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Contains fulltext : 248871.pdf (Publisher’s version ) (Open Access) BACKGROUND: Previous studies showed that lifestyle behaviors (cigarette smoking, alcohol, coffee) are inversely associated with Parkinson's disease (PD). The prodromal phase of PD raises the possibility that these associations may be explained by reverse causation. OBJECTIVE: To examine associations of lifestyle behaviors with PD using two-sample Mendelian randomisation (MR) and the potential for survival and incidence-prevalence biases. METHODS: We used summary statistics from publicly available studies to estimate the association of genetic polymorphisms with lifestyle behaviors, and from Courage-PD (7,369 cases, 7,018 controls; European ancestry) to estimate the association of these variants with PD. We used the inverse-variance weighted method to compute odds ratios (ORIVW) of PD and 95%confidence intervals (CI). Significance was determined using a Bonferroni-corrected significance threshold (p = 0.017). RESULTS: We found a significant inverse association between smoking initiation and PD (ORIVW per 1-SD increase in the prevalence of ever smoking = 0.74, 95%CI = 0.60-0.93, p = 0.009) without significant directional pleiotropy. Associations in participants ≤67 years old and cases with disease duration ≤7 years were of a similar size. No significant associations were observed for alcohol and coffee drinking. In reverse MR, genetic liability toward PD was not associated with smoking or coffee drinking but was positively associated with alcohol drinking. CONCLUSION: Our findings are in favor of an inverse association between smoking and PD that is not explained by reverse causation, confounding, and survival or incidence-prevalence biases. Genetic liability toward PD was positively associated with alcohol drinking. Conclusions on the association of alcohol and coffee drinking with PD are hampered by insufficient statistical power.

This study was funded by the Medical Research Council, the European Community’s Seventh Framework Program grant [agreement HEALTH-F2-2009-241909 (Project EU-GEI)], São Paulo Research Foundation (grant 2012/0417-0), the National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King’s College London, the NIHR BRC at University College London and the Wellcome Trust (grant 101272/Z/12/Z)., Tripoli, G., Quattrone, D., Ferraro, L., Gayer-Anderson, C., Rodriguez, V., La Cascia, C., La Barbera, D., Sartorio, C., Seminerio, F., Tarricone, I., Berardi, D., Szöke, A., Arango, C., Tortelli, A., Llorca, P.-M., De Haan, L., Velthorst, E., Bobes, J., Bernardo, M., Sanjuán, J., Santos, J.L., Arrojo, M., Del-Ben, C.M., Menezes, P.R., Selten, J.-P., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., Lasalvia, A., Tosato, S., Richards, A., O'donovan, M., Rutten, B.P.F., Os, J.V., Morgan, C., Sham, P.C., Murray, R.M., Murray, G.K., Di Forti, M.

Premorbid functioning and cognitive measures may reflect gradients of developmental impairment across diagnostic categories in psychosis. In this study, we sought to examine the associations of current cognition and premorbid adjustment with symptom dimensions in a large first episode psychosis (FEP) sample. We used data from the international EU-GEI study. Bifactor modelling of the Operational Criteria in Studies of Psychotic Illness (OPCRIT) ratings provided general and specific symptom dimension scores. Premorbid Adjustment Scale estimated premorbid social (PSF) and academic adjustment (PAF), and WAIS-brief version measured IQ. A MANCOVA model examined the relationship between symptom dimensions and PSF, PAF, and IQ, having age, sex, country, self-ascribed ethnicity and frequency of cannabis use as confounders. In 785 patients, better PSF was associated with fewer negative (B=-0.12, 95% C.I. -0.18, -0.06, p

Introduction: Hyper-religiosity has been reported in patients affected by frontotemporal dementia (FTD) with asymmetrical, predominantly right-sided frontotemporal atrophy. Case report: We report a FTD patient carrying a double genetic variant (p.Cys139Arg and c.*78C > T) in the progranulin (GRN) gene who showed an unusual clinical phenotype characterized by hyper-religiosity behavior and visual hallucinations with exclusively religious content. Noteworthy, this patient exhibited a slow clinical and radiological rate of disease progression and a predominantly left-sided frontotemporal atrophy. Discussion and conclusion: The simultaneous presence of these GRN variants in our FTD patient with predominant atrophy in the left (dominant) hemisphere could determine the unusual phenotype with hyper-religiosity and visual hallucinations with exclusively religious content and influence the slow rate of disease progression.

Idiopathic normal pressure hydrocephalus (iNPH) shares clinical and radiological features with progressive supranuclear palsy (PSP) and Alzheimer’s disease (AD). Corpus callosum (CC) involvement in these disorders is well established on structural MRI and diffusion tensor imaging (DTI), but alterations overlap and lack specificity to underlying tissue changes. We propose a semi-automated approach to assess CC integrity in iNPH based on the spatial distribution of DTI-derived principal diffusion direction orientation (V1). We processed DTI data from 121 subjects (Site1: iNPH = 23, PSP = 27, controls = 14; ADNI: AD = 35, controls = 22) to obtain V1, fractional anisotropy (FA) and mean diffusivity (MD) maps. To increase the estimation accuracy of DTI metrics, analyses were restricted to the midsagittal CC portion (± 6 slices from midsagittal plane). Group-wise comparison of normalized altered voxel count in midsagittal CC was performed using Kruskal–Wallis tests, followed by post hoc comparisons (Bonferroni-corrected p

The European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (EUGEI); The Spanish sample was supported by the Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, PI19/024) (...), Velthorst, E., Mollon, J., Murray, R.M., de Haan, L., Germeys, I.M., Glahn, D.C., Arango, C., van der Ven, E., Di Forti, M., Bernardo, M., Guloksuz, S., Delespaul, P., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Santos, J.L., Jiménez-López, E., Sanjuan, J., Aguilar, E.J., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Atbaşoğlu, C., Saka, M.C., Üçok, A., Alptekin, K., Akdede, B., Binbay, T., Altınyazar, V., Ulaş, H., Yalınçetin, B., Gümüş-Akay, G., Beyaz, B.C., Soygür, H., Cankurtaran, E.Ş., Kaymak, S.U., Maric, N.P., Mihaljevic, M.M., Petrovic, S.A., Mirjanic, T., Del-Ben, C.M., Ferraro, L., Gayer-Anderson, C., Jones, P.B., Jongsma, H.E., Kirkbride, J.B., La Cascia, C., Lasalvia, A., Tosato, S., Llorca, P.-M., Menezes, P.R., Morgan, C., Quattrone, D., Menchetti, M., Selten, J.-P., Szöke, A., Tarricone, I., Tortelli, A., McGuire, P., Valmaggia, L., Kempton, M.J., van der Gaag, M., Riecher-Rössler, A., Bressan, R.A., Barrantes-Vidal, N., Nelson, B., McGorry, P., Pantelis, C., Krebs, M.-O., Ruhrmann, S., Sachs, G., Rutten, B.P.F., van Os, J., Alizadeh, B.Z., van Amelsvoort, T., Bartels-Velthuis, A.A., Bruggeman, R., van Beveren, N.J., Luykx, J.J., Cahn, W., Simons, C.J.P., Kahn, R.S., Schirmbeck, F., van Winkel, R., Calem, M., Tognin, S., Modinos, G., Pisani, S., Kraan, T.C., van Dam, D.S., Burger, N., Amminger, G.P., Politis, A., Goodall, J., Borgwardt, S., Studerus, E., Gadelha, A., Brietzke, E., Asevedo, G., Asevedo, E., Zugman, A., Domínguez-Martínez, T., Monsonet, M., Cristóbal-Narváez, P., Racioppi, A., Kwapil, T.R., Kazes, M., Daban, C., Bourgin, J., Gay, O., Mam-Lam-Fook, C., Nordholm, D., Rander, L., Krakauer, K., Glenthøj, L.B., Glenthøj, B., Gebhard, D., Arnhold, J., Klosterkötter, J., Lasser, I., Winklbaur, B., Reichenberg, A., EU-GEI High Risk Study

Introduction Indocyanine green (ICG) is commonly used to visualize cerebral vasculature, particularly in the management of cerebral aneurysms. There have also been attempts to use ICG for visualization of tumors. Injection of ICG followed by immediate fluorescence microscopy is limited by the short time window for imaging and administration and restricted depth of imaging. Second Window Indocyanine Green (SWIG) addresses these issues by allowing for longer contrast times and the imaging of deeper regions of brain tissue. Biopsy of spinal cord lesions is often difficult for a variety of reasons, including the delicate nature of the tissue and differentiating normal from lesional tissue visually, especially in lesions with heterogeneous enhancement. Methods In this case report, we describe the use of second window ICG to facilitate the visualization of a spinal cord lesion and subsequent biopsy of the lesion. Results This patient is a 24-year-old female who had recurrence of a suprasellar germinoma. An MRI of the rest of the neuraxis was performed to assess for the presence of drop metastases. The spinal cord from C2-5 was expanded with areas of patchy enhancement; however, this lesion was asymptomatic. The patient's oncologist requested a biopsy of this lesion to help direct subsequent care of her recurrent germinoma. The day before surgery, the patient had an intravenous injection of ICG dye. She then underwent a C3-5 laminectomy for biopsy of her cervical intramedullary lesion. After opening of the dura, no visible abnormality of the spinal cord could be identified. A Stryker endoscope showed an area of ICG uptake in the cord at approximately the C3-4 level. A midline myelotomy was centered over the ICG demarcated area and several samples were taken for pathology. Final biopsy results determined the lesion to be spinal cord parenchyma with perivascular and intraparenchymal lymphocytes – not consistent with spinal cord tumor or germinoma. Conclusion Second Window ICG is effective in visualizing otherwise visually unremarkable spinal cord lesions. This technology can facilitate biopsy of these lesions and possibly their surgical resection.

Deep grey nuclei of the human brain accumulate minerals both in aging and in several neurodegenerative diseases. Mineral deposition produces a shortening of the transverse relaxation time which causes hypointensity on magnetic resonance (MR) imaging. The physician often has difficulties in determining whether the incidental hypointensity of grey nuclei seen on MR images is related to aging or neurodegenerative pathology. We investigated the hypointensity patterns in globus pallidus, putamen, caudate nucleus, thalamus and dentate nucleus of 217 healthy subjects (ages, 20-79 years; men/women, 104/113) using 3T MR imaging. Hypointensity was detected more frequently in globus pallidus (35.5%) than in dentate nucleus (32.7%) and putamen (7.8%). A consistent effect of aging on hypointensity (p < 0.001) of these grey nuclei was evident. Putaminal hypointensity appeared only in elderly subjects whereas we did not find hypointensity in the caudate nucleus and thalamus of any subject. In conclusion, the evidence of hypointensity in the caudate nucleus and thalamus at any age or hypointensity in the putamen seen in young subjects should prompt the clinician to consider a neurodegenerative disease.

PURPOSE The activity of androgen-deprivation therapy (ADT) in androgen receptor–positive (AR+) salivary gland carcinomas (SGCs) has been established in the past few years. Second-line treatment in castration-resistant patients is still unknown. We investigated the activity of abiraterone acetate as second-line treatment in ADT-resistant, AR+ patients with SGC. METHODS This was a single-institution phase II trial. A two-stage Simon's design was applied. The primary end point was confirmed objective response rate. Secondary end points were disease control rate, safety, progression-free survival, and overall survival. Patients were eligible when the following criteria were met: histologic diagnosis of AR-overexpressing SGC, measurable disease according to RECIST 1.1, clinical and/or radiologic progression on ADT, suppressed serum testosterone, and no limits for the number of previous chemotherapy lines. All patients received abiraterone 1 g daily plus prednisone 10 mg and luteinizing hormone-releasing hormone agonist until progression or unacceptable toxicities. RESULTS From 2015 to 2019, 24 AR+ patients with SGC (23 men; median age 65.8 years) were treated within the study. The overall response rate was 21% (5 partial responses), with a disease control rate of 62.5%. The median duration of response was 5.82 months. Median progression-free survival was 3.65 months (95% CI, 1.94 to 5.89), and median overall survival was 22.47 months (95% CI, 6.74 to not reached). Objective response to previous ADT did not correlate with the activity of abiraterone. Adverse events (AEs) were recorded in 22 cases (92%) with grade 3 AEs in six patients (25%): fatigue (two), flushing (one), supraventricular tachycardia (one), and two non–drug-related AEs. No drug-related grade 4 or 5 AEs were recorded. CONCLUSION Abiraterone plus luteinizing hormone-releasing hormone agonist is active and safe as a second-line option in AR-expressing, castration-resistant SGC.

Objectives To assess the impact of pregnancy on cardiac function and fibrosis by cardiovascular magnetic resonance (CMR) in patients with repaired Tetralogy of Fallot (rToF). Background CMR T1 mapping can assess diffuse myocardial fibrosis which is associated to adverse clinical outcomes. Right ventricular (RV) accelerated remodeling is reported in rToF women with experienced pregnancy. Methods We included rToF women from the national registry of congenital heart disease to perform CMR, assessing functional data, T1 mapping/ extracellular volume fraction (ECV). The results including clinical data were compared between women with experienced pregnancy vs non-experienced pregnancy and healthy individuals. Results Fifty rToF women performed CMR, median age 36 (range 21–67) years. Fifteen were nulliparous. T1 mapping was compared to 30 controls, (14 women) median age 42 (24–64) years. In the left ventricle (LV), T1 times and ECV in all rToF women vs female controls were 1248 ± 61 ms/ 25.8 ± 2.9% vs 1255 ± 40 ms/ 26.8 ± 3.1%, p = 0.7 and p = 0.3, respectively. In rToF, RV T1 times was 1385 ± 124 ms and ECV 37.7 ± 5.4%. There was no association to parity or age in rToF LV T1/ ECV, p = 0.9 for both, or RV T1/ECV, p = 0.4 and p = 0.6, respectively. Indexed LV mass was higher in the rToF pregnancy group, 43 ± 10 vs 38 ± 6 g/m2, p = 0.03 while RV ejection fraction was lower, 49 ± 7% vs 53 ± 6%, p = 0.04. Conclusion Women with rTOF showed evidence of increased RV CMR markers suggestive of diffuse fibrosis while LV CMR markers were within normal values. Having experienced pregnancy might affect RV function, however without association to CMR biomarkers.

PurposeFinancial and nonfinancial disclosures are still anchored to conventional notions of transparency, whereby corporations “push” information out to various stakeholders. Such information is now “pulled” from various sources and addresses aspects of corporate behavior that go well beyond those envisioned by the disclosure framework. This shift makes notions of values, measurement and accountability more fragmented, complex and difficult. The paper aims to bring the accounting scholarly debate back to what and how transparency can be achieved especially in relation to issues of social inequality and sustainability.Design/methodology/approachAfter an analysis of the limitations of current approaches to disclosure, the paper proposes a shift toward normative policies that profit of years of critique of positivism.FindingsDrawing on the notion of value-added, the paper ends with a new income statement design, labeled as Value-Added Statement for Nature, which recognizes Nature as a further stakeholder and forces human stakeholders to give voice, or at least acknowledge the lack of voice, for non-human actors.Originality/valueThe author proposes a shift in the perspective, practice and institutional arrangements in which disclosure occurs. Measurement and transparency need to happen in communication exercises, which do not presuppose what needs to be made transparent once and for good but define procedures on how to make fragmented, complex, multiple and volatile notions of value transparent. Income statements and accounting more in general is to be reconceived as a platform where stakeholders will have to continuously negotiate what counts as the common good in the interest of all, including Nature.

Our online randomized controlled trial on 6230 healthcare workers (HCWs) tests the impact that three nudges - social norms, reminding the impact on beneficiaries, and defaults - have on the intention to vaccinate against seasonal influenza across job families. Willingness to get a flu shot was higher among subjects invited to imagine themselves working at the local health authority (LHA) with the greatest immunization coverage within their region relative to their counterparts prompted to imagine working at the LHA with the lowest coverage. Reminding the impact of flu vaccination on beneficiaries had different effects across job families, with physicians caring more benefits for themselves, nurses about patients' benefits, and technicians about family and friends. Default responses anchoring toward a high rather than a low vaccination intention increased the willingness to immunize among all HCW except physicians. Targeted nudges can be considered in developing interventions to promote influenza vaccination among HCWs.

The work was supported by: Clinician Scientist Medical Research Council fellowship (project reference MR/M008436/1) to MDF; the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care South London at King’s College Hospital NHS Foundation Trust to DQ; DFG Heisenberg professorship (no. 389624707) to UR. National Institute for Health Research (NIHR) Biomedical Research Centre for Mental Health at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care. The EU-GEI Project is funded by the European Community’s Seventh Framework Programme under grant agreement No. HEALTH-F2-2010-241909 (Project EU-GEI). The Brazilian study was funded by the São Paulo Research Foundation under grant number 2012/0417-0., Quattrone, D., Ferraro, L., Tripoli, G., La Cascia, C., Quigley, H., Quattrone, A., Jongsma, H.E., Del Peschio, S., Gatto, G., Gayer-Anderson, C., Jones, P.B., Kirkbride, J.B., La Barbera, D., Tarricone, I., Berardi, D., Tosato, S., Lasalvia, A., Szöke, A., Arango, C., Bernardo, M., Bobes, J., Del Ben, C.M., Menezes, P.R., Llorca, P.-M., Santos, J.L., Sanjuán, J., Tortelli, A., Velthorst, E., De Haan, L., Rutten, B.P.F., Lynskey, M.T., Freeman, T.P., Sham, P.C., Cardno, A.G., Vassos, E., Van Os, J., Morgan, C., Reininghaus, U., Lewis, C.M., Murray, R.M., Di Forti, M.

Background Idiopathic normal pressure hydrocephalus and PSP share several clinical and radiological features, making differential diagnosis, at times, challenging. Objectives To differentiate idiopathic normal pressure hydrocephalus from PSP using MR volumetric and linear measurements. Methods Twenty-seven idiopathic normal pressure hydrocephalus patients, 103 probable PSP patients, and 43 control subjects were consecutively enrolled. Automated ventricular volumetry was performed using Freesurfer 6 on MR T1 -weighted images. Linear measurements, such as callosal angle and a new measure, termed MR Hydrocephalic Index, were calculated on MR T1 -weighted images. Receiver operating characteristic analyses were used for differentiating between patient groups. Generalizability and reproducibility of the results were validated, dividing each participant group in two cohorts used as training and testing subsets. Results Ventricular volumes and linear measurements (callosal angle and Magnetic Resonance Hydrocephalic Index) revealed greater ventricular enlargement in patients with idiopathic normal pressure hydrocephalus than in PSP patients and controls. PSP patients had ventricular volume larger than controls. Automated ventricular volumetry and Magnetic Resonance Hydrocephalic Index were the most accurate measures (98.5%) in differentiating patients with idiopathic normal pressure hydrocephalus from PSP patients, whereas callosal angle misclassified several PSP patients and showed low positive predictive value (70.0%) in differentiating between these two diseases. All measurements accurately differentiated idiopathic normal pressure hydrocephalus patients from controls. Accuracy values obtained in the training set (automated ventricular volumetry, 98.4%; Magnetic Resonance Hydrocephalic Index, 98.4%; callosal angle, 87.5%) were confirmed in the testing set. Conclusions Our study demonstrates that AVV and Magnetic Resonance Hydrocephalic Index were the most accurate measures for differentiation between idiopathic normal pressure hydrocephalus and PSP patients. Magnetic Resonance Hydrocephalic Index is easy to measure and can be used in clinical practice to prevent misdiagnosis and ineffective shunt procedures in idiopathic normal pressure hydrocephalus mimics. © 2020 International Parkinson and Movement Disorder Society.

OBJECTIVE Accurate diagnosis is particularly challenging in Parkinson's disease (PD), multiple system atrophy (MSAp), and progressive supranuclear palsy (PSP). We compare the utility of 3 promising biomarkers to differentiate disease state and explain disease severity in parkinsonism: the Automated Imaging Differentiation in Parkinsonism (AID-P), the Magnetic Resonance Parkinsonism Index (MRPI), and plasma-based neurofilament light chain protein (NfL). METHODS For each biomarker, the area under the curve (AUC) of receiver operating characteristic curves were quantified for PD versus MSAp/PSP and MSAp versus PSP and statistically compared. Unique combinations of variables were also assessed. Furthermore, each measures association with disease severity was determined using stepwise multiple regression. RESULTS For PD versus MSAp/PSP, AID-P (AUC, 0.900) measures had higher AUC compared with NfL (AUC, 0.747) and MRPI (AUC, 0.669), P

Background: Progressive supranuclear palsy (PSP) patients can show ventricular enlargement mimicking normal pressure hydrocephalus (NPH). The aim of this study was to distinguish PSP patients with marked ventricular dilatation (PSP-vd) from those with normal ventricular system and to evaluate the coexistence of NPH in PSP-vd patients. Methods: One hundred three probable PSP patients, 18 definite NPH patients, and 41 control subjects were enrolled in the study. Evans index (EI) > 0.32 associated with callosal angle (CA) < 100° was used to identify PSP-vd patients. Automated ventricular volumetry (AVV) and Magnetic Resonance Hydrocephalic Index (MRHI) were performed on T1-weighted MR images to evaluate the presence of NPH in PSP-vd patients. Results: Twelve (11.6%) out of 103 PSP patients had both abnormal EI and CA values (PSP-vd). In two of these 12 patients, AVV and MRHI values suggested PSP + NPH. In the remaining 10 PSP-vd patients, AVV and MRHI values were higher than PSP patients with normal ventricular system and controls, but lower than PSP + NPH and NPH patients, suggesting a non-hydrocephalic ventricular enlargement. Discussion: Our study provides evidence that the combination of EI and CA biomarkers allowed to identify PSP patients with marked ventricular dilatation mimicking NPH. Only a few of these patients had PSP + NPH. Recognition of these PSP patients with enlarged ventricles can positively impact the care of this disease, helping clinicians to identify patients with PSP + NPH who could benefit from shunt procedure and avoid surgery in those with enlarged ventricles without NPH.

Background: The R2 component of blink reflex recovery cycle (R2BRrc) is a simple neurophysiological tool to detect the brainstem hyperexcitability commonly occurring in several neurological diseases such as Parkinson's disease and atypical parkinsonisms. In our study, we investigated for the first time the usefulness of R2BRrc to assess brainstem excitability in patients with idiopathic Normal Pressure Hydrocephalus (iNPH) in comparison with healthy subjects. Methods: Eighteen iNPH patients and 25 age-matched control subjects were enrolled. R2BRrc was bilaterally evaluated at interstimulus intervals (ISIs) of 100, 150, 200, 300, 400, 500 and 750 ms in all participants. We investigated the diagnostic performance of R2BRrc in differentiating iNPH patients from control subjects using ROC analysis. Midbrain area and Magnetic Resonance Hydrocephalic Index (MRHI), an MRI biomarker for the diagnosis of iNPH, were measured on T1-weighted MR images, and correlations between R2BRrc values and MRI measurements were investigated. Results: Fourteen (78%) of 18 iNPH patients showed an enhanced R2BRrc at ISIs 100-150-200 ms, while no control subjects had abnormal R2BRrc. The mean amplitude of bilateral R2BRrc at the shortest ISIs (100-150-200 ms) showed high accuracy in differentiating iNPH patients from controls (AUC = 0.89). R2BRrc values significantly correlated with midbrain area and MRHI values. Conclusions: This study represents the first evidence of brainstem hyperexcitability in iNPH patients. Given its low cost and wide availability, R2BRrc could be a useful tool for selecting elderly subjects with mild gait and urinary dysfunction who should undergo an extensive diagnostic workup for the diagnosis of NPH.

Introduction Track density imaging (TDI) has been proven to be a useful approach able to investigate white matter (WM) anatomical integrity in several neurodegenerative conditions, such as Parkinson's disease (PD) and classical phenotype of Progressive Supranuclear Palsy (PSP) also known as Richardson's syndrome (RS). To the best of our knowledge, no studies have assessed WM changes in PSP-predominant parkinsonism (PSP–P) patients by using a TDI approach, and no studies have explored the potential role of these changes in discriminating patients with PSP-P from those with PSP-RS and PD. Methods We used TDI to characterize WM changes in 31 PSP-P compared to 36 PSP-RS, 36 PD and 37 healthy controls (HC). Then, a support vector machine (SVM) approach was used to evaluate the performance of TDI in discriminating between patient groups. Results Relative to HC and PD patients, decreased track density in PSP-P patients was found in several WM regions such as the midbrain, superior cerebellar peduncles, cerebellum and corticospinal tract. By contrast, higher values of track density were observed in PSP-P patients compared to PSP-RS. SVM approach using TDI differentiated patients with PSP-P from PD and PSP-RS with an area under the curve of 0.90 and 0.76, respectively. Conclusions Our findings suggest that TDI may represent a useful approach for characterizing WM changes in PSP-P patients representing a potential new MRI biomarker in distinguishing this PSP phenotype from PD.

AIM Disorganization has been considered as a clinical domain close to the core of psychosis. However, it has received poor attention, especially at the illness onset. Moreover, most of the studies examining disorganized symptoms have been conducted in patients with chronic psychosis and research in the early stages of illness is still relatively scarce. Thus, the aims of this study were (a) to longitudinally monitor the stability of disorganization in patients with first episode psychosis (FEP) across a 1-year follow-up period, and (b) to investigate any relevant association of disorganized symptoms with functioning, psychopathology and the specific treatment components of an 'early intervention in psychosis' (EIP) program along the 1 year of follow-up. METHODS At baseline, 312 FEP participants (aged 12-35 years) completed the positive and negative syndrome scale (PANSS) and the global assessment of functioning (GAF). Spearman's correlations and multiple linear regression analysis were used. RESULTS At baseline, disorganization showed significant associations with all PANSS subscores, and a relevant negative correlation with GAF score. Across the follow-up, FEP individuals showed a significant improvement in disorganization severity. This decrease was specifically related to both baseline antipsychotic dosage and the number of individual cognitive-behavioural therapy sessions offered across the 1-year follow-up period. CONCLUSIONS Disorganization is clinically relevant in FEP patients, already ate the enrollment in an EIP program. However, it tends to improve over time together with the delivery of specialized, person-tailored FEP interventions within a specific EIP protocol.

Veno-venous extracorporeal membrane oxygenation (V-V ECMO) represents a component of the treatment strategy for severe respiratory failure. Clinical evidence on the management of the lung during V-V ECMO are limited just as the consensus regarding timing of weaning. The monitoring of the carbon dioxide (CO2) removal (V ' CO2TOT) is subdivided into two components: the membrane lung (ML) and the native lung (NL) are both taken into consideration to evaluate the improvement of the function of the lung and to predict the time to wean off ECMO. We enrolled patients with acute respiratory distress syndrome (ARDS). The V ' CO2NL ratio (V ' CO2NL/V ' CO2TOT) value was calculated based on the distribution of CO2 between the NL and the ML. Of 18 patients, 15 were successfully weaned off of V-V ECMO. In this subgroup, we observed a significant increase in the V ' CO2NL ratio comparing the median values of the first and last quartiles (0.32 vs. 0.53, p = 0.0045), without observing any modifications in the ventilation parameters. An increase in the V ' CO2NL ratio, independently from any change in ventilation could, despite the limitations of the study, indicate an improvement in pulmonary function and may be used as a weaning index for ECMO.

Purpose: To evaluate the efficacy and safety of Escherichia coli Nissle 1917 (EcN) in association with levofloxacin in patients with chronic bacterial prostatitis (CBP). Methods: Patients with CBP referred to our clinic from September 2017 to July 2019 were enrolled. At baseline, the symptomatology was assessed with the NIH-Chronic Prostatitis Symptom Index (NIH-CPSI), while the Meares–Stamey test was used to diagnose the infection. Patients were randomized (1:1) in two groups (A and B). All subjects underwent oral administration of Levoxacin® 500mg once daily for 4weeks. Only the patients in Group B underwent oral administration of EcN® 320mg, twice daily for 4weeks and then once daily for 8weeks. After 3months, each patient repeated the NIH-CPSI questionnaire, while the Meares–Stamey test was repeated at 3 and 6months in patients who reported persistent symptoms. All adverse events (AEs) were recorded. Results: A total of 110 patients were enrolled. After 3months patients in Group B reported a significantly lower NIH-CPSI score (5.85 ± 3.07 vs. 7.64 ± 3.86; p = 0.009) and biological recurrences rate (9.8 vs. 26.9%; p = 0.043). At 6months the biological recurrences rate was significantly lower in Group B (8.7 vs. 28.9%; p = 0.038). Only three patients in Group A and six in Group B (p = 0.25) complained mild AEs. Conclusions: Combination therapy with EcN and levofloxacin allows a better control of symptoms and biological recurrences in patients with CBP, without worsening the safety of the treatment.

BackgroundFirst episode psychosis (FEP) patients who use cannabis experience more frequent psychotic and euphoric intoxication experiences compared to controls. It is not clear whether this is consequent to patients being more vulnerable to the effects of cannabis use or to their heavier pattern of use. We aimed to determine whether extent of use predicted psychotic-like and euphoric intoxication experiences in patients and controls and whether this differs between groups.MethodsWe analysed data on patients who had ever used cannabis (n = 655) and controls who had ever used cannabis (n = 654) across 15 sites from six countries in the EU-GEI study (2010–2015). We used multiple regression to model predictors of cannabis-induced experiences and to determine if there was an interaction between caseness and extent of use.ResultsCaseness, frequency of cannabis use and money spent on cannabis predicted psychotic-like and euphoric experiences (p ⩽ 0.001). For psychotic-like experiences (PEs) there was a significant interaction for caseness × frequency of use (p < 0.001) and caseness × money spent on cannabis (p = 0.001) such that FEP patients had increased experiences at increased levels of use compared to controls. There was no significant interaction for euphoric experiences (p > 0.5).ConclusionsFEP patients are particularly sensitive to increased psychotic-like, but not euphoric experiences, at higher levels of cannabis use compared to controls. This suggests a specific psychotomimetic response in FEP patients related to heavy cannabis use. Clinicians should enquire regarding cannabis related PEs and advise that lower levels of cannabis use are associated with less frequent PEs.

For the analysis and conservation of architectural heritage a multi-disciplinary approach is required. In the specific case of early concrete buildings, survey and experimental investigations const...

To compare depression and anxiety between elite volleyball players (VP) and amateur athletes (AA). Depression and anxiety levels were assessed in 31 elite VP and 26 AA. The International Physical Activity Questionnaire was administered to assess physical activity level (PAL). Beck Depression Inventory II (BDI-II) and State-Trait Anxiety Inventory-Form Y 1–2 were administered to assess an individual’s depression and anxiety levels. VP showed a significantly lower depression (p = 0.018) and trait anxiety (p = 0.038) levels than AA (BDI-II z-score = − 0.27 ± 0.82 vs 0.32 ± 1.11 in VP and AA, respectively; STAI-Y2 z-score = − 0.28 ± 0.85 vs 0.34 ± 1.08 in VP and AA, respectively). A significant main effect of gender was observed for STAI-Y1 (p = 0.025) and STAI-Y2 (p = 0.014). In detail, females had higher state and trait anxiety levels than males. PAL did not significantly adjust values of participants (AA and VP) in BDI-II, STAI-Y1, and STAI-Y2. Results suggest that the practice of supervised volleyball sport, rather than unsupervised recreational activity, might positively influence an individual’s depression and anxiety levels. Moreover, physical exercise specialists should consider a different psychological approach when working with females than males.

Introduction: Few data are available regarding intraoperative plasma concentrations of vancomycin administered as prophylaxis in pediatric cardiac surgery. The aims of this study were to investigate during pediatric cardiac surgery with cardiopulmonary bypass(CPB) the attainment of the area-under-the-curve of the vancomycin serum concentrations versus time over surgery to minimum inhibitory concentration ratio(AUCintra/MIC) of 400 (mg × h)/l and/or a target concentration of 15–20 mg/l. Methods: In a prospective study, 40 patients divided into four subgroups (neonates, infants, children Results: The median (interquartile range) age was 241.5 days (47–3898) and the median weight was 7.1 kg (3.1–37). The median AUCintra/MIC was 254.73 (165.89–508.06). In 11 patients the AUCintra/MIC target was not reached. Neonates displayed the lowest AUCintra/MIC values, and these were significantly lower than those of children ⩾10 years old (p = 0.02). Vancomycin concentrations were above the maximal target of 20 mg/l in 82.5% and 80% of patients at surgery and CPB start, respectively. At CPB and surgery end, 42.5% of patients showed vancomycin concentrations above 20 mg/l and 42.5% below 15 mg/l. Patients⩾10 years old showed the highest peak values whereas neonates were those with the lowest troughs. AUCintra/MIC correlated with age(r:0.36, p = 0.02), weight(r:0.35, p = 0.03), intraoperative protein value(r:0.40, p = 0.01), CPB priming volume/kg(r:−0.33, p = 0.04), CPB duration(r:0.36, p = 0.02) and vancomycin troughs(r:0.35, p = 0.04). Conclusions: An AUCintra/MIC ⩾400 target was not reached in one-quarter of children undergoing heart surgery. Vancomycin peaked before the start of surgery and neonates were those with the lowest troughs. Vancomycin concentrations are affected by CPB hemodilution and by patients’ age and weight.

Summary Background Progressive supranuclear palsy is a neurodegenerative disorder associated with tau protein aggregation. Tilavonemab (ABBV-8E12) is a monoclonal antibody that binds to the N-terminus of human tau. We assessed the safety and efficacy of tilavonemab for the treatment of progressive supranuclear palsy. Methods We did a phase 2, multicentre, randomised, placebo-controlled, double-blind study at 66 hospitals and clinics in Australia, Canada, France, Germany, Italy, Japan, Spain, and the USA. Participants (aged ≥40 years) diagnosed with possible or probable progressive supranuclear palsy who were symptomatic for less than 5 years, had a reliable study partner, and were able to walk five steps with minimal assistance, were randomly assigned (1:1:1) by interactive response technology to tilavonemab 2000 mg, tilavonemab 4000 mg, or matching placebo administered intravenously on days 1, 15, and 29, then every 28 days through to the end of the 52-week treatment period. Randomisation was done by the randomisation specialist of the study sponsor, who did not otherwise participate in the study. The sponsor, investigators, and participants were unaware of treatment allocations. The primary endpoint was the change from baseline to week 52 in the Progressive Supranuclear Palsy Rating Scale (PSPRS) total score in the intention-to-treat population. Adverse events were monitored in participants who received at least one dose of study drug. Prespecified interim futility criteria were based on a model-based effect size of 0 or lower when 60 participants had completed the 52-week treatment period and 0·12 or lower when 120 participants had completed the 52-week treatment period. This study is registered at ClinicalTrials.gov, number NCT02985879. Findings Between Dec 12, 2016, and Dec 31, 2018, 466 participants were screened, 378 were randomised. The study was terminated on July 3, 2019, after prespecified futility criteria were met at the second interim analysis. A total of 377 participants received at least one dose of study drug and were included in the efficacy and safety analyses (2000 mg, n=126; 4000 mg, n=125; placebo, n=126). Least squares mean change from baseline to week 52 in PSPRS was similar in all groups (between-group difference vs placebo: 2000 mg, 0·0 [95% CI –2·6 to 2·6], effect size 0·000, p>0·99; 4000 mg, 1·0 [–1·6 to 3·6], –0·105, p=0·46). Most participants reported at least one adverse event (2000 mg, 111 [88%]; 4000 mg, 111 [89%]; placebo, 108 [86%]). Fall was the most common adverse event (2000 mg, 42 [33%]; 4000 mg, 54 [43%]; placebo, 49 [39%]). Proportions of patients with serious adverse events were similar among groups (2000 mg, 29 [23%]; 4000 mg, 34 [27%]; placebo, 33 [26%]). Fall was the most common treatment-emergent serious adverse event (2000 mg, five [4%]; 4000 mg, six [5%]; placebo, six [5%]). 26 deaths occurred during the study (2000 mg, nine [7%]; 4000 mg, nine [7%]; placebo, eight [6%]) but none was drug related. Interpretation A similar safety profile was seen in all treatment groups. No beneficial treatment effects were recorded. Although this study did not provide evidence of efficacy in progressive supranuclear palsy, the findings provide potentially useful information for future investigations of passive immunisation using tau antibodies for progressive supranuclear palsy. Funding AbbVie Inc.

Introduction Quantitative MR planimetric measurements were reported to discriminate between progressive supranuclear palsy (PSP) and non-PSP parkinsonism, yet few data exist on the usefulness of these markers in early disease stages. Methods The pons-to-midbrain area ratio (P/M) and the Magnetic Resonance Parkinsonism Index (MRPI) as well as new indices, termed P/M2.0 and MRPI2.0, multiplying the former by a ratio of the third ventricle (3rdV) width/frontal horns (FH) width, were calculated on T1-weighted images in 84 patients with clinically unclassifiable neurodegenerative parkinsonism (CUP) at the time of imaging. Areas under the curve (AUCs) of these markers for predicting future PSP was determined. The final clinical diagnosis was made after at least 24 months of follow-up. Results Final diagnosis was Parkinson's disease in 55 patients, multiple system atrophy in 12 cases, and PSP in 17. At baseline imaging, patients with a final PSP diagnosis had significantly higher MRPI, P/M, MRPI2.0 and P/M2.0 values compared to the other groups. AUCs in discriminating between future PSP and non-PSP parkinsonism were 0.91 for both the P/M and the MRPI and 0.98 for the P/M2.0 and the MRPI2.0. Conclusions Brainstem-derived MR planimetric measures yield high diagnostic accuracy for separating PSP from non-PSP parkinsonism in early disease stages when clinical criteria are not yet fully met. Consistent with the underlying pathology in PSP, our study suggests that inclusion of 3rdV width makes P/M2.0 and MRPI2.0 more accurate in diagnosing early stage PSP patients than the P/M and MRPI.

One of the most severe complications of narcotic drugs misuse are induced psychotic disorders. Their frequency is varies from 5.2 to 100% and depends on the type of drug. This review provides current data and discussion on the similarities and differences between induced psychosis and schizophrenia. Possible interaction of pathogenic pathways, the possibility of differentiation at the clinical level and the main difficulties in clear diagnostic are discussed. The problem of transformation of induced psychoses into schizophrenia and the significance of differentiated treatment are also considered.

Introduction Parkinson's disease (PD), a progressive neurodegenerative disease, can be misdiagnosed with atypical conditions such as Progressive Supranuclear Paralysis (PSP) due to overlapping clinical features. MicroRNAs (miRNAs) are small non-coding RNAs with a key role in post-transcriptional gene regulation. The aim was to identify a set of differential exosomal miRNAs biomarkers, which may aid in diagnosis. Methods We analyzed the serum level of 188 miRNAs in a discovery set, by using RTqPCR based TaqMan assay, in a small cohort of healthy controls, PD and PSP patients. Subsequently, the differentially expressed miRNAs, between PSP and PD patients, were further tested in a larger and independent cohort of 33 healthy controls, 40 PD and 20 PSP patients. The most accurate diagnostic exosomal miRNAs classifiers were identified in a logistic regression model. Results A statistically significant set of three exosomal miRNAs: miR-21-3p, miR-22-3p and miR-223-5p, discriminated PD from HC (area under the curve of 0.75), and a set of three exosomal miRNAs, miR-425-5p, miR-21-3p, and miR-199a-5p, discriminated PSP from PD with good diagnostic accuracy (area under the curve of 0.86). Finally, the classifier that best discriminated PSP from PD consisted of six exosomal miRNAs (area under the curve = 0.91), with diagnostic sensitivity and specificity of 0.89 and 0.90, respectively. Conclusions Based on our analysis, these data showed that exosomal miRNAs could act as biomarkers to differentiate between PSP and PD.

Objective: Structural abnormalities in thalami and basal ganglia, in particular the globus pallidus (GP), are a neuroimaging hallmark of hereditary aceruloplasminemia (HA), yet few functional imaging data exit in HA carriers. This study investigated the iron-related structural and functional abnormalities in an Italian HA family. Methods: Multimodal imaging was used including structural 3 T MRI, functional imaging (SPECT imaging with 123I-ioflupane (DAT-SPECT), cardiac 123I metaiodobenzylguanidine (123I-MIBG) scintigraphy, and 18F-fluorodeoxyglucose (18F-FDG)-PET imaging). In the proband, MRI and scintigraphic evaluations were performed at baseline, 2 and 4 years (structural imaging), and 2 years of follow-up period (functional imaging). Results: We investigated two cousins carrying a novel splicing homozygous mutation in intron 6 (IVS6 + 1 G > A) of CP gene. Interestingly, MRI features in both subjects were characterized by marked iron accumulation in the thalami and basal ganglia nuclei, while GP was not affected. MRI performed in the proband at 2 and 4 years of follow-up confirmed progressive neurodegeneration of the thalami and basal ganglia without the involvement of GP. Functional imaging showed reduced putaminal DAT uptake in both cousins, whereas cardiac MIBG and FDG uptakes performed in the proband were normal. Longitudinal scintigraphic investigations did not show significant changes over the time. Conclusions: For HA carriers, our findings demonstrate that GP was spared by iron accumulation over the time. The nigrostriatal presynaptic dopaminergic system was damaged while the cardiac sympathetic system remained longitudinally preserved, thus expanding the imaging features of this rare inherited disorder.

Tremor is an impairing symptom associated with several neurological diseases. Some of such diseases are neurodegenerative, and tremor characterization may be of help in differential diagnosis. To date, electromyography (EMG) is the gold standard for the analysis and diagnosis of tremors. In the last decade, however, several studies have been conducted for the validation of different techniques and new, non-invasive, portable, or even wearable devices have been recently proposed as complementary tools to EMG for a better characterization of tremors. Such devices have proven to be useful for monitoring the efficacy of therapies or even aiding in differential diagnosis. The aim of this review is to present systematically such new solutions, trying to highlight their potentialities and limitations, with a hint to future developments.

Introduction Apomorphine is a dopamine agonist used in Parkinson's disease (PD), which matches levodopa in terms of the magnitude of effect on the cardinal motor features, such as tremor and bradykinesia. The beneficial effect of this treatment on PD patients with tremor-dominant has widely been demonstrated, although the underlying neural correlates are unknown. We sought to examine the effects of apomorphine on topological characteristics of resting-state functional connectivity networks in tremor-dominant PD (tdPD) patients. Methods Sixteen tdPD patients were examined using a combined electromyography-functional magnetic resonance imaging approach. Patients were scanned twice following either placebo (subcutaneous injection of 1 mL saline solution) or 1 mg of apomorphine injection. Graph analysis methods were employed to investigate the modular organization of functional connectivity networks before and after drug treatment. Results After injection of apomorphine, evident reduction of tremor symptoms was mirrored by a significant increase in overall connectivity strength and reorganization of the modular structure of the basal ganglia and of the fronto-striatal module. Moreover, we found an increase in the centrality of motor and premotor regions. No differences were found between pre- and post-placebo sessions. Conclusion These results provide new evidence about the effects of apomorphine at a large-scale neural network level showing that drug treatment modifies the brain functional organization of tdPD, increasing the overall resting-state functional connectivity strength, the segregation of striato-frontal regions and the integrative role of motor areas.

Psychotic patients with a lifetime history of cannabis use generally show better cognitive functioning than other psychotic patients. Some authors suggest that cannabis-using patients may have been less cognitively impaired and less socially withdrawn in their premorbid life. Using a dataset comprising 948 patients with first-episode psychosis (FEP) and 1313 population controls across 6 countries, we examined the extent to which IQ and both early academic (Academic Factor [AF]) and social adjustment (Social Factor [SF]) are related to the lifetime frequency of cannabis use in both patients and controls. We expected a higher IQ and a better premorbid social adjustment in psychotic patients who had ever used cannabis compared to patients without any history of use. We did not expect such differences in controls. In both patients and controls, IQ was 3 points higher among occasional-users than in never-users (mean difference [Mdiff] = 2.9, 95% CI = [1.2, 4.7]). Both cases and control daily-users had lower AF compared to occasional (Mdiff = −0.3, 95% CI = [−0.5; −0.2]) and never-users (Mdiff = −0.4, 95% CI = [−0.6; −0.2]). Finally, patient occasional (Mdiff = 0.3, 95% CI = [0.1; 0.5]) and daily-users (Mdiff = 0.4, 95% CI = [0.2; 0.6]) had better SF than their never-using counterparts. This difference was not present in controls (Fgroup*frequency(2, 2205) = 4.995, P = .007). Our findings suggest that the better premorbid social functioning of FEP with a history of cannabis use may have contributed to their likelihood to begin using cannabis, exposing them to its reported risk-increasing effects for Psychotic Disorders.

Introduction We investigated the imaging counterpart of two functional domains (ocular motor dysfunction and postural instability) in progressive supranuclear palsy (PSP) patients classified according to the new clinical diagnostic criteria. Methods Forty-eight patients with probable PSP-Richardson's syndrome (PSP-RS), 30 with probable PSP-parkinsonism (PSP-P), 37 with Parkinson's disease (PD), and 38 controls were enrolled. For each functional domain, PSP patients were stratified by two certainty levels: vertical supranuclear gaze palsy (O1) and slowness of vertical saccades (O2) for ocular motor dysfunction; early unprovoked falls and tendency to fall on the pull-test for postural instability. Voxel-based morphometry (VBM), whole-brain fractional anisotropy (FA) and MR planimetric measurements were analysed and compared across patient groups. Results O1 was present in 64%, and O2 in 36% of all PSP patients. All PSP-RS patients showed early unprovoked falls. TBSS whole-brain analysis revealed that superior cerebellar peduncles (SCPs) were the only structures with significantly lower FA values in PSP-RS compared with PSP-P patients. PSP/O1 patients had lower FA values in midbrain than PSP/O2 patients. By contrast, VBM revealed no differences in grey matter volume between PSP patient groups. MR Planimetric measurements confirmed atrophy of midbrain and SCPs, in line with DTI findings. Conclusions Our study demonstrates that SCPs were significantly more damaged in patients with PSP-RS in comparison with PSP-P patients, thus suggesting the role of SCPs in developing postural instability. Midbrain damage was less severe in O2 than in O1 patients, suggesting that the degree of vertical ocular dysfunction reflects the severity of midbrain atrophy.

Background No prospective study of patients with Parkinson's disease (PD) has investigated the appearance of vertical gaze abnormalities, a feature suggestive of progressive supranuclear palsy (PSP). Objective To identify, within a cohort of patients with an initial diagnosis of PD, those who developed vertical gaze abnormalities during a 4-year follow-up, and to investigate the performance of new imaging biomarkers in predicting vertical gaze abnormalities. Methods A total of 110 patients initially classified as PD and 74 controls were enrolled. All patients underwent clinical assessment at baseline and every year up to the end of the follow-up. The pons/midbrain area ratio 2.0 and the Magnetic Resonance Parkinsonism Index 2.0 were calculated. Results After 4-year follow-up, 100 of 110 patients maintained the diagnosis of PD, whereas 10 PD patients (9.1%) developed vertical gaze abnormalities, suggesting an alternative diagnosis of PSP-parkinsonism. At baseline, the Magnetic Resonance Parkinsonism Index 2.0 was the most accurate biomarker in differentiating PD patients who developed vertical gaze abnormalities from those who maintained an initial diagnosis of PD. At the end of follow-up, both of these biomarkers accurately distinguished PSP-parkinsonism from PD. Conclusions Our results demonstrate that a number of patients with an initial diagnosis of PD developed vertical gaze abnormalities during a 4-year follow-up, and the diagnosis was changed from PD to PSP-parkinsonism. In PD patients, baseline Magnetic Resonance Parkinsonism Index 2.0 showed the best performance in predicting the clinical evolution toward a PSP-parkinsonism phenotype, enabling PSP-parkinsonism patients to be identified at the earliest stage of the disease for promising disease-modifying therapies. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Aim: The aim of this study was to evaluate the corticospinal tract (CST) diffusion profile in pure lower motor neuron disease (pLMND) patients who at baseline did not show any clinical or electrophysiological involvement of upper motor neurons (UMN), and in amyotrophic lateral sclerosis (ALS) patients. Materials and Methods: Fifteen ALS patients with delayed central motor conduction time (CMCT) and 14 pLMND patients with normal CMCT were enrolled together with 15 healthy controls. Fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) maps were obtained. The tract profile of CST was reconstructed with the automated fiber quantification tool and its diffusion properties were quantified voxel-by-voxel and then compared pairwise between groups. Moreover, a random forest (RF) classifier was trained to evaluate the ability of CST diffusion metrics in distinguishing pairwise the groups from the controls. Results: ALS patients presented wide microstructural abnormalities in the entire CST as assessed by FA decrease and RD increase while pLMND patients showed focal FA decrease and a larger AD increase in the cerebral peduncle and posterior limb of the internal capsule in comparison with controls. RF revealed that diffusion tensor imaging (DTI) metrics accurately distinguished ALS patients and pLMND patients from controls (96.67 and 95.71% accuracy, respectively). Conclusions: Our study demonstrates that the CST was impaired in both ALS and pLMND patients, thus suggesting that DTI metrics are a reliable tool in detecting subtle changes of UMN in pLMND patients, also in the absence of clinical and CMCT abnormalities.

We compared GABAergic function and neuronal excitability in the hippocampal tissue of seven sporadic MTLE patients with a patient carrying a SCN1A loss‐of‐function mutation. All had excellent outcome from anterior temporal lobectomy, and neuropathological study always showed characteristic hippocampal sclerosis (Hs). Compared to MTLE patients, there was a more severe impairment of GABAergic transmission, due to the lower GABAergic activity related to the NaV1.1 loss‐of‐function, in addition to the typical GABA‐current rundown, a hallmark of sporadic MTLE. Our results give evidence that a pharmacological rescuing of the GABAergic dysfunction may represent a promising strategy for the treatment of these patients.

Background After the emergence of Covid-19 in China, Hubei Province, the epidemic quickly spread to Europe. France was quickly hit and our institution was one of the first French university to receive patients infected with Sars-COV2. The predicted massive influx of patients motivated the cancellation of all elective surgical procedures planned to free hospitalization beds and to free intensive care beds. Nevertheless, we should properly select patients who will be canceled to avoid life-threatening. The retained surgical indications are surgical emergencies, oncologic surgery, and organ transplantation. Material and methods We describe the organization of our institution which allows the continuation of these surgical activities while limiting the exposure of our patients to the Sars Cov2. Results After 4 weeks of implementation of intra-hospital protocols for the control of the Covid-19 epidemic, 112 patients were operated on (104 oncology or emergency surgeries and 8 liver transplants). Only one case of post-operative contamination was observed. No mortality related to Covid-19 was noted. No cases of contamination of surgical care personnel have been reported. Conclusion We found that the performance of oncological or emergency surgery is possible, safe for both patients and caregivers., Highlights • During Covid-19 pandemic, we should properly select patients to avoid a life threatening. • Need to continue surgical activities while limiting the exposure to the Sars Cov2. • With all preventive actions, no mortality related to Covid-19 was noted. • With all preventive actions, no cases of contamination of surgical care personnel.

Background Acute pancreatitis is a rare but recognised complication of clozapine leading to termination of treatment. Case presentation We present the case of a 39-year-old man with treatment-resistant schizoaffective disorder and a history of recurrent acute pancreatitis attributed to clozapine. After 15 years of unremitting symptoms with disruptive and aggressive behaviour, he was admitted for a clozapine rechallenge. Despite experiencing two further episodes of acute pancreatitis during clozapine treatment that led to its temporary withdrawal, clozapine was successfully re-established under gastroenterology consultation with close monitoring which resulted in progressively marked improvement of his mental state. Conclusions This case demonstrates that patients who develop pancreatitis during clozapine treatment may be cautiously rechallenged with specialist gastroenterology support.

The treatment of patients with recurrent and/or metastatic (R/M) salivary gland adenoid cystic carcinoma (ACC) remains an unmet need.Patients with R/M disease with a history of clinical or symptomatic disease progression within 6 months and a maximum of 1 previous line of chemotherapy or a multiple kinase inhibitor received oral lenvatinib at a dose of 24 mg/day. The primary endpoint was the objective response rate; secondary endpoints included quality of life (QOL) (according to the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Items [EORTC QLQ-C30] and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Module Head and Neck Module [EORTC QLQ-HN35]), progression-free survival and overall survival, duration of response, and toxicities.Twenty-eight patients with R/M ACC were enrolled. Among 26 evaluable patients, 3 partial responses (11.5%) were reported. Target lesion reductions between 23% to 28% were observed in 4 of 20 patients with stable disease. Treatment-related adverse events were frequent (all grades, 96%; grade≥3 in 50% of cases according to version 4.03 of the National Cancer Institute Common Terminology Criteria for Adverse Events). The dose of lenvatinib was reduced in 24 patients, whereas in 21 patients the dose was reduced within the first 12 weeks and 4 patients maintained the full dose throughout treatment. The QOL deteriorated between baseline and 6 months with regard to Fatigue and Dry Mouth. There was no evidence of changes in Swallowing and Physical Functioning. At a median follow-up of 29 months, 2 patients remained on treatment, 10 patients were off protocol for disease progression and were alive with disease, and 14 patients had died of disease progression. The median overall survival, progression-free survival, and duration of response were 27 months, 9.1 months, and 3.1 months, respectively.Lenvatinib appears to have modest activity in ACC. Toxicities are common but manageable and QOL was found to deteriorate in some domains.

Comment

Key Points Question Can widely available measures of atrophy on magnetic resonance imaging increase diagnostic certainty of underlying frontotemporal lobar degeneration (FTLD) and estimate clinical deterioration in the behavioral variant of frontotemporal dementia (bvFTD)? Findings This diagnostic/prognostic study investigated the clinical utility of 5 validated visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index. When combined, VAS showed excellent diagnostic performance for differentiating between bvFTD with high and low confidence of FTLD and for the estimation of longitudinal clinical deterioration, whereas the Magnetic Resonance Parkinsonism Index was increased in bvFTD with underlying 4-repeat tauopathies. Meaning These findings suggest that, in bvFTD, VAS can be used to increase diagnostic certainty of underlying FTLD and estimate longitudinal clinical deterioration., This diagnostic/prognostic study assesses the utility of 6 visual atrophy scales and the Magnetic Resonance Parkinsonism Index in patients with behavioral variant frontotemporal dementia to distinguish those with high vs low confidence of frontotemporal lobar degeneration., Importance The presence of atrophy on magnetic resonance imaging can support the diagnosis of the behavioral variant of frontotemporal dementia (bvFTD), but reproducible measurements are lacking. Objective To assess the diagnostic and prognostic utility of 6 visual atrophy scales (VAS) and the Magnetic Resonance Parkinsonism Index (MRPI). Design, Setting, and Participants In this diagnostic/prognostic study, data from 235 patients with bvFTD and 225 age- and magnetic resonance imaging–matched control individuals from 3 centers were collected from December 1, 1998, to September 30, 2019. One hundred twenty-one participants with bvFTD had high confidence of frontotemporal lobar degeneration (FTLD) (bvFTD-HC), and 19 had low confidence of FTLD (bvFTD-LC). Blinded clinicians applied 6 previously validated VAS, and the MRPI was calculated with a fully automated approach. Cortical thickness and subcortical volumes were also measured for comparison. Data were analyzed from February 1 to June 30, 2020. Main Outcomes and Measures The main outcomes of this study were bvFTD-HC or a neuropathological diagnosis of 4-repeat (4R) tauopathy and the clinical deterioration rate (assessed by longitudinal measurements of Clinical Dementia Rating Sum of Boxes). Measures of cerebral atrophy included VAS scores, the bvFTD atrophy score (sum of VAS scores in orbitofrontal, anterior cingulate, anterior temporal, medial temporal lobe, and frontal insula regions), the MRPI, and other computerized quantifications of cortical and subcortical volumes. The areas under the receiver operating characteristic curve (AUROC) were calculated for the differentiation of participants with bvFTD-HC and bvFTD-LC and controls. Linear mixed models were used to evaluate the ability of atrophy measures to estimate longitudinal clinical deterioration. Results Of the 460 included participants, 296 (64.3%) were men, and the mean (SD) age was 62.6 (11.4) years. The accuracy of the bvFTD atrophy score for the differentiation of bvFTD-HC from controls (AUROC, 0.930; 95% CI, 0.903-0.957) and bvFTD-HC from bvFTD-LC (AUROC, 0.880; 95% CI, 0.787-0.972) was comparable to computerized measures (AUROC, 0.973 [95% CI, 0.954-0.993] and 0.898 [95% CI, 0.834-0.962], respectively). The MRPI was increased in patients with bvFTD and underlying 4R tauopathies compared with other FTLD subtypes (14.1 [2.0] vs 11.2 [2.6] points; P

The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) Project was funded by grant agreement Health-F2-2010-241909 (Project EU-GEI) from the European Community’s Seventh Framework programme., Tarricone, I., D'Andrea, G., Jongsma, H.E., Tosato, S., Gayer-Anderson, C., Stilo, S.A., Suprani, F., Iyegbe, C., Van Der Ven, E., Quattrone, D., Di Forti, M., Velthorst, E., Rossi Menezes, P., Arango, C., Parellada, M., Lasalvia, A., La Cascia, C., Ferraro, L., Bobes, J., Bernardo, M., Sanjuán, I., Santos, J.L., Arrojo, M., Del-Ben, C.M., Tripoli, G., Llorca, P.-M., De Haan, L., Selten, J.-P., Tortelli, A., Szöke, A., Muratori, R., Rutten, B.P., Van Os, J., Jones, P.B., Kirkbride, J.B., Berardi, D., Murray, R.M., Morgan, C.

Involuntary tremor at rest is observed in patients with Parkinson’s disease (PD) or essential tremor (ET). Electromyography (EMG) studies have shown that phase displacement between antagonistic muscles at prevalent tremor frequency can accurately differentiate resting tremor in PD from that detected in ET. Currently, phase evaluation is qualitative in most cases. The aim of this study is to develop and validate a new mobile tool for the automated and quantitative characterization of phase displacement (resting tremor pattern) in ambulatory clinical settings. A new low-cost, wearable mobile device, called µEMG, is described, based on low-end instrumentation amplifiers and simple digital signal processing (DSP) capabilities. Measurements of resting tremor characteristics from this new device were compared with standard EMG. A good level of agreement was found in a sample of 21 subjects (14 PD patients with alternating resting tremor pattern and 7 ET patients with synchronous resting tremor pattern). Our results demonstrate that tremor analysis using µEMG is easy to perform and it can be used in routine clinical practice for the automated quantification of resting tremor patterns. Moreover, the measurement process is handy and operator-independent.

Progressive supranuclear palsy (PSP) is a rare, rapidly progressive neurodegenerative disease. Richardson's syndrome (PSP-RS) and predominant parkinsonism (PSP-P) are characterized by wide range of cognitive and behavioural disturbances, but these variants show similar cognitive pattern of alterations, leading difficult differential diagnosis. For this reason, we explored with an Artificial Intelligence approach, whether cognitive impairment could differentiate the phenotypes. Forty Parkinson's disease (PD) patients, 25 PSP-P, 40 PSP-RS, and 34 controls were enrolled following the consensus criteria diagnosis. Participants were evaluated with neuropsychological battery for cognitive domains. Random Forest models were used for exploring the discriminant power of the cognitive tests in distinguishing among the four groups. The classifiers for distinguishing diseases from controls reached high accuracies (86% for PD, 95% for PSP-P, 99% for PSP-RS). Regarding the differential diagnosis, PD was discriminated from PSP-P with 91% (important variables: HAMA, MMSE, JLO, RAVLT_I, BDI-II) and from PSP-RS with 92% (important variables: COWAT, JLO, FAB). PSP-P was distinguished from PSP-RS with 84% (important variables: JLO, WCFST, RAVLT_I, Digit span_F). This study revealed that PSP-P, PSP-RS and PD had peculiar cognitive deficits compared with healthy subjects, from which they were discriminated with optimal accuracies. Moreover, high accuracies were reached also in differential diagnosis. Most importantly, Machine Learning resulted to be useful to the clinical neuropsychologist in choosing the most appropriate neuropsychological tests for the cognitive evaluation of PSP patients.

Although automatic prediction of Alzheimer’s disease (AD) from Magnetic Resonance Imaging (MRI) showed excellent performance, Machine Learning (ML) algorithms often provide high accuracy at the expense of interpretability of findings. Indeed, building ML models that can be understandable has fundamental importance in clinical context, especially for early diagnosis of neurodegenerative diseases. Recently, a novel interpretability algorithm has been proposed, the Explainable Boosting Machine (EBM), which is a glassbox model based on Generative Additive Models plus Interactions GA2Ms and designed to show optimal accuracy while providing intelligibility. Thus, the aim of present study was to assess – for the first time – the EBM reliability in predicting the conversion to AD and its ability in providing the predictions explainability. In particular, two-hundred brain MRIs from ADNI of Mild Cognitive Impairment (MCI) patients equally divided into stable (sMCI) and progressive (pMCI) were processed with Freesurfer for extracting twelve hippocampal subfields volumes, which already showed good AD prediction power. EBM models with and without pairwise interactions were built on training set (80%) comprised of these volumes, and global explanations were investigated. The performance of classifiers was evaluated with AUC-ROC on test set (20%) and local explanations of four randomly selected test patients (sMCIs and pMCIs correctly classified and misclassified) were given. EBMs without and with pairwise interactions showed accuracies of respectively 80.5% and 84.2%, thus demonstrating high prediction accuracy. Moreover, EBM provided practical clinical knowledge on why a patient was correctly or incorrectly predicted as AD and which hippocampal subfields drove such prediction.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder, affecting 5%of the elderly population. Currently, the diagnosis of PD is mainly based on clinical features and no definitive diagnostic biomarkers have been identified. The discovery of biomarkers at the earliest stages of PD is of extreme interest. This review focuses on the current findings in the field of circulating non-coding RNAs in PD. We briefly describe the more established circulating biomarkers in PD and provide a more thorough review of non-coding RNAs, in particular microRNAs, long non-coding RNAs and circular RNAs, differentially expressed in PD, highlighting their potential for being considered as biomarkers for diagnosis. Together, these studies hold promise for the use of peripheral biomarkers for the diagnosis of PD.