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Background: Preclinical and clinical evidence suggests that impaired gamma-aminobutyric (GABA) control, leading to disinhibition within the sensorimotor system, might play a role in dystonia. Aim of this study is the in vivo assessment of the GABAergic system in dystonia using positron emission tomography (PET) and (11) C-flumazenil, a selective GABA(A) receptor ligand. Methods: Fourteen subjects with primary dystonia (9 carriers of the DYT1 mutation and 5 sporadic cases) were compared to 11 controls, using a simplified reference tissue model to measure binding potential. Results: Voxel-based analyses showed a reduction in GABA(A) receptor expression/affinity both in DYT1 carriers and sporadic patients in primary motor and premotor cortex, primary and secondary somatosensory cortex, and in the motor component of the cingulate gyrus. Conclusions: Dysfunction of GABA(A) receptors in sensorimotor systems in primary (genetic and sporadic) dystonia supports the view that lack of GABAergic control may be associated with the generation of dystonic movements. [ABSTRACT FROM AUTHOR]

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) targeting the thalamic ventral intermediate nucleus (VIM) is an innovative treatment for drug-refractory essential tremor (ET). The relationship between lesion characteristics, dentate-rubro-thalamic-tract (DRTT) involvement and clinical benefit remains unclear., Objectives: To investigate whether clinical outcome is related to lesion volume and/or its overlap with the DRTT. To compare the reliability of probabilistic versus deterministic tractography in reconstructing the DRTT and improving VIM targeting., Methods: Forty ET patients who underwent MRgFUS thalamotomy between 2019 and 2022 were retrospectively analyzed. Clinical outcomes and adverse effects were recorded at 1/6/12 months after the procedure. The DRTT was generated using deterministic and probabilistic tractography on preoperative diffusion-tensor 3 T-images and location and volume of the lesion were calculated., Results: Probabilistic tractography identified both decussating (d-DRTT) and non-decussating (nd-DRTT) components of the DRTT, whereas the deterministic approach only identified one component overlapping with the nd-DRTT. Despite the lesions predominantly intersecting the medial portion of the d-DRTT, with a significantly greater overlap in responder patients, we observed only a non-significant correlation between tremor improvement and increased d-DRTT-lesion overlap (r = 0.22, P = 0.20). The lesion volume demonstrated a significant positive correlation with clinical improvement at 1-day MRI (r = 0.42, P < 0.01)., Conclusion: Variability in the reconstructed DRTT position relative to the lesion center of mass, even among good responders, suggests that this fiber bundle is unlikely to be considered the sole target for a successful MRgFUS thalamotomy in ET. Indirect individualized targeting allows for more precise and reproducible identification of actual treatment coordinates than the direct method., (© 2024 The Author(s). Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Patients affected by Parkinson's disease (PD) display a tendency toward making risky choices in value-based conditions. Possible causes may encompass the pathophysiologic characteristics of PD that affect neural structures pivotal for decision making (DM) and the dopaminergic medications that may bias choices. Nevertheless, excluding patients with concurrent impulse control disorders, results are few and mixed. Conversely, other factors, such as individual differences (e.g., emotional state, impulsivity, consideration for future consequences) and cognitive functioning, in particular executive functions (EFs), are involved, even though few studies investigated their possible role. The present study investigated (1) the differences in value-based DM between 33 patients with PD without impulse control disorders and 33 matched healthy controls, and (2) the relationships among decisional performances, EFs, and individual differences in a group of 42 patients with PD who regularly undertake dopaminergic medications. All participants underwent an individual assessment to investigate value-based DM, cognitive abilities, and individual differences associated with DM. Nonparametric analyses showed the presence of riskier decisions in patients compared with healthy controls, depending on the characteristics of the decisional situation. Moreover, parameters of the decisional tasks involving the number of risky choices were significantly related to the posology of dopaminergic medications, EFs, and individual differences. Findings were discussed, highlighting possible clinical implications., (© 2024. The Author(s).)

The substantial deformation exhibited by hyperelastic cylindrical shells under pressurization makes them an ideal platform for programmable inflatable structures. If negative pressure is applied, the cylindrical shell will buckle, leading to a sequence of rich deformation modes, all of which are fully recoverable due to the hyperelastic material choice. While the initial buckling event under vacuum is well understood, here, the post-buckling regime is explored and a region in the design space is identified in which a coupled twisting-contraction deformation mode occurs; by carefully controlling the geometry of our homogeneous shells, the proportion of contraction versus twist can be controlled. Additionally, bending as a post-buckling deformation mode can be unlocked by varying the thickness of our shells across the circumference. Since these soft shells can fully recover from substantial deformations caused by buckling, then these instability-driven deformations are harnessed to build soft machines capable of a programmable sequence of movements with a single actuation input., (© 2024 Wiley‐VCH GmbH.)

MRI-guided focused ultrasound (MRgFUS) lesioning is an innovative, safe and effective treatment which provides an innovative development in the field of minimally invasive stereotactic neurosurgery. Based on the application of focused ultrasound energy under full MR planning and thermal imaging control, unilateral lesioning of the thalamus, subthalamic nucleus, and globus pallidus is indicated for the treatment of movement disorders, including essential tremor, Parkinson's disease, and dystonia. We started to apply this technique in February 2019 for the treatment of patients with movement disorders. The authors developed a diagnostic therapeutic care pathway, which is herewith proposed and applied as an explication of standard clinical practice in use. The project was the result of the application of different methods such as Health Technology Assessment (HTA), Strengths, Weaknesses, Opportunities and Threats analysis (SWOT) and Demin -Plan, Do, Check, Act (PDCA) cycle. The aim of this project was to standardize the MRgFUS diagnostic-therapeutic pathway (DTP), describe its application and the appropriateness of different phases (patient selection, intervention phase and follow-up). Here, we described in detail our experience in the DTP application from 2019 up to now in 610 patients with movement disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Rinaldo, Cilia, Leta, Gammone, Andreasi, Colucci, Braccia, Telese, Poli, Levi, Romito, Ghilemetti, De Martin, Fumagalli, Epifani, Prioni, Amami, Piacentini, Elia, Devigili, Nazzi, Ciceri, Stanziano, Grisoli, Caldiera, Catotti, DiMeco, Moreschi and Eleopra.)

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is increasingly used to treat drug-resistant essential tremor (ET). Data on MRgFUS thalamotomy in dystonic tremor (DT) are anecdotal., Objectives: To investigate efficacy, safety, and differences in target coordinates of MRgFUS thalamotomy in DT versus ET., Methods: Ten patients with DT and 35 with ET who consecutively underwent MRgFUS thalamotomy were followed for 12 months. Although in both groups the initial surgical planning coordinates corresponded to the ventralis intermediate (Vim), the final target could be modified intraoperatively based on clinical response., Results: Tremor significantly improved in both groups. The thalamic lesion was significantly more anterior in DT than ET. Considering both ET and DT groups, the more anterior the lesion, the lower the odds ratio for adverse events., Conclusions: MRgFUS thalamotomy is safe and effective in DT and ET. Compared to classical Vim coordinates used for ET, more anterior targeting should be considered for DT., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Heterozygous mutations in the GBA gene, encoding the lysosomal enzyme β-glucocerebrosidase (GCase), are the most frequent genetic risk factor for Parkinson's disease (PD). GBA -related PD (GBA-PD) patients have higher risk of dementia and reduced survival than non-carriers. Preclinical studies and one open-label trial in humans demonstrated that the chaperone ambroxol (ABX) increases GCase levels and modulates α-synuclein levels in the blood and cerebrospinal fluid (CSF)., Methods and Analysis: In this multicentre, double-blind, placebo-controlled, phase II clinical trial, we randomise patients with GBA-PD in a 1:1 ratio to either oral ABX 1.2 g/day or placebo. The duration of treatment is 52 weeks. Each participant is assessed at baseline and weeks 12, 26, 38, 52 and 78. Changes in the Montreal Cognitive Assessment score and the frequency of mild cognitive impairment and dementia between baseline and weeks 52 are the primary outcome measures. Secondary outcome measures include changes in validated scales/questionnaires assessing motor and non-motor symptoms. Neuroimaging features and CSF neurodegeneration markers are used as surrogate markers of disease progression. GCase activity, ABX and α-synuclein levels are also analysed in blood and CSF. A repeated-measures analysis of variance will be used for elaborating results. The primary analysis will be by intention to treat., Ethics and Dissemination: The study and protocols have been approved by the ethics committee of centres. The study is conducted according to good clinical practice and the Declaration of Helsinki. The trial findings will be published in peer-reviewed journals and presented at conferences., Trial Registration Numbers: NCT05287503, EudraCT 2021-004565-13., Competing Interests: Competing interests: RC has received speaking honoraria from Zambon Italia; Zambon SAU; Bial Italia Srl; advisory board fees from Bial; research support from the Italian Ministry of Health; he is Editor-in-Chief of the neuromuscular and movement disorders section of Brain Sciences (MDPI); Associate Editor of Parkinsonism and Related Disorders (Elsevier) and Frontiers in Ageing Neuroscience., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with Parkinson's disease (PD) and GBA gene mutations (GBA-PD) develop nonmotor complications more frequently than noncarriers. However, an objective characterization of both cardiovascular and sudomotor autonomic dysfunction using extensive clinical and instrumental measures has never been provided so far. Survival is reduced in GBA-PD regardless of age and dementia, suggesting that other hitherto unrecognized factors are involved., Objectives: To provide instrumental measures of pattern and severity of autonomic dysfunction in GBA-PD and explore their correlation with other non-motor symptoms and implications for clinical practice., Methods: In this cross-sectional study, 21 GBA-PD and 24 matched PD noncarriers underwent extensive assessment of motor and non-motor features, including neuropsychological testing. Cardiovascular autonomic function was explored through a comprehensive battery of indexes, including power spectral analysis of the R-R intervals and blood pressure short-term variability during resting state and active maneuvers. Dynamic Sweat Test was used to assess post-ganglionic sudomotor dysfunction., Results: Despite minimal or absent clinical correlates, cardiovagal and sympathetic indexes, heart rate variability parameters and sudomotor postganglionic function were more severely impaired in GBA-PD than noncarriers (overcoming relatively preserved compensatory peripheral sympathetic function), suggesting more prominent cardiac sympatho-vagal demodulation, efferent baroreflex failure and peripheral sympathetic dysfunction in GBA-PD. Cardiovascular dysautonomia showed marginal correlations with cognitive impairment., Conclusions: Compared to PD noncarriers, GBA-PD display more severe instrumental autonomic abnormalities, which may be underestimated by purely clinical measures, despite their relevance on morbidity and mortality. This supports the necessity of implementing instrumental autonomic assessment in all GBA-PD, regardless of clinically overt symptoms., (© 2023 The Authors. Movement Disorders Clinical Practice published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome.

The United Nations Framework Convention on Climate Change (UNFCCC) has recently established the Reducing Emissions from Deforestation and forest Degradation (REDD+) program, which requires countries to report their carbon emissions and sink estimates through national greenhouse gas inventories (NGHGI). Thus, developing automatic systems capable of estimating the carbon absorbed by forests without in situ observation becomes essential. To support this critical need, in this work, we introduce ReUse, a simple but effective deep learning approach to estimate the carbon absorbed by forest areas based on remote sensing. The proposed method's novelty is in using the public above-ground biomass (AGB) data from the European Space Agency's Climate Change Initiative Biomass project as ground truth to estimate the carbon sequestration capacity of any portion of land on Earth using Sentinel-2 images and a pixel-wise regressive UNet. The approach has been compared with two literature proposals using a private dataset and human-engineered features. The results show a more remarkable generalization ability of the proposed approach, with a decrease in Mean Absolute Error and Root Mean Square Error over the runner-up of 16.9 and 14.3 in the area of Vietnam, 4.7 and 5.1 in the area of Myanmar, 8.0 and 1.4 in the area of Central Europe, respectively. As a case study, we also report an analysis made for the Astroni area, a World Wildlife Fund (WWF) natural reserve struck by a large fire, producing predictions consistent with values found by experts in the field after in situ investigations. These results further support the use of such an approach for the early detection of AGB variations in urban and rural areas.

Background: Magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy is a safe and effective procedure for drug-resistant tremor in Parkinson's disease (PD)., Objective: The aim of this study was to demonstrate that MRgFUS ventralis intermedius thalamotomy in early-stage tremor-dominant PD may prevent an increase in dopaminergic medication 6 months after treatment compared with matched PD control subjects on standard medical therapy., Methods: We prospectively enrolled patients with early-stage PD who underwent MRgFUS ventralis intermedius thalamotomy (PD-FUS) and patients treated with oral dopaminergic therapy (PD-ODT) with a 1:2 ratio. We collected demographic and clinical data at baseline and 6 and 12 months after thalamotomy., Results: We included 10 patients in the PD-FUS group and 20 patients in the PD-ODT group. We found a significant increase in total levodopa equivalent daily dose and levodopa plus monoamine oxidase B inhibitors dose in the PD-ODT group 6 months after thalamotomy., Conclusions: In early-stage tremor-dominant PD, MRgFUS thalamotomy may be useful to reduce tremor and avoid the need to increase dopaminergic medications. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Sporadic Creutzfeldt-Jakob disease (sCJD) is a rare neurodegenerative disorder caused by the conformational conversion of the prion protein (PrP C ) into an abnormally folded form, named prion (or PrP Sc ). The combination of the polymorphism at codon 129 of the PrP gene (coding either methionine or valine) with the biochemical feature of the proteinase-K resistant PrP (generating either PrP Sc type 1 or 2) gives rise to different PrP Sc strains, which cause variable phenotypes of sCJD. The definitive diagnosis of sCJD and its classification can be achieved only post-mortem after PrP Sc identification and characterization in the brain. By exploiting the Real-Time Quaking-Induced Conversion (RT-QuIC) assay, traces of PrP Sc were found in the olfactory mucosa (OM) of sCJD patients, thus demonstrating that PrP Sc is not confined to the brain. Here, we have optimized another technique, named protein misfolding cyclic amplification (PMCA) for detecting PrP Sc in OM samples of sCJD patients. OM samples were collected from 27 sCJD and 2 genetic CJD patients (E200K). Samples from 34 patients with other neurodegenerative disorders were included as controls. Brains were collected from 26 sCJD patients and 16 of them underwent OM collection. Brain and OM samples were subjected to PMCA using the brains of transgenic mice expressing human PrP C with methionine at codon 129 as reaction substrates. The amplified products were analyzed by Western blot after proteinase K digestion. Quantitative PMCA was performed to estimate PrP Sc concentration in OM. PMCA enabled the detection of prions in OM samples with 79.3% sensitivity and 100% specificity. Except for a few cases, a predominant type 1 PrP Sc was generated, regardless of the tissues analyzed. Notably, all amplified PrP Sc were less resistant to PK compared to the original strain. In conclusion, although the optimized PMCA did not consent to recognize sCJD subtypes from the analysis of OM collected from living patients, it enabled us to estimate for the first time the amount of prions accumulating in this biological tissue. Further assay optimizations are needed to faithfully amplify peripheral prions whose recognition could lead to a better diagnosis and selection of patients for future clinical trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Cazzaniga, Bistaffa, De Luca, Portaleone, Catania, Redaelli, Tramacere, Bufano, Rossi, Caroppo, Giovagnoli, Tiraboschi, Di Fede, Eleopra, Devigili, Elia, Cilia, Fiorini, Bongianni, Salzano, Celauro, Quarta, Mammana, Legname, Tagliavini, Parchi, Zanusso, Giaccone and Moda.)

Introduction: Subthalamic nucleus deep brain stimulation (STN-DBS) is an established treatment for patients with Parkinson's disease (PD) with motor complications; the contribution of sex in determining the outcome is still not understood., Methods: We included 107 patients (71 males) with PD consecutively implanted with STN-DBS at our center. We reviewed patient charts from our database and retrospectively collected demographical and clinical data at baseline and at three follow-up visits (1, 5 and 10 years)., Results: We found a long-lasting effect of DBS on motor complications, despite a progressive worsening of motor performances in the ON medication condition. Bradykinesia and non-dopaminergic features seem to be the major determinant of this progression. Conversely to males, females showed a trend towards worsening in bradykinesia already at 1-year follow-up and poorer scores in non-dopaminergic features at 10-year follow-up. Levodopa Equivalent Daily Dose (LEDD) was significantly reduced after surgery compared to baseline values; however, while in males LEDD remained significantly lower than baseline even 10 years after surgery, in females LEDD returned at baseline values. Males showed a sustained effect on dyskinesias, but this benefit was less clear in females; the total electrical energy delivered was consistently lower in females compared to males. The profile of adverse events did not appear to be influenced by sex., Conclusion: Our data suggest that there are no major differences on the motor effect of STN-DBS between males and females. However, there may be some slight differences that should be specifically investigated in the future and that may influence therapeutic decisions in the chronic follow-up., (© 2021. Fondazione Società Italiana di Neurologia.)

Background: Detection of the pathological and disease-associated alpha-synuclein (αSyn D ) in the brain is required to formulate the definitive diagnosis of multiple system atrophy (MSA) and Parkinson's disease (PD). We recently showed that αSyn D can be detected in the olfactory mucosa (OM) of MSA and PD patients. For this reason, we have performed the first interlaboratory study based on α-synuclein Real-Time Quaking-Induced Conversion (αSyn&#95;RT-QuIC) analysis of OM samples collected from PD and MSA patients with the parkinsonian (MSA-P) and cerebellar (MSA-C) phenotypes., Methods: OM samples were prospectively collected from patients with a probable diagnosis of MSA-P (n = 20, mean disease duration 4.4 years), MSA-C (n = 10, mean disease duration 4 years), PD (n = 13, mean disease duration 8 years), and healthy control subjects (HS) (n = 11). Each sample was analyzed by αSyn&#95;RT-QuIC in two independent specialized laboratories, one located in Italy (ITA-lab) and one located in the USA (USA-lab). Both laboratories have developed and used harmonized αSyn&#95;RT-QuIC analytical procedures. Results were correlated with demographic and clinical data., Results: The αSyn&#95;RT-QuIC analysis reached a 96% interrater agreement of results (IAR) between laboratories (Kappa = 0.93, 95% CI 0.83-1.00). In particular, αSyn&#95;RT-QuIC seeding activity was found in the OM of 9/13 patients with PD (sensitivity 69%, IAR 100%) and 18/20 patients with MSA-P (sensitivity 90%, IAR 100%). Interestingly, samples collected from patients with MSA-C did not induce αSyn&#95;RT-QuIC seeding activity, except for one subject in USA-lab. Therefore, we found that MSA-P and MSA-C induced opposite effects. Regardless of disease diagnosis, the αSyn&#95;RT-QuIC seeding activity correlated with some clinical parameters, including the rigidity and postural instability., Conclusions: Our study provides evidence that OM-αSyn D may serve as a novel biomarker for accurate clinical diagnoses of PD, MSA-P, and MSA-C. Moreover, αSyn&#95;RT-QuIC represents a reliable assay that can distinguish patients with MSA-P from those with MSA-C, and may lead to significant advancements in patients stratification and selection for emerging pharmacological treatments and clinical trials., (© 2021. The Author(s).)

Background: Huntington's disease (HD) is a neurodegenerative disorder characterized by involuntary movements, cognitive decline, and behavioral changes. The complex constellation of clinical symptoms still makes the therapeutic management challenging. In the new era of functional neurosurgery, deep brain stimulation (DBS) may represent a promising therapeutic approach in selected HD patients., Methods: Articles describing the effect of DBS in patients affected by HD were selected from Medline and PubMed by the association of text words with MeSH terms as follows: "Deep brain stimulation," "DBS," and "HD," "Huntington's disease," and "Huntington." Details on repeat expansion, age at operation, target of operation, duration of follow-up, stimulation parameters, adverse events, and outcome measures were collected., Results: Twenty eligible studies, assessing 42 patients with HD, were identified. The effect of globus pallidus internus (GPi) DBS on Unified Huntington's Disease Rating Scale (UHDRS) total score revealed in 10 studies an improvement of total score from 5.4 to 34.5%, and in 4 studies, an increase of motor score from 3.8 to 97.8%. Bilateral GPi-DBS was reported to be effective in reducing Chorea subscore in all studies, with a mean percentage reduction from 21.4 to 73.6%., Conclusions: HD patients with predominant choreic symptoms may be the best candidates for surgery, but the role of other clinical features and of disease progression should be elucidated. For this reason, there is a need for more reliable criteria that may guide the selection of HD patients suitable for DBS. Accordingly, further studies including functional outcomes as primary endpoints are needed., (© 2021. Fondazione Società Italiana di Neurologia.)

Inflatable robots are becoming increasingly popular, especially in applications where safe interactions are a priority. However, designing multifunctional robots that can operate with a single pressure input is challenging. A potential solution is to couple inflatables with passive valves that can harness the flow characteristics to create functionality. In this study, simple, easy to fabricate, lightweight, and inexpensive mechanical valves are presented that harness viscous flow and snapping arch principles. The mechanical valves can be fully integrated on-board, enabling the control of the incoming airflow to realize multifunctional robots that operate with a single pressure input, with no need for electronic components, cables, or wires. By means of three robotic demos and guided by a numerical model, the capabilities of the valves are demonstrated and optimal input profiles are identified to achieve prescribed functionalities. The study enriches the array of available mechanical valves for inflatable robots and enables new strategies to realize multifunctional robots with on-board flow control., (© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Objectives: Levodopa-Carbidopa Intrajejunal gel (LCIG) infusion is an effective intervention for people with advanced Parkinson's disease (PD). Although age may not be a limiting factor for LCIG implant, no data are available on late elderly PD (LE-PD) subjects. In this cross-sectional, we aimed to demonstrate if older age may impact on quality of life (QoL), motor and non-motor symptoms severity, and profile of side effects in PD treated with LCIG., Methods: Out of 512 PD subjects treated with LCIG at 9 Italian PD centers, we selected 25 LE-PD defined as age ≥ 80 years at last follow-up who were available to attend the study visit. Twenty-five PD patients (Control-PD, defined as age < 75 years at last follow-up) matched to LE-PD by disease and LCIG duration served as control group. The following motor and non-motor variables were ascertained: quality of life (PDQ-8), time spent in ON, wearing-off Questionnaire, Unified PD Rating Scale, freezing of gait questionnaire, Parkinson's disease sleep scale-2, Non Motor Symptoms Scale (NMSS), and MOCA., Results: No statistically significant differences were found between LE-PD and Control-PD on PDQ-8 and several motor and non-motor variables. LE-PD had less frequent and milder impulsive-compulsive behaviors and milder dyskinesia. At multivariable regression, worse quality of life was associated with UPDRS-III and NMSS scores but not to age at study visit and age at LICG implant. Rate of adverse effects was similar in both groups. Drop-out rate calculated in the whole PD cohort was comparable between the two groups., Conclusion: Our data provide evidence that valuable LCIG infusion might be achieved in late elderly PD.

BACKGROUND AND OBJECTIVE: Safinamide is a novel anti-parkinsonian drug with possible anti-dyskinetic properties. Parkinson's disease (PD) is a complex disease. The objective of this systematic review and meta-analysis is to evaluate the efficacy and safety of safinamide administration compared to placebo in PD patients on multiple outcomes., Methods: PubMed, EMBASE, Cochrane CENTRAL, LILACS, and trial databases were searched up to 23 December 2020 for randomized controlled studies (RCTs) comparing safinamide to placebo, alone or as add-on therapy in PD. Data were extracted from literature and regulatory agencies. Primary outcomes were ON-time without troublesome dyskinesia, OFF-time, and Unified Parkinson's Disease Rating Scale (UPDRS) section III (UPDRS-III). Secondary outcomes included any dyskinesia rating scale (DRS), ON-time with troublesome dyskinesia, UPDRS-II, and Parkinson's Disease Questionnaire 39 (PDQ-39). In order to estimate mean difference (MD) and odds ratios with 95% confidence intervals (CI), generic inverse variance and Mantel-Haenszel methods were used for continuous and dichotomous variables, respectively. Analyses were performed grouping by PD with (PDwMF) or without (PDwoMF) motor fluctuations, safinamide dose, and concomitant dopaminergic treatment. Summary of findings with GRADE were performed., Results: Six studies with a total of 2792 participants were identified. In PDwMF patients, safinamide 100 mg as add-on to levodopa (L-dopa) significantly increased ON-time without troublesome dyskinesia (MD = 0.95 h; 95% CI from 0.41 to 1.49), reduced OFF-time (MD = - 1.06 h; 95% CI from - 1.60 to - 0.51), and improved UPDRS-III (MD = - 2.77; 95% CI from - 4.27 to - 1.28) with moderate quality of evidence. Similar results were observed for the 50 mg dose. However, the quality of evidence was moderate only for ON-time without troublesome dyskinesia, whereas for OFF-time and UPDRS-III was low. In PDwoMF patients taking a single dopamine agonist, safinamide 100 mg resulted in little to no clinically significant improvement in UPDRS-III (MD = - 1.84; 95% CI from - 3.19 to - 0.49), with moderate quality of evidence. Conversely, in PDwoMF patients, the 200 mg and 50 mg doses showed nonsignificant improvement in UPDRS-III, with very low and moderate quality of evidence, respectively. In PDwMF patients taking safinamide 100 mg or 50 mg, nonsignificant differences were observed for ON-time with troublesome dyskinesia and DRS, with high and low quality of evidence, respectively. In the same patients, UPDRS-II was significantly improved at the 100 mg and 50 mg dose, with high and moderate quality of evidence. In PDwoMF, UPDRS-II showed a little yet significant difference only at 100 mg, with low quality of evidence. PDQ-39 resulted significantly improved only with the 100 mg dose in PDwMF, with low quality of evidence., Conclusion: Overall, safinamide is effective in PDwMF patients taking L-dopa both at 100 and 50 mg daily. Evidence for efficacy in early PD is limited. Further trials are needed to better evaluate the anti-dyskinetic properties of safinamide.

Objective: The study was undertaken to identify a monogenic cause of early onset, generalized dystonia., Methods: Methods consisted of genome-wide linkage analysis, exome and Sanger sequencing, clinical neurological examination, brain magnetic resonance imaging, and protein expression studies in skin fibroblasts from patients., Results: We identified a heterozygous variant, c.388G>A, p.Gly130Arg, in the eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) gene, segregating with early onset isolated generalized dystonia in 5 patients of a Taiwanese family. EIF2AK2 sequencing in 191 unrelated patients with unexplained dystonia yielded 2 unrelated Caucasian patients with an identical heterozygous c.388G>A, p.Gly130Arg variant, occurring de novo in one case, another patient carrying a different heterozygous variant, c.413G>C, p.Gly138Ala, and one last patient, born from consanguineous parents, carrying a third, homozygous variant c.95A>C, p.Asn32Thr. These 3 missense variants are absent from gnomAD, and are located in functional domains of the encoded protein. In 3 patients, additional neurological manifestations were present, including intellectual disability and spasticity. EIF2AK2 encodes a kinase (protein kinase R [PKR]) that phosphorylates eukaryotic translation initiation factor 2 alpha (eIF2α), which orchestrates the cellular stress response. Our expression studies showed abnormally enhanced activation of the cellular stress response, monitored by PKR-mediated phosphorylation of eIF2α, in fibroblasts from patients with EIF2AK2 variants. Intriguingly, PKR can also be regulated by PRKRA (protein interferon-inducible double-stranded RNA-dependent protein kinase activator A), the product of another gene causing monogenic dystonia., Interpretation: We identified EIF2AK2 variants implicated in early onset generalized dystonia, which can be dominantly or recessively inherited, or occur de novo. Our findings provide direct evidence for a key role of a dysfunctional eIF2α pathway in the pathogenesis of dystonia. ANN NEUROL 2021;89:485-497., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Introduction: Specific pre-existing medical conditions (e.g. hypertension or obesity), advanced age and male sex appear linked to more severe manifestations of SARS Co-V2 infection, thus raising the question of whether Parkinson's disease (PD) poses an increased risk of morbidity and mortality in COVID-19 patients., Methods: In order to describe the outcome of COVID-19 in multi-centre a cohort of PD patients and explore its potential predictors, we gathered the clinical information of 117 community-dwelling patients with COVID-19 followed in 21 tertiary centres in Italy, Iran, Spain, and the UK., Results: Overall mortality was 19.7%, with a significant effect of co-occurrence of dementia, hypertension, and PD duration., Conclusions: The frailty caused by advanced PD poses an increased risk of mortality during COVID-19., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

The impact of coronavirus disease 2019 (COVID-19) on clinical features of Parkinson's disease (PD) has been poorly characterized so far. Of 141 PD patients resident in Lombardy, we found 12 COVID-19 cases (8.5%), whose mean age and disease duration (65.5 and 6.3 years, respectively) were similar to controls. Changes in clinical features in the period January 2020 to April 2020 were compared with those of 36 PD controls matched for sex, age, and disease duration using the clinical impression of severity index for PD, the Movement Disorders Society Unified PD Rating Scale Parts II and IV, and the nonmotor symptoms scale. Motor and nonmotor symptoms significantly worsened in the COVID-19 group, requiring therapy adjustment in one third of cases. Clinical deterioration was explained by both infection-related mechanisms and impaired pharmacokinetics of dopaminergic therapy. Urinary issues and fatigue were the most prominent nonmotor issues. Cognitive functions were marginally involved, whereas none experienced autonomic failure. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Kirigami, the Japanese art of paper cutting, has recently enabled the design of stretchable mechanical metamaterials that can be easily realized by embedding arrays of periodic cuts into an elastic sheet. Here, kirigami principles are exploited to design inflatables that can mimic target shapes upon pressurization. The system comprises a kirigami sheet embedded into an unstructured elastomeric membrane. First, it is shown that the inflated shape can be controlled by tuning the geometric parameters of the kirigami pattern. Then, by applying a simple optimization algorithm, the best parameters that enable the kirigami inflatables to transform into a family of target shapes at a given pressure are identified. Furthermore, thanks to the tessellated nature of the kirigami, it is shown that we can selectively manipulate the parameters of the single units to allow the reproduction of features at different scales and ultimately enable a more accurate mimicking of the target., (© 2020 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Infectious disease is still a major threat in the world today. Five decades ago, it was considered soon to be eradicated, but the adaptation of pathogens to environmental pressure, such as antimicrobials, encouraged the emergence and reemergence of infectious disease. The fight with infectious disease starts with prevention, diagnosis, and treatment. Diagnosis can be upheld by observing the cause of disease under the microscope or detecting the presence of nucleic acid and proteins of the pathogens. The molecular techniques span from classical polymerase chain reaction (PCR) to sequencing the nucleic acid composition. Here, we are reviewing the works have been undertaken to utilize a portable sequencer, MinION, in various aspects of infectious disease management.

Humans are highly skilled at analysing complex acoustic scenes. The segregation of different acoustic streams and the formation of corresponding neural representations is mostly attributed to the auditory cortex. Decoding of selective attention from neuroimaging has therefore focussed on cortical responses to sound. However, the auditory brainstem response to speech is modulated by selective attention as well, as recently shown through measuring the brainstem's response to running speech. Although the response of the auditory brainstem has a smaller magnitude than that of the auditory cortex, it occurs at much higher frequencies and therefore has a higher information rate. Here we develop statistical models for extracting the brainstem response from multi-channel scalp recordings and for analysing the attentional modulation according to the focus of attention. We demonstrate that the attentional modulation of the brainstem response to speech can be employed to decode the attentional focus of a listener from short measurements of 10 s or less in duration. The decoding remains accurate when obtained from three EEG channels only. We further show how out-of-the-box decoding that employs subject-independent models, as well as decoding that is independent of the specific attended speaker is capable of achieving similar accuracy. These results open up new avenues for investigating the neural mechanisms for selective attention in the brainstem and for developing efficient auditory brain-computer interfaces., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

People with normal hearing thresholds can nonetheless have difficulty with understanding speech in noisy backgrounds. The origins of such supra-threshold hearing deficits remain largely unclear. Previously we showed that the auditory brainstem response to running speech is modulated by selective attention, evidencing a subcortical mechanism that contributes to speech-in-noise comprehension. We observed, however, significant variation in the magnitude of the brainstem's attentional modulation between the different volunteers. Here we show that this variability relates to the ability of the subjects to understand speech in background noise. In particular, we assessed 43 young human volunteers with normal hearing thresholds for their speech-in-noise comprehension. We also recorded their auditory brainstem responses to running speech when selectively attending to one of two competing voices. To control for potential peripheral hearing deficits, and in particular for cochlear synaptopathy, we further assessed noise exposure, the temporal sensitivity threshold, the middle-ear muscle reflex, and the auditory-brainstem response to clicks in various levels of background noise. These tests did not show evidence for cochlear synaptopathy amongst the volunteers. Furthermore, we found that only the attentional modulation of the brainstem response to speech was significantly related to speech-in-noise comprehension. Our results therefore evidence an impact of top-down modulation of brainstem activity on the variability in speech-in-noise comprehension amongst the subjects.

Background: Parkinson's disease (PD) is a neurodegenerative disorder whose diagnosis is often challenging because symptoms may overlap with neurodegenerative parkinsonisms. PD is characterized by intraneuronal accumulation of abnormal α-synuclein in brainstem while neurodegenerative parkinsonisms might be associated with accumulation of either α-synuclein, as in the case of Multiple System Atrophy (MSA) or tau, as in the case of Corticobasal Degeneration (CBD) and Progressive Supranuclear Palsy (PSP), in other disease-specific brain regions. Definite diagnosis of all these diseases can be formulated only neuropathologically by detection and localization of α-synuclein or tau aggregates in the brain. Compelling evidence suggests that trace-amount of these proteins can appear in peripheral tissues, including receptor neurons of the olfactory mucosa (OM)., Methods: We have set and standardized the experimental conditions to extend the ultrasensitive Real Time Quaking Induced Conversion (RT-QuIC) assay for OM analysis. In particular, by using human recombinant α-synuclein as substrate of reaction, we have assessed the ability of OM collected from patients with clinical diagnoses of PD and MSA to induce α-synuclein aggregation, and compared their seeding ability to that of OM samples collected from patients with clinical diagnoses of CBD and PSP., Results: Our results showed that a significant percentage of MSA and PD samples induced α-synuclein aggregation with high efficiency, but also few samples of patients with the clinical diagnosis of CBD and PSP caused the same effect. Notably, the final RT-QuIC aggregates obtained from MSA and PD samples owned peculiar biochemical and morphological features potentially enabling their discrimination., Conclusions: Our study provide the proof-of-concept that olfactory mucosa samples collected from patients with PD and MSA possess important seeding activities for α-synuclein. Additional studies are required for (i) estimating sensitivity and specificity of the technique and for (ii) evaluating its application for the diagnosis of PD and neurodegenerative parkinsonisms. RT-QuIC analyses of OM and cerebrospinal fluid (CSF) can be combined with the aim of increasing the overall diagnostic accuracy of these diseases, especially in the early stages., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Mitochondrial dynamics and quality control are crucial for neuronal survival and their perturbation is a major cause of neurodegeneration. m-AAA complex is an ATP-dependent metalloprotease located in the inner mitochondrial membrane and involved in protein quality control. Mutations in the m-AAA subunits AFG3L2 and paraplegin are associated with autosomal dominant spinocerebellar ataxia (SCA28) and autosomal recessive hereditary spastic paraplegia (SPG7), respectively. We report a novel m-AAA-associated phenotype characterized by early-onset optic atrophy with spastic ataxia and L-dopa-responsive parkinsonism. The proband carried a de novo AFG3L2 heterozygous mutation (p.R468C) along with a heterozygous maternally inherited intragenic deletion of SPG7. Functional analysis in yeast demonstrated the pathogenic role of AFG3L2 p.R468C mutation shedding light on its pathogenic mechanism. Analysis of patient's fibroblasts showed an abnormal processing pattern of OPA1, a dynamin-related protein essential for mitochondrial fusion and responsible for most cases of hereditary optic atrophy. Consistently, assessment of mitochondrial morphology revealed a severe fragmentation of the mitochondrial network, not observed in SCA28 and SPG7 patients' cells. This case suggests that coincidental mutations in both components of the mitochondrial m-AAA protease may result in a complex phenotype and reveals a crucial role for OPA1 processing in the pathogenesis of neurodegenerative disease caused by m-AAA defects., (© 2018 Wiley Periodicals, Inc.)

This study aimed to investigate phosphorylated α-synuclein (p-syn) in autonomic skin nerves of Parkinson disease (PD) patients with and without orthostatic hypotension (OH). We studied 28 PD patients with normal corrected Mini-Mental State Examination including 14 patients with neurogenic OH (PD + OH) and 14 matched patients did not complain of OH (PD - OH); 7 of whom were re-evaluated over a follow-up period (4 ± 2 years). Skin biopsy was performed in proximal and distal sites. PD + OH patients showed a higher p-syn deposition than PD - OH, with widespread autonomic cholinergic and adrenergic skin nerve involvement. Over the follow-up period, PD - OH patients showed an increase in motor dysfunction scores without autonomic symptoms and a slight increase of skin p-syn deposition but still lower than PD + OH, mainly restricted to adrenergic fibers of skin vessels (SV). In summary, PD + OH patients showed a wide involvement of p-syn deposits in autonomic cholinergic and adrenergic skin nerves compared with PD - OH, and PD - OH patients showed a lower load of skin p-syn restricted to adrenergic fibers of SV still persisting over the follow-up period. The data supported a different pathogenesis between PD + OH and PD - OH and may help to identify a specific diagnostic trait for PD + OH.

Cerebral palsy (CP) is a heterogeneous group of syndromes that cause a non-progressive disorder of early onset, with abnormal control of movement and posture. Various aetiologies can cause the CP clinical spectrum, but all have a disruption of motor control in common. CP can be divided into four major types based on the motor disability: predominant spastic, dyskinetic, ataxic and mixed form. Dyskinetic CP (DCP) is the most common cause of acquired dystonia in children. The treatment of DCP is challenging because most individuals have mixed degrees of chorea, athetosis and dystonia. Pharmacological treatment is often unsatisfactory. Functional neurosurgery, in particular deep brain stimulation targeting the basal ganglia or the cerebellum, is emerging as a promising therapeutic approach in selected patients with DCP. We evaluated herein the effects of DBS on patients with DCP in a review of published patient data in the largest available studies., (Copyright © 2017. Published by Elsevier Ltd.)