacodynamics readouts to monitor their efficacy in preclinical models and in HD patients.

Background: Transcutaneous vagus nerve stimulation (VNS) showed early evidence of efficacy for the gait treatment of Parkinson's disease (PD). Objectives: Providing data on neurophysiological and clinical effects of transauricular VNS (taVNS). Methods: Ten patients with recording deep brain stimulation (DBS) have been enrolled in a within participant design pilot study, double‐blind crossover sham‐controlled trial of taVNS. Subthalamic local field potentials (β band power), Unified Parkinson's Disease Rating Scales (UPDRS), and a digital timed‐up‐and‐go test (TUG) were measured and compared with real versus sham taVNS during medication‐off/DBS‐OFF condition. Results: The left taVNS induced a reduction of the total β power in the contralateral (ie, right) subthalamic nucleus and an improvement of TUG time, speed, and variability. The taVNS‐induced β reduction correlated with the improvement of gait speed. No major clinical changes were observed at UPDRS. Conclusions: taVNS is a promising strategy for the management of PD gait, deserving prospective trials of chronic neuromodulation. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. [ABSTRACT FROM AUTHOR]