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Since the initial description of Essential Tremor (ET), the entity of ET with rest tremor has proven to be a controversial concept. Some authors argued it could be a late manifestation of ET, others suggested it could be a variant of ET, yet others suggested it could represent a transitional state between ET and Parkinson's disease. The novel tremor classification has proposed the construct of ET-plus to differentiate patients with rest tremor from pure ET. However, there is no clarity of what ET-plus rest tremor represents. With the aim of shedding light on this controversial entity, we have, therefore, systematically reviewed all clinical, electrophysiological, imaging and anatomopathological studies indexed in the Medline database published both before and after the new tremor classification and involving patients with ET-plus rest tremor. Forty-four studies involving 4028 patients were included in this review and analyzed in detail by means of descriptive statistics. The results of the current review suggest that ET-plus rest tremor is a heterogenous group of conditions: thus, rest tremor might represent a late feature of ET, might reflect a different disorder with higher age at onset and lower dependance on genetic susceptibility than ET, might suggest the development of Parkinson's disease or might indicate a misdiagnosis of ET. The reviewed lines of evidence refuse recent claims arguing against the construct of ET-plus, which should be viewed as a syndrome with different possible underpinnings, and highlights methodological issues to be solved in future research.

Background Depression is a prodromic and a frequent non-motor symptom of Parkinson’s disease, associated to reduced quality of life and poor outcomes. The diagnosis of depression in parkinsonian patients represents a challenge due to the overlapping of symptoms typical of the two conditions. Methods A Delphi panel survey was performed to reach a consensus amongst different Italian specialists on four main topics: the neuropathological correlates of depression, main clinical aspects, diagnosis, and management of depression in Parkinson’s disease. Results and conclusion Experts have recognized that depression is an established risk factor of PD and that its anatomic substrate is related to the neuropathological abnormalities typical of the disease. Multimodal and SSRI antidepressant have been confirmed as a valid therapeutic option in the treatment of depression in PD. Tolerability, safety profile, and potential efficacy on broad spectrum of symptoms of depression including cognitive symptoms and anhedonia should be considered when selecting an antidepressant and the choice should be tailored on the patients’ characteristics.

Objective The Fist-Palm Test (FiPaT) is a novel non-verbal task to be used at the patient’s bedside for a cognitive functions screening. The aims of this study are to analyze (I) the qualitative and quantitative performance features at FiPaT, (II) the psychometric characteristics of FiPaT, and (III) the correlation between FiPat and traditional cognitive assessments in subjects with normal cognition (NC), Mild Cognitive Impairment-single domain (MCI-sd), and Mild Cognitive Impairment-multiple domain (MCI-md). Methods One hundred-thirteen subjects (53M/60F), with a mean age of 66.28 ± 7.22 years and 11.08 ± 4.93 years of education, were recruited and underwent a complete neuropsychological battery and FiPaT. Results We found 68 subjects with NC, 31 with MCI-sd, and 14 with MCI-md and a high reliability of the FiPaT (alpha =0.762). The number of FiPaT errors correlated with age and all neuropsychological tests, except for the memory recall test. Subjects with MCI had greater FiPaT errors than subjects with NC. The FiPaT, used with the MOCA test, predicted the presence of MCI, with a variance of 44%. Conclusion The FiPaT is an acceptable and reliable non-verbal test, able to screen for global cognitive status, attention, and executive functions, and to predict the MCI. Future studies will validate this initial findings as well as the discriminatory role of the FiPaT in detecting specific types of cognitive impairment.

Major progress has occurred during the last decade in the field of tremor. From the clinical standpoint, a new classification has completely revised the nosology of tremor syndromes and has re-conceptualized essential tremor as a syndrome rather than a single disease entity, fueling an ongoing enlightened debate. Significant advances have been obtained in terms of instrumental measurement of tremor, remarking on the possibility of developing novel treatment strategies based on tremor characteristics, namely tremor-phase. Moreover, a better understanding of the pathophysiological mechanisms has further led to the suggestion of refining the classification of tremor syndromes according to their driving underpinnings. Finally, surgical options such as deep brain stimulation and focused ultrasound thalamotomy are now part of the therapeutic portfolio for tremor, but several oral drugs, including long-chain alcohols, T-channel blockers, allosteric modulators of potassium channels, and of GABA-A receptors, are currently being tested and hold promise. This review will discuss the key milestones in tremor research of the last 10 years, with a focus on the most common tremor syndromes, namely essential tremor, dystonic tremor, and Parkinsonian tremor.

Background The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. Objective In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA. Methods We analyzed [11 C]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. Results We observed a conspicuous pattern of elevated regional [11 C]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. Conclusions We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an α-synucleinopathy that remains strikingly incurable. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

We describe a case of intrathecal methotrexate toxicity and perform a literature review of existing cases.A 23-year-old man who received diagnosis of acute lymphoblastic leukemia and started chemotherapy according to the LAL1913 protocol underwent CNS prophylaxis with intrathecal methotrexate. About 1 month after, he developed a flaccid paraparesis. CSF analysis showed albumin/cytological dissociation. Spinal MRI showed thickening of the ventral roots of the cauda equina with contrast enhancement. Nerve conduction studies showed severe lower limb motor axonal neuropathy. Needle examination showed acute denervation involving L3-S1 roots. Methotrexate was stopped, and the patient was treated with intravenous immunoglobulins, followed by high-dose intravenous methylprednisolone, with a gradual improvement. Three months later, the spine MRI was normal. Electrophysiological and imaging findings were indicative of pure motor L3-S1 polyradiculopathy.Literature review of existing cases confirm the relatively selective involvement of lumbosacral ventral roots in intrathecal methotrexate toxicity. Pathophysiologic mechanisms suggest either a direct toxicity with localized folate deficiency or an immune-mediated mechanism, the latter consistent, in our patient, with the albumin/cytological dissociation and response to immunomodulatory treatments. Pure motor polyradiculopathy of the lower limbs is rare but predictable complication of intrathecal methotrexate, which can benefit from early withdrawal and immunomodulatory treatments.

Background The evidence about the language performance profile of multiple system atrophy (MSA) is limited, but its definition may lead to a more comprehensive characterization of the disorder and contribute to clarify the involvement of the basal ganglia in language abilities. Objective The objectives of the study were: (1) to evaluate the reliability of the Screening for Aphasia in NeuroDegeneration (SAND) in MSA patients; (2) compare the linguistic profiles among MSA and Parkinson’s disease (PD) patients and healthy controls (HC), and (3) assess relationships between language impairment and cognitive status and MSA motor subtypes. Methods and results Forty patients with a diagnosis of MSA, 22 HC and 17 patients with PD were enrolled in the present study. By excluding the writing task that showed a poor acceptability, we showed that the MSA-tailored SAND Global Score is an acceptable, consistent and reliable tool to screen language disturbances in MSA. MSA patients performed worse than HC, but not than PD, in MSA-tailored SAND Global Score, repetition, reading and semantic association tasks. We did not find significant differences between MSA phenotypes. MSA patients with mild cognitive impairment-multiple domain presented worse language performances as compared to MSA patients with normal cognition and mild cognitive impairment-single domain. Conclusion The MSA-tailored SAND Global Score is a consistent and reliable tool to screen language disturbances in MSA. Language disturbances characterize MSA patients irrespective of disease phenotype, and parallel the decline of global cognitive functions.

The exact pathophysiology of cognitive impairment in multiple system atrophy (MSA) is unclear. In our longitudinal study, we aimed to analyze (I) the relationships between cognitive functions and some subcortical structures, such as putamen and cerebellum assessed by voxel-based morphometry (VBM) and T1-weighted/T2-weighted (T1w/T2w) ratio, and (II) the neuroimaging predictors of the progression of cognitive deficits. Twenty-six patients with MSA underwent a comprehensive neuropsychological battery, motor examination, and brain MRI at baseline (T0) and 1-year follow-up (T1). Patients were then divided according to cognitive status into MSA with normal cognition (MSA-NC) and MSA with mild cognitive impairment (MCI). At T1, we divided the sample according to worsening/non worsening of cognitive status compared to baseline evaluation. Logistic regression analysis showed that age (β = − 9.45, p = .02) and T1w/T2w value in the left putamen (β = 230.64, p = .01) were significant predictors of global cognitive status at T0, explaining 65% of the variance. Logistic regression analysis showed that ∆-values of WM density in the cerebellum/brainstem (β = 2188.70, p = .02) significantly predicted cognitive worsening at T1, explaining 64% of the variance. Our results suggest a role for the putamen and cerebellum in the cognitive changes of MSA, probably due to their connections with the cortex. The putaminal T1w/T2w ratio may deserve further studies as a marker of cognitive impairment in MSA.

AgF2 has been proposed as a cuprate analogue which requires strong correlation and marked covalence. On the other hand, fluorides are usually quite ionic and 4d transition metals tend to be less correlated than their 3d counterparts, which calls for further scrutiny. We combine valence band photoemission and Auger-Meitner spectroscopy of AgF and AgF2 together with computations in small clusters to estimate values of the Ag 4d Coulomb interaction U 4d and charge-transfer energy. Based on these values, AgF2 can be classified as a charge-transfer correlated insulator according to the Zaanen-Sawatzky-Allen classification scheme. Thus, we confirm that the material is a cuprate analogue from the point of view of correlations, suggesting that it should become a high-temperature superconductor if metallization is achieved by doping. We present also a computation of the Hubbard U in density functional "+U" methods and discuss its relation to the Hubbard U in spectroscopies., Comment: 12 pages, 10 figures

Temporal muscle thickness (TMT) is a new potential MRI biomarker, which has shown prognostic relevance in neuro-oncology. We aim at investigating the potential prognostic value of TMT in patients with Amyotrophic Lateral Sclerosis (ALS). We retrospectively evaluated 30 ALS patients, whose clinical, Magnetic Resonance Imaging (MRI) and Electrodiagnostic testing (EDX) data were available, in comparison to age-matched 30 healthy subjects. TMT calculated on T1-weighted MR images was significantly lower in ALS patients than in healthy subjects (p&nbsp

A relationship between sleep disorders and cognitive dysfunctions was reported in Parkinson’s Disease (PD), however, some studies did not confirm the link. A meta-analytic study was performed to investigate the relationship between sleep disorders and cognitive dysfunctions, and to clarify the evolution of cognitive status in PD patients with sleep disorders. The systematic literature search was performed up to November 2020 using PubMed, Scopus, and PsycINFO databases. We included studies published in peer-reviewed journals in English providing results about neuropsychological comparison between patients with or without sleep disorders. Meta-analysis on cross-sectional data included 54 studies for REM Sleep Behavior Disorder (RBD), 22 for Excessive Daytime Sleepiness (EDS), 7 for Obstructive Sleep Apnea (OSA), 13 for Restless Legs Syndrome (RLS), and 5 for insomnia, the meta-analysis on longitudinal data included 7 studies. RBD was related to deficits of global cognitive functioning, memory, executive functions, attention/working memory, language, and visuospatial abilities. EDS was associated with deficits of global cognitive functioning and attention and working memory abilities, whereas RLS and OSA were related to global cognitive dysfunction. Moreover, we revealed that PD patients with RBD and those with EDS performed worse than PD patients without sleep disorders at follow-up rather than baseline evaluation. Our results suggest that sleep disorders are associated with cognitive deficits supporting indirectly that these, especially the REM Sleep Behavior Disorder, reflect abnormalities of frontal networks and posterior cortical areas. Sleep disorders in patients with PD seem to also increase the risk for long-term cognitive decline.

Curved magnets attract considerable interest for their unusually rich phase diagram, often encompassing exotic (e.g., topological or chiral) spin states. Micromagnetic simulations are playing a central role in the theoretical understanding of such phenomena; their predictive power, however, rests on the availability of reliable model parameters to describe a given material or nanostructure. Here we demonstrate how noncollinear-spin polarized density-functional theory can be used to determine the flexomagnetic coupling coefficients in real systems. By focusing on monolayer CrI_{3}, we find a crossover as a function of curvature between a magnetization normal to the surface to a cycloidal state, which we rationalize in terms of effective anisotropy and Dzyaloshinskii-Moriya contributions to the magnetic energy. Our results reveal an unexpectedly large impact of spin-orbit interactions on the curvature-induced anisotropy, which we discuss in the context of existing phenomenological models., We acknowledge financial support from the Swedish Research Council (VR—2018-06807). M. S. acknowledges the support of Ministerio de Ciencia e Innovación (MICINN-Spain) through Grant No. PID2019–108573GBC22, and Severo Ochoa FUNFUTURE center of excellence (CEX2019-000917-S); of Generalitat de Catalunya (Grant No. 2017 SGR1506); and of the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (Grant Agreement No. 724529). P. B. and S. P. acknowledge financial support from Italian MIUR under the PRIN project “Tuning and Understanding Quantum Phases in 2D Materials— Quantum2D,” Grant No. 2017Z8TS5B and “TWEET: Towards Ferroelectricity in Two Dimensions,” Grant No. 2017YCTB59, respectively. D. A. and S. P. acknowledge financial support by the Nanoscience Foundries and Fine Analysis (NFFA-MIUR Italy) project. The authors thankfully acknowledge the computer resources at Pirineus and the technical support provided by CSUC (RES-FI- 2021-1-0034). Additionally, computational work was done on resources at PDC, Stockholm, via the Swedish National Infrastructure for Computing (SNIC)., With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).

BackgroundLevodopa (LD) is the most effective drug in the treatment of Parkinson’s disease (PD). Unfortunately, prolonged use of LD leads to complications, mainly motor/non-motor fluctuations (MNMF) and dyskinesias (DYS). Women seem more prone to develop such LD-related complications. Nonetheless, there is a paucity of prospective studies examining gender-related predictors of MNMF and DYS. Among several factors, which concur with a very complex scenario, changes in LD pharmacokinetics influence the drug’s effectiveness. The present study aimed to assess gender-related differences in LD pharmacokinetics in patients with PD at their first-ever intake of LD.Materials and MethodsThis is a multicentric study enrolling patients with PD, who were LD-naïve and received a single dose of LD/benserazide (100/25 mg) formulation. All participants gave their written informed consent, and the study was approved by the local Ethics Committees. To measure plasma LD concentrations and pharmacokinetic parameters (AUC, Cmax, Tmax, t1/2), fasting blood samples were collected before drug intake and then at 8-time points until 260 min. LD concentrations were measured by ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC-MS). Multiple linear regression analyses were performed to identify the predictors of the parameters.ResultsThirty-five patients (16 women and 19 men) were consecutively enrolled. Area under curve (AUC) and maximum plasma concentration (Cmax) were significantly higher in women than men (p = 0.0006 and p = 0.0014, respectively). No statistically significant difference was found regarding Tmax and t1/2. Multiple linear regression analyses revealed that female sex (β = 1.559116, 95% CI 0.8314479 2.286785; p < 0.0001) and body mass index (BMI) (β = −0.0970631, 95% CI −0.1733004 −0.0208258; p = 0.014) significantly predicted AUC. Only female sex significantly predicted Cmax (β = 1,582.499, 95% CI 731.581 2,433.417; p = 0.001). Moreover, only BMI significantly predicted t1/2 (β = 0.0756267, 95% CI 0.0143407 0.1369126; p = 0.017). Stratifying by gender, BMI was confirmed to significantly predict t1/2 in women (β = 0.1300486, 95% CI 0.0172322 0.242865; p = 0.027), but not in men.ConclusionThis study provides novel insights on gender differences in LD pharmacokinetics, possibly contributing to the later development of motor complications and dyskinesia in PD.

Hyposmia is a common finding in Parkinson’s disease (PD) and is usually tested through the University of Pennsylvania Smell Identification Test (UPSIT). The aim of our study is to provide a briefer version of the Italian-adapted UPSIT test, able to discriminate between PD patients and healthy subjects (HS). By means of several univariate and multivariate (machine-learning-based) statistical approaches, we selected 8 items by which we trained a partial-least-square discriminant analysis (PLS-DA) and a decision tree (DT) model: class predictions of both models performed better with the 8-item version when compared to the 40-item version. An area under the receiver operating characteristic (AUC-ROC) curve built with the selected 8 odors showed the best performance (sensitivity 86.8%, specificity 82%) in predicting the PD condition at a cut-off point of ≤ 6. These performances were higher than those previously calculated for the 40-item UPSIT test (sensitivity 82% and specificity 88.2 % with a cut-off point of ≤ 21). Qualitatively, our selection contains one odor (i.e., apple) which is Italian-specific, supporting the need for cultural adaptation of smell testing; on the other hand, some of the selected best discriminating odors are in common with existing brief smell test versions validated on PD patients of other cultures, supporting the view that disease-specific odor patterns may exist and deserve a further evaluation.

Parkinson’s Disease (PD) is a neurodegenerative disease which involves both motor and non-motor symptoms. Non-motor mental symptoms are very common among patients with PD since the earliest stage. In this context, gait analysis allows to detect quantitative gait variables to distinguish patients affected by non-motor mental symptoms from patients without these symptoms. A cohort of 68 PD subjects (divided in two groups) was acquired through gait analysis (single and double task) and spatial temporal parameters were analysed; first with a statistical analysis and then with a machine learning (ML) approach. Single-task variables showed that 9 out of 16 spatial temporal features were statistically significant for the univariate statistical analysis (p-value< 0.05). Indeed, a statistically significant difference was found in stance phase (p-value=0.032), swing phase (p-value=0.042) and cycle length (p-value=0.03) of the dual task. The ML results confirmed the statistical analysis, in particular, the Decision Tree classifier showed the highest accuracy (80.9%) and also the highest scores in terms of specificity and precision. Our findings indicate that patients with non-motor mental symptoms display a worse gait pattern, mainly dominated by increased slowness and dynamic instability.

Background The clinical differentiation between Parkinson disease (PD) and multiple system atrophy (MSA) is difficult. Objectives Arterial spin labeling (ASL) is an advanced MRI technique that obviates the use of an exogenous contrast agent for the estimation of cerebral perfusion. We explored the value of ASL in combination with structural MRI for the differentiation between PD and MSA. Methods Ninety-four subjects (30 PD, 30 MSA and 34 healthy controls) performed a morphometric and ASL-MRI to measure volume and perfusion values within basal ganglia and cerebellum. A region-of-interest analysis was performed to test for structural atrophy and regional blood flow differences between groups. Results MSA patients showed higher subcortical atrophy than both PD patients and HC, while no differences were observed between the latter. MSA and PD showed lower volume-corrected perfusion values than HC in several cerebellar areas (Crus I, Crus II, right VIIb, right VIIIa, right VIIIb), right caudate and both thalami. MSA and PD patients displayed similar perfusion values in all aforementioned areas, but the right cerebellar area VIIIb (lower in MSA) and right caudate and both thalami (lower in PD). Similar results were obtained when comparing PD and MSA patients with the parkinsonian variant. Conclusions A perfusion reduction was equally observed in both MSA and PD patients in cerebellar areas that are putatively linked to cognitive (i.e., executive) rather than motor functions. The observed hypo-perfusion could not be explained by atrophy, suggesting the involvement of the cerebellum in the pathophysiology of both MSA and PD.

Introduction Cognitive deficits and neuropsychiatric symptoms occur in parkinsonian and cerebellar subtypes of Multiple System Atrophy (MSA-P and MSA-C). These symptoms have been investigated mainly in cross-sectional studies. The present 1-year follow-up study aimed at evaluating the evolution of cognitive and neuropsychiatric profile in patients with MSA-C and MSA-P. Methods Twenty-nine patients with MSA-P, 21 with MSA-C and 30 healthy subjects (HCs) underwent a neuropsychological battery and questionnaires assessing depression and apathy (T0). After 1 year (T1), patients with MSA-C and MSA-P underwent the same neuropsychological and neuropsychiatric tools employed at T0. Results At T0, MSA-P and MSA-C groups were more depressed and apathetic and performed worse on tests assessing repetition abilities, executive and attentive functions than HCs. MSA-P and MSA-C groups did not differ on cognitive variables and neuropsychiatric scales. At T1, a significant worsening in spatial planning and psychomotor speed in MSA-C group and a significant worsening in memory, spatial planning, repetition abilities and functional autonomy in MSA-P group were found. The prevalence of apathy increased in both subtypes, whereas the prevalence of depression was reduced in MSA-C and relatively consistent in MSA-P. Conclusions The finding revealed a wide-ranging worsening of cognitive functions in MSA-P and a significant decline in processing speed in MSA-C. These results underline the relevance of evaluating cognitive and psychiatric features of MSA over the course of the disease in the daily clinical practice.

Background Available evidence reports conflicting data on retinal thickness in progressive supranuclear palsy (PSP). In studies including healthy controls, PSP showed either the thinning of the retinal nerve fiber layer, macular ganglion cell, inner nuclear, or outer retina layer. Objectives The goals of the present study were to describe retinal layer thickness in a large cohort of PSP compared to healthy controls and in PSP phenotypes using spectral-domain optical coherence tomography (SD-OCT). The additional objective was to verify the relationship between retinal layers thickness and clinical variables in PSP. Methods Using a cross-sectional design, we examined retinal structure in 27 PSP patients and 27 controls using standard SD-OCT. Motor and cognitive impairment in PSP was rated with the PSP rating scale and the Montreal Cognitive Assessment battery (MoCA), respectively. Eyes with poor image quality or confounding diseases were excluded. SD-OCT measures of PSP and controls were compared with parametric testing, and correlations between retinal layer thicknesses and disease severity were evaluated. Results PSP showed significant thinning of the inner retinal layer (IRL), ganglion cell layer (GCL), inner plexiform layer (IPL), and the outer plexiform layer (OPL) compared to healthy controls. PSP phenotypes showed similar retinal layer thicknesses. Retinal layer thickness correlated with MoCA visuospatial subscore (p Conclusions We demonstrated PSP patients disclosed thinner IRL, GCL, IPL, and OPL compared to healthy controls. Furthermore, we found a significant correlation between visuospatial abilities and retinal layers suggesting the existence of a mutual relationship between posterior cognitive function and retinal structure.

Guillain-Barrè syndrome (GBS) is an acute immune-mediated neuropathy, possibly triggered by a recent infection or vaccination, and driven by an immune attack targeting the peripheral nervous system. GBS typically leads to ascending limb weakness, often with sensory and cranial nerve involvement 1–2 weeks after immune stimulation, but emergency and neurology physicians should be aware of its important clinical heterogeneity. In rare cases, bilateral facial nerve palsy can be the main clinical manifestation, as the case of the variant formerly known as bilateral facial weakness with paresthesias. An increasing number of case reports of GBS in patients receiving COVID-19 vaccination have been reported both during the pre-clinical phase and after large-scale authorities’ approval. We report two cases of bifacial palsy with paresthesias, a rare variant of GBS, both occurring after the first dose of COVID-19 vaccine Vaxzevria™ (formerly COVID-19 vaccine AstraZeneca), showing a favorable outcome after high-dose immunoglobulin therapy, and discuss the literature of GBS post-COVID-19 vaccination.

KAgF$_3$ is a quasi one-dimensional quantum antiferromagnet hosting a series of intriguing structural and magnetic transitions. Here we use powder neutron diffraction, $\mu$SR spectroscopy, and Density Functional Theory calculations to elucidate the low temperature magnetic phases. Below $T_{N1}=29$K we find that the material orders as an A-type antiferromagnet with an ordered moment of 0.47$\mu_{\rm B}$. Both neutrons and muons provide evidence for an intermediate phase at temperatures $T_{N1}, Comment: 11 pages, 8 figures. Supplementary information is included in a separate file

Motivated by the recent wealth of exotic magnetic phases emerging in two-dimensional frustrated lattices, we investigate the origin of possible magnetism in the monolayer family of triangular lattice materials $MX_2$ ($M$={V, Mn, Ni}, $X$={Cl, Br, I}). We first show that consideration of general properties such as filling and hybridization enables to formulate trends for the most relevant magnetic interaction parameters. In particular, we observe that the effects of spin-orbit coupling (SOC) can be effectively tuned through the ligand elements as the considered 3$d$ transition metal ions do not strongly contribute to the anisotropic component of the inter-site exchange interaction. Consequently, we find that the corresponding SOC matrix-elements differ significantly from the atomic limit. In a next step and by using two complementary approaches based on first principles, we extract realistic effective spin models and find that in the case of heavy ligand elements, SOC effects manifest in anisotropic exchange and single-ion anisotropy only for specific fillings.

The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA.In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA.We analyzed [We observed a conspicuous pattern of elevated regional [We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an α-synucleinopathy that remains strikingly incurable. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder in which environmental (lifestyle, dietary, infectious disease) factors as well as genetic make-up play a role. Metabolomics, an evolving research field combining biomarker discovery and pathogenetics, is particularly useful in studying complex pathophysiology in general and Parkinson's disease (PD) specifically. PD, the second most frequent neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of intraneural inclusions of α-synuclein aggregates. Although considered a predominantly movement disorder, PD is also associated with number of non-motor features. Metabolomics has provided useful information regarding this neurodegenerative process with the aim of identifying a disease-specific fingerprint. Unfortunately, many disease variables such as clinical presentation, motor system involvement, disease stage and duration substantially affect biomarker relevance. As such, metabolomics provides a unique approach to studying this multifactorial neurodegenerative disorder.

The objective of the present study was to describe gait parameters of progressive supranuclear palsy (PSP) phenotypes at early stage verifying the ability of gait analysis in discriminating between disease phenotypes and between the other variant syndromes of PSP (vPSP) and Parkinson's disease (PD). Nineteen PSP (10 PSP-Richardson's syndrome, five PSP-parkinsonism, and four PSP-progressive gait freezing) and nine PD patients performed gait analysis in single and dual tasks. Although phenotypes showed similar demographic and clinical variables, Richardson's syndrome presented worse cognitive functions. Gait analysis demonstrated worse parameters in Richardson's syndrome compared with the vPSP. The overall diagnostic accuracy of the statistical model during dual task was almost 90%. The correlation analysis showed a significant relationship between gait parameters and visuo-spatial, praxic, and attention abilities in PSP-Richardson's syndrome only. vPSP presented worse gait parameters than PD. Richardson's syndrome presents greater gait dynamic instability since the earliest stages than other phenotypes. Computerized gait analysis can differentiate between PSP phenotypes and between vPSP and PD.

Altres ajuts: Projekt DEAL; German Research Foundation (Grant KFO 219). To identify predictors of 36-month follow-up quality of life (QoL) outcome after bilateral subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson's disease (PD). In this ongoing, prospective, multicenter international study (Cologne, Manchester, London) including 73 patients undergoing STN-DBS, we assessed the following scales preoperatively and at 6-month and 36-month follow-up: PD Questionnaire-8 (PDQ-8), NMSScale (NMSS), Scales for Outcomes in PD (SCOPA)-motor examination, -activities of daily living, and -complications, and levodopa equivalent daily dose (LEDD). We analyzed factors associated with QoL improvement at 36-month follow-up based on (1) correlations between baseline test scores and QoL improvement, (2) step-wise linear regressions with baseline test scores as independent and QoL improvement as dependent variables, (3) logistic regressions and receiver operating characteristic curves using a dichotomized variable "QoL responders"/"non-responders". At both follow-ups, NMSS total score, SCOPA-motor examination, and -complications improved and LEDD was reduced significantly. PDQ-8 improved at 6-month follow-up with subsequent decrements in gains at 36-month follow-up when 61.6% of patients were categorized as "QoL non-responders". Correlations, linear, and logistic regression analyses found greater PDQ-8 improvements in patients with younger age, worse PDQ-8, and worse specific NMS at baseline, such as 'difficulties experiencing pleasure' and 'problems sustaining concentration'. Baseline SCOPA scores were not associated with PDQ-8 changes. Our results provide evidence that 36-month QoL changes depend on baseline neuropsychological and neuropsychiatric non-motor symptoms burden. These findings highlight the need for an assessment of a wide range of non-motor and motor symptoms when advising and selecting individuals for DBS therapy.

Propagating atomic vibrational waves, phonons, rule important thermal, mechanical, optoelectronic and transport characteristics of materials. Thus the knowledge of phonon dispersion, namely the dependence of vibrational energy on momentum is a key ingredient to understand and optimize the material's behavior. However, despite its scientific importance in the last decade, the phonon dispersion of a freestanding monolayer of two dimensional (2D) materials such as graphene and its local variations has still remained elusive because of experimental limitations of vibrational spectroscopy. Even though electron energy loss spectroscopy (EELS) in transmission has recently been shown to probe the local vibrational charge responses, these studies are yet limited to polar materials like boron nitride or oxides, in which huge signals induced by strong dipole moments are present. On the other hand, measurements on graphene performed by inelastic x-ray (neutron) scattering spectroscopy or EELS in reflection do not have any spatial resolution and require large microcrystals. Here we provide a new pathway to determine the phonon dispersions down to the scale of an individual freestanding graphene monolayer by mapping the distinct vibration modes for a large momentum transfer. The measured scattering intensities are accurately reproduced and interpreted with density functional perturbation theory (DFPT). Additionally, a nanometre-scale mapping of selected momentum (q) resolved vibration modes using graphene nanoribbon structures has enabled us to spatially disentangle bulk, edge and surface vibrations.

In Parkinson's disease (PD), pain represents a significant issue in terms of prevalence, clinical features, and treatment. Painful manifestations not strictly related to the disease are often amplified by the motor dysfunction. On the other hand, typical pain problems may specifically concern this vulnerable population. In turn, pain may have a deep impact on patients' health-related quality of life. However, pain treatment in PD remains an unmet need as only about half of patients with pain use analgesics and pain is often managed by simply increasing doses of PD medications. In this complex scenario, pain treatments should follow multimodal approaches through a careful combination of pharmacological agents with non-pharmacological strategies, depending on the type of pain and the clinical context. A multidisciplinary approach involving medical specialists from different disciplines could be a winning strategy to address the issue. This work is aimed to provide practical suggestions useful for different types of clinicians and care professionals for pain management in this vulnerable population.

Background and purpose: Parkinson disease (PD) patients are classically classified according to two alternative motor subtyping methods: (i) tremor-dominant versus postural instability and gait disorder; (ii) tremor-dominant versus akinetic-rigid. The degree of overlap between the two classification systems at diagnosis of PD and their temporal stability, as well as the correspondence between the two systems, were examined over a follow-up period of 4years. Methods: Newly diagnosed, untreated PD patients were classified as tremor-dominant versus postural instability and gait disorder and tremor-dominant versus akinetic-rigid at baseline and after 2 and 4years. Results: There was a poor overlap between the two classification systems at any time point and baseline subtype status could not predict 4-year subtype membership. In fact, about half of our cohort shifted category during the first 2years, regardless of the classification scheme adopted. A lower rate of shift was observed from 2- to 4-year follow-up. Conclusions: The two classical motor subtyping methods of PD poorly overlap, which implies that a patient can be categorized as tremor-dominant in one classification system but not in the other. Moreover, their temporal instability undermines their prognostic value in the early stage of PD.

Significance Antiferromagnets can host strong quantum fluctuations in their ground state if they combine both low dimensionality and low spin. Materials based on copper oxides (spin-1/2 ions in layered or 1D structures) are unique in optimizing the tendency to strong quantum fluctuations. As a bonus, they show extremely large magnetic interactions, which lead to interesting quantum effects at relatively high temperatures as anomalous transport properties and high-Tc superconductivity in doped systems. Obtaining similar features with other ions has been a long-standing goal. We show that silver and fluorine (which are next to copper and oxygen in the periodic table) in the commercial compound AgF2 reach the goal, paving the way for a different generation of quantum materials., The parent compound of high-Tc superconducting cuprates is a unique Mott insulator consisting of layers of spin-12 ions forming a square lattice and with a record high in-plane antiferromagnetic coupling. Compounds with similar characteristics have long been searched for without success. Here, we use a combination of experimental and theoretical tools to show that commercial AgF2 is an excellent cuprate analog with remarkably similar electronic parameters to La2CuO4 but larger buckling of planes. Two-magnon Raman scattering and inelastic neutron scattering reveal a superexchange constant reaching 70% of that of a typical cuprate. We argue that structures that reduce or eliminate the buckling of the AgF2 planes could have an antiferromagnetic coupling that matches or surpasses the cuprates.

Multiferroic materials have garnered wide interest for their exceptional static and dynamical magnetoelectric properties. In particular, type-II multiferroics exhibit an inversion-symmetry-breaking magnetic order which directly induces a ferroelectric polarization through various mechanisms, such as the spin-current or the inverse Dzyaloshinskii-Moriya effect. This intrinsic coupling between the magnetic and dipolar order parameters results in record-strength magnetoelectric effects. Two dimensional materials possessing such intrinsic multiferroic properties have been long sought for harnessing magnetoelectric coupling in nanoelectronic devices. Here, we report the discovery of type-II multiferroic order in a single atomic layer of the transition metal-based van der Waals material NiI2. The multiferroic state of NiI2 is characterized by a proper-screw spin helix with given handedness, which couples to the charge degrees of freedom to produce a chirality-controlled electrical polarization. We use circular dichroic Raman measurements to directly probe the magneto-chiral ground state and its electromagnon modes originating from dynamic magnetoelectric coupling. Using birefringence and second-harmonic generation measurements, we detect a highly anisotropic electronic state simultaneously breaking three-fold rotational and inversion symmetry, and supporting polar order. The evolution of the optical signatures as a function of temperature and layer number surprisingly reveals an ordered magnetic, polar state that persists down to the ultrathin limit of monolayer NiI2. These observations establish NiI2 and transition metal dihalides as a new platform for studying emergent multiferroic phenomena, chiral magnetic textures and ferroelectricity in the two-dimensional limit.

Background Richardson’s syndrome (RS) is considered the most symmetric phenotype of progressive supranuclear palsy (PSP) as opposed to PSP with predominant corticobasal syndrome (PSP-CBS) or parkinsonism (PSP-P). Objectives Evaluate asymmetrical motor and higher cortical features in probable PSP-RS and compare the degree of asymmetry of cortical lobes and hemispheres between PSP-RS, PSP-CBS, PSP-P, and age-matched healthy controls (HC). Methods Asymmetry of motor and higher cortical features evaluated with an extensive videotaped neurologic examination was investigated in 28 PSP-RS, 8 PSP-CBS, and 14 PSP-P. Brain MRI to compute the laterality index (LI) was performed in 36 patients as well as in 56 HC. Results In PSP-RS, parkinsonism was the most common asymmetric motor feature (53.6%), followed by dystonia and myoclonus (21.4% and 17.9%, respectively). Among higher cortical features, limb apraxia was found asymmetric in about one-third of patients. PSP-RS disclosed higher LI for hemispheres compared to HC, indicating a greater degree of asymmetry (p = 0.003). The degree of asymmetry of clinical features was not different between PSP-RS and those qualifying for PSP-CBS or PSP-P. As for imaging, LI was not different between PSP-RS, PSP-CBS, and PSP-P in any cortical region. Conclusions Motor and higher cortical features are asymmetric in up to 50% of PSP-RS who also present a greater degree of asymmetry in hemispheres compared to age-matched HC. Lateralization of clinical features should be annotated in PSP.

We aimed to study the attitude of Italian neurologists in the use of conventional MRI in patients with idiopathic adult-onset focal dystonia. Patients were included in the Italian Dystonia Registry by experts working in different Italian centers. MRI was available for 1045 of the 1471 (71%) patients included in the analysis. Using logistic regression analysis, we found that MRI was more likely to be performed in patients with cervical dystonia, spasmodic dysphonia, or non-task-specific upper limb dystonia, whereas it was less likely to be performed in patients with blepharospasm or task-specific upper limb dystonia. We did not find differences in the number of MRIs performed between neurological centers in Northern, Central, and Southern Italy. We conclude that although the diagnosis of idiopathic adult-onset dystonia is mainly based on clinical grounds, many movement disorder experts rely on MRI to confirm a diagnosis of idiopathic dystonia. We suggest that neuroimaging should be used in patients with adult-onset focal dystonia to rule out secondary forms.

Progressive supranuclear palsy (PSP) is a rare and rapidly progressing atypical parkinsonism. Albeit existing clinical criteria for PSP have good specificity and sensitivity, there is a need for biomarkers able to capture early objective disease-specific abnormalities. This study aimed to identify gait patterns specifically associated with early PSP. The study population comprised 104 consecutively enrolled participants (83 PD and 21 PSP patients). Gait was investigated using a gait analysis system during normal gait and a cognitive dual task. Univariate statistical analysis and binary logistic regression were used to compare all PD patients and all PSP patients, as well as newly diagnosed PD and early PSP patients. Gait pattern was poorer in PSP patients than in PD patients, even from early stages. PSP patients exhibited reduced velocity and increased measures of dynamic instability when compared to PD patients. Application of predictive models to gait data revealed that PD gait pattern was typified by increased cadence and longer cycle length, whereas a longer stance phase characterized PSP patients in both mid and early disease stages. The present study demonstrates that quantitative gait evaluation clearly distinguishes PSP patients from PD patients since the earliest stages of disease. First, this might candidate gait analysis as a reliable biomarker in both clinical and research setting. Furthermore, our results may offer speculative clues for conceiving early disease-specific rehabilitation strategies.

Ferroelectricity in hafnia is often regarded as a breakthrough discovery in ferroelectrics, potentially able to revolutionize the whole field. Despite increasing interests, a deep and comprehensive understanding of the many factors driving ferroelectric stabilization is still lacking. We here address the phase transition in terms of a Landau-theory-based approach, by analyzing symmetry-allowed distortions connecting the high-symmetry paraelectric tetragonal phase to the low-symmetry polar orthorhombic phase. By means of first-principles simulations, we find that the ${\mathrm{\ensuremath{\Gamma}}}_{3\ensuremath{-}}$ polar mode is only weakly unstable, whereas the other two symmetry-allowed distortions, ${\mathrm{Y}}_{2+}$ and ${\mathrm{Y}}_{4\ensuremath{-}}$ (showing a nonpolar and antipolar behavior, respectively), are hard modes. While none of the modes, taken alone or combined with one other mode, is able to drive the transition, the key factor in stabilizing the ferroelectric phase is identified as the strong trilinear coupling among the three modes. Furthermore, the experimentally acknowledged importance of substrate-induced effects in the growth of ${\mathrm{HfO}}_{2}$ ferroelectric thin films, along with the lack of a clear order parameter in the transition, suggested the extension of our analysis to strain effects. Our findings suggest a complex behavior of the ${\mathrm{Y}}_{2+}$ mode, which can become unstable under certain conditions (i.e., a tensile strain applied along the $a$ direction), and an overall weakly unstable behavior for the ${\mathrm{\ensuremath{\Gamma}}}_{3\ensuremath{-}}$ polar mode for all the strain conditions. In any case, a robust result emerges from our analysis: independently of the different applied strain (be it compressive or tensile, applied along the $a, b$, or $c$ orthorhombic axis), the need for a simultaneous excitation of the three coupled modes remains unaltered. Finally, when applied to mimic experimental growth conditions under strain, our analysis shows a further stabilization of the ferroelectric phase with respect to the unstrained case, in agreement with experimental findings.

Parkinson's disease (PD) is a multifactorial neurodegenerative disorder in which environmental (lifestyle, dietary, infectious disease) factors as well as genetic make-up play a role. Metabolomics, an evolving research field combining biomarker discovery and pathogenetics, is particularly useful in studying complex pathophysiology in general and Parkinson's disease (PD) specifically. PD, the second most frequent neurodegenerative disorder, is characterized by the loss of dopaminergic neurons in the substantia nigra and the presence of intraneural inclusions of ?-synuclein aggregates. Although considered a predominantly movement disorder, PD is also associated with number of non-motor features. Metabolomics has provided useful information regarding this neurodegenerative process with the aim of identifying a disease-specific fingerprint. Unfortunately, many disease variables such as clinical presentation, motor system involvement, disease stage and duration substantially affect biomarker relevance. As such, metabolomics provides a unique approach to studying this multifactorial neurodegenerative disorder.

Background Parkinson's Disease-related Psychosis (PDP) encompasses a spectrum of symptoms ranging from “minor” hallucinations to formed hallucinations and delusions. Notably, cognitive impairment has been recognized as the strongest risk factor for PDP. Several evidences suggest a possible role of cigarette smoking in both cognition and psychotic syndromes. Objectives To evaluate the possible independent association between cigarette smoking and PDP in a large cohort of non-demented PD patients. Methods A cohort of non-demented PD patients was selected from the FRAGAMP study population. All participants underwent a standardised structured questionnaire to assess demographic, clinical and environmental exposure data. Clinical features were assessed using UPDRS, HY stage, AIMS, MMSE and Hamilton Rating Scale for Depression. Presence of psychotic symptoms was assessed using UPDRS-I.2 score. Diagnosis of PDP was made according to NINDS/NIMH criteria. Results Four hundred eighty-five non-demented PD patients were enrolled [292 men (60.2%); mean age ± SD 65.6 ± 9.8]. Among them, 28 (5.8%) had PDP. Multivariate analysis, adjusting by HY stage, MMSE and LED, shown an independent association between PDP and “nightmares-abnormal movements during sleep” and current smoking [adjOR 7.39 (95%CI 1.45–37.69; P-value 0.016)]. Conclusions Our findings provide interesting insights about the possible role of current smoking in facilitating the occurrence of psychotic symptoms in PD.

Objective To perform the genetic characterization of a cohort with familial parkinsonism and cognitive-behavioral syndrome. Methods A Next Generation Sequencing – based targeted sequencing of 32 genes associated to various neurodegenerative phenotypes, plus a screening for SNCA Copy Number Variations and C9orf72 repeat expansion, was applied in a cohort of 85 Italian patients presenting with parkinsonism and cognitive and/or behavioral syndrome and a positive familial history for any neurodegenerative disorder (i.e., dementia, movement disorders, amyotrophic lateral sclerosis). Results Through this combined genetic approach, we detected potentially relevant genetic variants in 25.8% of patients with familial parkinsonism and cognitive and/or behavioral syndrome. Peculiar phenotypes are described (Cortico-basal syndrome with APP, Posterior Cortical Atrophy with GBA, Progressive Supranuclear Palsy-like with GRN, Multiple System Atrophy with TARDBP). The majority of patients presented a rigid-bradykinetic parkinsonian syndrome, while rest tremor was less common. Myoclonic jerks, pyramidal signs, dystonic postures and vertical gaze disturbances were more frequently associated with the presence of a pathogenic variant in one of the tested genes. Conclusions Given the syndromic approach adopted in our study, we were able to provide a detailed clinical description of patients beyond the boundaries of specific clinical diagnoses and describe peculiar phenotypes. This observation further supports the knowledge that genetic disorders present phenotypic overlaps across different neurodegenerative syndromes, highlighting the limitations of current clinical diagnostic criteria defining sharp boundaries between distinct conditions.

We present a combined polarized neutron and x-ray scattering study on two enantiopure langasite single crystals aimed at the determination of their absolute structural and magnetic chiralities and the coupling between them. Our respective data sets unambiguously reveal two samples of opposite structural chirality, where the magnetic handedness is pinned by the structural one. Simple energy considerations of the magnetic exchange and single-ion anisotropy parameters reveal that it is not the Dzyaloshinskii-Moriya interaction but the local single-ion anisotropy on a triangular plaquette which plays a key role in stabilizing one of the two magnetic helices.

Density functional theory calculations were performed for the electronic and the ferroelectric properties of the bulk and the monolayer benzylammonium lead-halide (BA2PbCl4). Our calculations indicate that both the bulk and monolayer systems display a band gap of ∼3.3 eV (HSE06+SOC) and a spontaneous polarization of ∼5.4 μC/cm2. The similar physical properties of bulk and monolayer systems suggest a strong decoupling among the layers in this hybrid organic-inorganic perovskite. Both the ferroelectricity, through associated structure distortion, and the spin-orbit coupling, through splitting induced in the electronic bands, significantly influence the band gaps. Most importantly, we found for the first time in a two-dimensional hybrid organic-inorganic class of material, a peculiar spin texture topology such as a unidirectional spin-orbit field, which may lead to a protection against spin decoherence.