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Background: Cerebrospinal fluid myelin oligodendrocyte glycoprotein IgG (CSF MOG-IgG) are found in a proportion of patients with MOG antibody-associated disorder (MOGAD) and have been associated with severe disease presentations. However, most studies did not systematically investigate the role of MOG-IgG intrathecal synthesis (ITS)., Methods: We retrospectively studied 960 consecutive patients with paired serum and CSF samples screened for MOG-IgG using a live cell-based assays. MOG-IgG-specific antibody index (AI MOG ) was systematically calculated using serum and CSF titres to assess MOG-IgG ITS, and clinical features were compared between MOG-IgG CSF+/CSF- and ITS+/ITS- patients., Results: MOG-IgG were found in 55/960 patients (5.7%; serum+/CSF-: 58.2%, serum+/CSF+: 34.5%; serum-/CSF+: 7.3%). Serum/CSF MOG-IgG titres showed a moderate correlation in patients without ITS (ρ=0.47 (CI 0.18 to 0.68), p<0.001), but not in those with ITS (ρ=0.14 (CI -0.46 to -0.65), p=0.65). There were no clinical-paraclinical differences between MOG-IgG CSF+ vs CSF- patients. Conversely, patients with MOG-IgG ITS showed pyramidal symptoms (73% vs 32%, p=0.03), spinal cord involvement (82% vs 39%, p=0.02) and severe outcome at follow-up (36% vs 5%, p=0.02) more frequently than those without MOG-IgG ITS. A multivariate logistic regression model indicated that MOG-IgG ITS was an independent predictor of a poor outcome (OR: 14.93 (CI 1.40 to 19.1); p=0.03). AI MOG correlated with Expanded Disability Status Scale (EDSS) scores at disease nadir and at last follow-up (p=0.02 and p=0.01)., Conclusions: Consistently with physiopathology, MOG-IgG ITS is a promising prognostic factor in MOGAD, and its calculation could enhance the clinical relevance of CSF MOG-IgG testing, making a case for its introduction in clinical practice., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: The present study aimed to explore the suitability of the vocabulary knowledge (VOC) test as an accurate and reliable proxy of cognitive reserve (CR) by evaluating its psychometric properties and discrimination accuracy compared with other CR measures in multiple sclerosis (MS)., Methods: Sixty-eight consecutive people with multiple sclerosis (pwMS), followed at our MS outpatient clinic, completed a clinical evaluation and neuropsychological assessment including: VOC, Brief Repeatable Battery of Neuropsychological Tests (BRB-N), Cognitive Reserve Index Questionnaire (CRIq), Beck Depression Inventory-II, and State-Trait Anxiety Inventory. Reliability, convergent and divergent validity, and discrimination accuracy of the VOC were assessed using educational level as reference standard. The possible effects of sociodemographic and clinical factors on VOC and their role in predicting global cognitive status were also explored., Results: VOC demonstrated good internal consistency (Cronbach's α = 0.894) and adequate construct validity. It showed an acceptable level of discrimination between pwMS with high and low CR, comparable to the CRIq score. Education strongly affected VOC scores, which in turn were independent of MS features. VOC emerged as an independent predictor of global cognitive status together with MS-related disability., Conclusion: We demonstrated the validity of VOC as a reliable CR measure in pwMS. Thus, CR may also be estimated using fixed objective measures, independent of brain pathology and clinical features. Early CR estimation may help clinicians identify pwMS at a higher risk of cognitive decline and plan strict neuropsychological monitoring and cognitive interventions., (© 2024. The Author(s).)

This article provides an overview of the use of 18 F-FDG PET/CT in various clinical scenarios of head-neck squamous cell carcinoma, ranging from initial staging to treatment-response assessment, and post-therapy follow-up, with a focus on the current evidence, debated issues, and innovative applications. Methodological aspects and the most frequent pitfalls in head-neck imaging interpretation are described. In the initial work-up, 18 F-FDG PET/CT is recommended in patients with metastatic cervical lymphadenectomy and occult primary tumor; moreover, it is a well-established imaging tool for detecting cervical nodal involvement, distant metastases, and synchronous primary tumors. Various 18 F-FDG pre-treatment parameters show prognostic value in terms of disease progression and overall survival. In this scenario, an emerging role is played by radiomics and machine learning. For radiation-treatment planning, 18 F-FDG PET/CT provides an accurate delineation of target volumes and treatment adaptation. Due to its high negative predictive value, 18 F-FDG PET/CT, performed at least 12 weeks after the completion of chemoradiotherapy, can prevent unnecessary neck dissections. In addition to radiomics and machine learning, emerging applications include PET/MRI, which combines the high soft-tissue contrast of MRI with the metabolic information of PET, and the use of PET radiopharmaceuticals other than 18 F-FDG, which can answer specific clinical needs.

Background: Live cell-based assay (LCBA) is the gold standard for MOG-IgG detection, and fixed CBA (FCBA) is a widely used commercial alternative. Recent criteria attributed a diagnostic value to MOG-IgG titration with both LCBA and FCBA, with low-titre samples requiring additional supporting features for MOGAD diagnosis. However, FCBA titration is not validated. We aimed to assess the impact of the criteria-based MOG-IgG testing in MOGAD diagnosis., Methods: Thirty-eight serum samples of LCBA MOG-IgG1-positive MOGAD patients were titred on MOG-IgG LCBA and FCBA, and the presence of supporting features for MOGAD assessed. MOGAD criteria were evaluated in four testing scenarios: (a) FCBA without titration; (b) FCBA with titration; c) LCBA without titration; (d) LCBA with titration., Results: FCBA without titration failed to reach MOGAD diagnosis in 11/38 patients (28.9%, negative results in 5, lack of supporting features in 6). Patients with unconfirmed diagnosis had optic neuritis (ON, n = 8), or transverse myelitis (TM, n = 3). FCBA with titration allowed MOGAD diagnosis in 4 additional patients. Correlation between LCBA and FCBA titres was moderate (Spearman's rho 0.6, p < 0.001)., Conclusions: FCBA yields high rate of misdiagnosis mainly due a lower analytical sensitivity. FCBA titration provides a moderate diagnostic advantage in FCBA positive patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Evusheld (EVS) was authorized by FDA and EMA as pre-exposure prophylaxis (PrEP) in people at high risk of severe Covid-19 outcomes, including people with Multiple Sclerosis (pwMS) on B-cell depleting (BCD) therapies-such as Ocrelizumab (OCR). In this population, no data on possible adverse drug reactions (ADRs) to EVS, B-lymphocytes (CD20 +) counts pre- and post-EVS injection, and comparison of percentage increase of IgG antibodies directed against SARS-CoV-2 trimeric spike protein (anti-TSP IgG) post-EVS and Covid-19 vaccine was available. The aim of this study was to better characterize the efficacy and safety profile of EVS in pwMS on BCD agents., Methods: 17 pwMS on OCR agreed to receive EVS as PrEP for Covid-19. Sera samples were collected before the first dose of Covid-19 vaccine (T0), 4 weeks after the second dose (T1), 4 weeks after third dose (T2), immediately before (T3) and 4 weeks after (T4) EVS., Results: Covid-19 vaccine ADRs were mild-to-moderate, whereas no ADRs were reported after EVS injection. A significant increase of anti-TSP IgG was found only at T0-T1 (Z = -3.059, p = .002) and T3-T4 (Z = -3.621, p < .001) time-points. The median percentage increase between T3-T4 was significantly higher with respect to the T0-T1(Z = -3.296, p = .001) and T1-T2 (Z = -3.059, p = .002) time-points., Conclusions: These results further support EVS safety and efficacy in boosting anti-TSP IgG titers in pwMS on OCR, with a statistically greater increase than that observed after completion of a full Covid-19 vaccine cycle, plus a booster dose., (© 2023. Fondazione Società Italiana di Neurologia.)

Background: Covid-19 pandemic impacted on management of people with Multiple Sclerosis (pwMS). Level of satisfaction of pwMS regarding the care received by the staff of Multiple Sclerosis Centers (MSCs) during the pandemic was not fully investigated. In a large patient-centered multicenter study, the therapeutic adherence and quality of care of MSCs was assessed., Methods: In April-May 2021, an online survey was widespread by 16 Italian MSCs. Frequencies, percentages and/or means and standard deviations were calculated to describe the sample. ANOVAs were performed to evaluate the effect of sociodemographic and clinical variables on overall pwMS' rating of MSC assistance., Results: 1670 pwMS completed the survey (67.3% women). During the pandemic, 88% did not change their disease modifying therapy schedule, and 89.1% reached their MSCs with no or little difficulties. Even if only 1.3% of participants underwent a tele-health follow-up visit with their MSC staff, the 80.1% believed that tele-health services should be improved regardless of pandemic. 92% of participants were satisfied of how their MSC took charge of their needs; ANOVAs revealed an effect of disease duration on pwMS' level of satisfaction on MSCs management during the pandemic., Conclusions: The results revealed an efficient MSCs response to Covid-19 pandemic and provided the basis for the implementing of tele-health services that would further improve the taking charge of patients, particularly those with longer disease, higher disability, and/or living far from their MSC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Antonio Gallo reports a relationship with Biogen that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Merck Serono that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Mylan ITALIA Srl that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Novartis that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Roche that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Sanofi Genzyme that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Antonio Gallo reports a relationship with Teva Health that includes: consulting or advisory, speaking and lecture fees, and travel reimbursement. Lorena Lorefice reports a relationship with Biogen that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Novartis that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Sanofi that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Sanofi Genzyme that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Merck Serono that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Teva Health that includes: consulting or advisory and speaking and lecture fees. Lorena Lorefice reports a relationship with Almirall Ltd that includes: speaking and lecture fees. Alvino Bisecco reports a relationship with Biogen that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Roche that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Merck & Co Inc that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Celgene Corp Los Angeles that includes: consulting or advisory and speaking and lecture fees. Alvino Bisecco reports a relationship with Sanofi Genzyme that includes: consulting or advisory and speaking and lecture fees. Massimiliano Calabrese reports a relationship with Biogen that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Bristol Myers Squibb that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Celgene Corp Los Angeles that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Sanofi Genzyme that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Merck Serono that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Novartis that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with Roche that includes: speaking and lecture fees. Massimiliano Calabrese reports a relationship with International Progressive MS Alliance that includes: funding grants. Massimiliano Calabrese reports a relationship with Ministry of Health that includes: funding grants. Massimiliano Di Filippo reports a relationship with Bayer AG that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Biogen Italy that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Sanofi Genzyme that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Merck & Co Inc that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Mylan ITALIA Srl that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Roche that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Siemens Healthineers that includes: speaking and lecture fees and travel reimbursement. Massimiliano Di Filippo reports a relationship with Teva Health that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Teva Health that includes: board membership. Gioacchino Tedeschi reports a relationship with Roche that includes: board membership. Gioacchino Tedeschi reports a relationship with Eli Lilly Italy that includes: board membership. Gioacchino Tedeschi reports a relationship with Allergan US that includes: board membership. Gioacchino Tedeschi reports a relationship with Sanofi-Aventis US LLC that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Merck Serono Ltd that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Bayer Schering Pharma AG that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Biogen Italy that includes: speaking and lecture fees and travel reimbursement. Gioacchino Tedeschi reports a relationship with Novartis that includes: speaking and lecture fees and travel reimbursement., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Cognitive deficits, including working memory, and visuospatial deficits are common and debilitating in Parkinson's disease. α-synucleinopathy in the hippocampus and cortex is considered as the major risk factor. However, little is known about the progression and specific synaptic mechanisms underlying the memory deficits induced by α-synucleinopathy. Here, we tested the hypothesis that pathologic α-Synuclein (α-Syn), initiated in different brain regions, leads to distinct onset and progression of the pathology. We report that overexpression of human α-Syn in the murine mesencephalon leads to late onset memory impairment and sensorimotor deficits accompanied by reduced dopamine D1 expression in the hippocampus. In contrast, human α-Syn overexpression in the hippocampus leads to early memory impairment, altered synaptic transmission and plasticity, and decreased expression of GluA1 AMPA-type glutamate receptors. These findings identify the synaptic mechanisms leading to memory impairment induced by hippocampal α-synucleinopathy and provide functional evidence of the major neuronal networks involved in disease progression., (© 2023. The Author(s).)

Introduction: Temporal lobe epilepsy due to hippocampal sclerosis (TLE-HS) is one of the most common drug-resistant epilepsy. Surgery is currently accepted as an effective and safe therapeutic approach compared to antiseizure medications (ASMs). The study aims to evaluate the effect of surgical treatment of TLE-HS on sleep profile and architecture by subjective and objective evaluation of sleep in basal condition after one month and one year., Methods: Thirteen patients with TLE-HS were recruited to undergo overnight polysomnography and a subjective evaluation of nocturnal sleep utilizing the Pittsburgh Sleep Quality Index (PSQI) and daytime somnolence through the Epworth Sleepiness Scale (ESS) in basal condition (T0), one month (T1) and one year after surgery (T2), respectively. Thirteen healthy controls (HC) matched for age, sex and BMI were recruited. Scoring and analysis of sleep macrostructure and cyclic alternating pattern (CAP) parameters were performed., Results: The comparison between patients in basal condition (T0) and HC showed a significant lower sleep efficiency (p = 0.003) and REM percentage (p < 0.001). Regarding CAP, patients at T0 showed higher total CAP rate (p < 0.001), CAP rate in N2 (p < 0.001), higher A3 (%) (p = 0.001), higher mean duration of A1 (p = 0.002), A3 index (p < 0.001), cycle in sequences (p < 0.001), lower B duration (p < 0.001), cycle mean duration (p < 0.001) than HC. Surgery did not induce significant changes in nocturnal macrostructural polysomnographic variables in T1 and T2. Lower CAP rate (T1 vs T0 and T2 vs T0 p < 0.001), CAP rate in N3 (T1 vs T0 and T2 vs T0 p < 0.001), A3 (%) (T1 vs T0 and T2 vs T0 p < 0.001); lower phase A2 index (T1 vs T0 p < 0.001) and A3 index (T1 vs T0 p < 0.001), lower phase A1 index (T2 vs T0 p < 0.001) and cycle in sequences (T2 vs T0 p = 0.002) higher B mean duration (T2 vs T0 p = 0.002). No significant differences were found between T1 and T2 in CAP parameters., Conclusion: We found a significant NREM sleep instability in patients with TLE-HS compared with HC. In addition, anterior temporal lobectomy (ATL) induced a significant improvement in sleep continuity as evaluated by cyclic alternating pattern already one month later and this effect persisted after one year. ALT seems to restore a more resilient sleeping brain., Competing Interests: Declaration of competing interest None declared., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Decision makers spend significant time and effort interpreting information derived from large multidimensional databases; data are usually represented by several dashboard diagrams. The Complexity Design (CoDe) methodology provides a technique modeling graphical reports on data extracted by a data warehouse, where the charts composing the dashboard diagrams are integrated with a visual representation of the logical relationships among them. The generated visualizations (CoDe Graphs) are automatically obtained by connecting dashboard diagrams through graphical conceptual links. After analyzing the state of the art regarding the evaluation of graphical representation comprehensibility, we propose a classification of those evaluation approaches and evaluate the comprehensibility of CoDe Graphs concerning dashboard reports through a controlled experiment, involving 47 participants. Results show that CoDe Graphs reduce participants effort while improving effectiveness and efficiency in comprehension tasks.

Detection of Premature Ventricular Contractions (PVC) is of crucial importance in the cardiology field, not only to improve the health system but also to reduce the workload of experts who analyze electrocardiograms (ECG) manually. PVC is a non-harmful common occurrence represented by extra heartbeats, whose diagnosis is not always easily identifiable, especially when done by long-term manual ECG analysis. In some cases, it may lead to disastrous consequences when associated with other pathologies. This work introduces an approach to identify PVCs using machine learning techniques without feature extraction and cross-validation techniques. In particular, a group of six classifiers has been used: Decision Tree, Random Forest, Long-Short Term Memory (LSTM), Bidirectional LSTM, ResNet-18, MobileNetv2, and ShuffleNet. Two types of experiments have been performed on data extracted from the MIT-BIH Arrhythmia database: (i) the original dataset and (ii) the balanced dataset. MobileNetv2 came in first in both experiments with high performance and promising results for PVCs' final diagnosis. The final results showed 99.90% of accuracy in the first experiment and 99.00% in the second one, despite no feature detection techniques were used. The approach we used, which was focused on classification without using feature extraction and cross-validation techniques, allowed us to provide excellent performance and obtain better results. Finally, this research defines as first step toward understanding the explanations for deep learning models' incorrect classifications., Competing Interests: The authors have declared that no competing interests exist.

Aim: The aim of this study is to assess whether there are some correlations between radiomics and baseline clinical-biological data of prostate cancer (PC) patients using Fluorine-18 Fluoroethylcholine ( 18 F-FECh) PET/CT., Methods: Digital rectal examination results (DRE), Prostate-Specific Antigen (PSA) serum levels, and bioptical-Gleason Score (GS) were retrospectively collected in newly diagnosed PC patients and considered as outcomes of PC. Thereafter, Volumes of interest (VOI) encompassing the prostate of each patient were drawn to extract conventional and radiomic PET features. Radiomic bivariate models were set up using the most statistically relevant features and then trained/tested with a cross-fold validation test. The best bivariate models were expressed by mean and standard deviation to the normal area under the receiver operating characteristic curves (mAUC, sdAUC)., Results: Semiquantitative and radiomic analyses were performed on 67 consecutive patients. tSUVmean and tSkewness were significant DRE predictors at univariate analysis (OR 1.52 [1.01; 2.29], p = 0.047; OR 0.21 [0.07; 0.65], p = 0.007, respectively); moreover, tKurtosis was an independent DRE predictor at multivariate analysis (OR 0.64 [0.42; 0.96], p = 0.03) Among the most relevant bivariate models, szm&#95;2.5D.z.entr + cm.clust.tend was a predictor of PSA levels (mAUC 0.83 ± 0.19); stat.kurt + stat.entropy predicted DRE (mAUC 0.79 ± 0.10); cm.info.corr.1 + szm&#95;2.5D.szhge predicted GS (mAUC 0.78 ± 0.16)., Conclusions: tSUVmean, tSkewness, and tKurtosis were predictors of DRE results only, while none of the PET parameters predicted PSA or GS significantly; 18 F-FECh PET/CT radiomic models should be tested in larger cohort studies of newly diagnosed PC patients.

Incidental memory can be challenged by increasing either the retention delay or the memory load. The dorsal hippocampus (dHP) appears to help with both consolidation from short-term (STM) to long-term memory (LTM), and higher memory loads, but the mechanism is not fully understood. Here we find that female mice, despite having the same STM capacity of 6 objects and higher resistance to distraction in our different object recognition task (DOT), when tested over 1 h or 24 h delays appear to transfer to LTM only 4 objects, whereas male mice have an STM capacity of 6 objects in this task. In male mice the dHP shows greater activation (as measured by c-Fos expression), whereas female mice show greater activation of the ventral midline thalamus (VMT). Optogenetic inhibition of the VMT-dHP pathway during off-line memory consolidation enables 6-object LTM retention in females, while chemogenetic VMT-activation impairs it in males. Thus, removing or enhancing sub-cortical inhibitory control over the hippocampus leads to differences in incidental memory., (© 2022. The Author(s).)

Since the discovery of lysosomes more than 70 years ago, much has been learned about the functions of these organelles. Lysosomes were regarded as exclusively degradative organelles, but more recent research has shown that they play essential roles in several other cellular functions, such as nutrient sensing, intracellular signalling and metabolism. Methodological advances played a key part in generating our current knowledge about the biology of this multifaceted organelle. In this review, we cover current methods used to analyze lysosome morphology, positioning, motility and function. We highlight the principles behind these methods, the methodological strategies and their advantages and limitations. To extract accurate information and avoid misinterpretations, we discuss the best strategies to identify lysosomes and assess their characteristics and functions. With this review, we aim to stimulate an increase in the quantity and quality of research on lysosomes and further ground-breaking discoveries on an organelle that continues to surprise and excite cell biologists., (© 2022 The Authors. Traffic published by John Wiley & Sons Ltd.)

Background: SNARE proteins play an important role in different biological functions. This study aims to investigate the contribution of a new class of molecular descriptors (called SNARER) related to the chemical-physical properties of proteins in order to evaluate the performance of binary classifiers for SNARE proteins., Results: We constructed a SNARE proteins balanced dataset, D128, and an unbalanced one, DUNI, on which we tested and compared the performance of the new descriptors presented here in combination with the feature sets (GAAC, CTDT, CKSAAP and 188D) already present in the literature. The machine learning algorithms used were Random Forest, k-Nearest Neighbors and AdaBoost and oversampling and subsampling techniques were applied to the unbalanced dataset. The addition of the SNARER descriptors increases the precision for all considered ML algorithms. In particular, on the unbalanced DUNI dataset the accuracy increases in parallel with the increase in sensitivity while on the balanced dataset D128 the accuracy increases compared to the counterpart without the addition of SNARER descriptors, with a strong improvement in specificity. Our best result is the combination of our descriptors SNARER with CKSAAP feature on the dataset D128 with 92.3% of accuracy, 90.1% for sensitivity and 95% for specificity with the RF algorithm., Conclusions: The performed analysis has shown how the introduction of molecular descriptors linked to the chemical-physical and structural characteristics of the proteins can improve the classification performance. Additionally, it was pointed out that performance can change based on using a balanced or unbalanced dataset. The balanced nature of training can significantly improve forecast accuracy., (© 2022. The Author(s).)

Mucopolysaccharidosis type IIIA (MPS-IIIA) is an autosomal recessive disorder caused by mutations in SGSH involved in the degradation of heparan sulfate. MPS-IIIA presents severe neurological symptoms such as progressive developmental delay and cognitive decline, for which there is currently no treatment. Brain targeting represents the main challenge for therapeutics to treat MPS-IIIA, and the development of small-molecule-based treatments able to reach the CNS could be a relevant advance for therapy. Using cell-based high content imaging to survey clinically approved drugs in MPS-IIIA cells, we identified fluoxetine, a selective serotonin reuptake inhibitor. Fluoxetine increases lysosomal and autophagic functions via TFEB activation through a RagC-dependent mechanism. Mechanistically, fluoxetine increases lysosomal exocytosis in mouse embryonic fibroblasts from MPS-IIIA mice, suggesting that this process may be responsible for heparan sulfate clearance. In vivo, fluoxetine ameliorates somatic and brain pathology in a mouse model of MPS-IIIA by decreasing the accumulation of glycosaminoglycans and aggregated autophagic substrates, reducing inflammation, and slowing down cognitive deterioration. We repurposed fluoxetine for potential therapeutics to treat human MPS-IIIA disease., Competing Interests: Declaration of interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)

In the era of digitized images, the goal is to extract information from them and create new knowledge thanks to Computer Vision techniques, Machine Learning and Deep Learning. This enables the use of images for early diagnosis and subsequent treatment of a wide range of diseases. In the dermatological field, deep neural networks are used to distinguish between melanoma and non-melanoma images. In this paper, we have underlined two essential points of melanoma detection research. The first aspect considered is how even a simple modification of the parameters in the dataset determines a change of the accuracy of classifiers. In this case, we investigated the Transfer Learning issues. Following the results of this first analysis, we suggest that continuous training-test iterations are needed to provide robust prediction models. The second point is the need to have a more flexible system architecture that can handle changes in the training datasets. In this context, we proposed the development and implementation of a hybrid architecture based on Cloud, Fog and Edge Computing to provide a Melanoma Detection service based on clinical and dermoscopic images. At the same time, this architecture must deal with the amount of data to be analyzed by reducing the running time of the continuous retrain. This fact has been highlighted with experiments carried out on a single machine and different distribution systems, showing how a distributed approach guarantees output achievement in a much more sufficient time.

The mammalian brain stores and distinguishes among episodic memories, i.e. memories formed during the personal experience, through a mechanism of pattern separation computed in the hippocampal dentate gyrus. Decision-making for food-related behaviors, such as the choice and intake of food, might be affected in obese subjects by alterations in the retrieval of episodic memories. Adult neurogenesis in the dentate gyrus regulates the pattern separation. Several molecular factors affect adult neurogenesis and exert a critical role in the development and plasticity of newborn neurons. Orexin-A/hypocretin-1 and downstream endocannabinoid 2-arachidonoylglycerol signaling are altered in obese mice. Here, we show that excessive orexin-A/2-arachidonoylglycerol/cannabinoid receptor type-1 signaling leads to the dysfunction of adult hippocampal neurogenesis and the subsequent inhibition of plasticity and impairment of pattern separation. By inhibiting orexin-A action at orexin-1 receptors we rescued both plasticity and pattern separation impairment in obese mice, thus providing a molecular and functional mechanism to explain alterations in episodic memory in obesity., (© 2021. The Author(s).)

Background : Radioactive 131 I (RAI) therapy is used in patients with differentiated thyroid cancer (DTC) after total thyroidectomy for remnant ablation, adjuvant treatment or treatment of persistent disease. 131 I retention data, which are used to indicate the time at which a 131 I treated DTC patient can be released from the hospital, may bring some insights regarding clinical factors that prolong the length of hospitalization. The aim of this study was to investigate the 131 I whole-body retention in DTC patients during 131 I therapy. Methods : We monitored 166 DTC patients to follow the 131 I whole-body retention during 131 I therapy with a radioactivity detector fixed on the ceiling of each protected room. A linear regression fit permitted us to estimate the whole-body 131 I effective half-life in each patient, and a relationship was sought between patients' clinical characteristics and whole-body effective 131 I half-life. Results: The effective 131 I half-life ranged from 4.08 to 56.4 h. At multivariable analysis, longer effective 131 I half-life was related to older age and extensive extra-thyroid disease. Conclusions: &nbsp; 131 I effective half-life during 131 I treatment in DTC patients is highly variable among patients and is significantly longer in older and in patients with RAI uptake in large thyroid remnants or in extrathyroidal disease that significantly prolongs the whole-body retention of 131 I.

Introduction: Bitemporal epilepsy (biTLE), a potential cause of failure in TLE surgery, is rarely associated with unilateral HS and could be suggested by not lateralizing ictal scalp EEG/interictal PET-FDG findings. We evaluated the proportion of biTLE in a population of drug-resistant TLE-HS subjects who underwent intracranial investigation for lateralizing purpose., Methods: We retrospectively included all consecutive refractory TLE-HS patients and not lateralizing ictal scalp EEG/interictal PET-FDG findings, investigated by intracranial bilateral longitudinal hippocampal electrodes. Demographic characteristics, electroclinical findings and seizure outcome were evaluated., Results: We identified 14 subjects (7 males; mean age 39.5 years; mean age at disease onset 14.4 years), 7 of them had biTLE diagnosed after intracranial investigations. In the remaining 7 with unilateral epileptogenesis (uniTLE) anterior temporal lobectomy was performed (6/7 were in Engel class I). Preoperative neuropsychological assessment differentiated biTLE from uniTLE, as it was normal in six uniTLE patients but only in one with biTLE (p < 0.05)., Conclusions: Not lateralizing ictal scalp EEG and functional imaging findings in TLEHS should alert about the possibility of a true biTLE also in presence of unilateral findings at MRI. Intracranial investigations with bilateral longitudinal hippocampal electrodes can localize the EZ with a good risk-benefit profile. Consistently with the warning on memory functions in TLE patients explored by using longitudinal hippocampal electrodes, further studies are needed to better define the optimal investigation strategy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/qims-21-36). The authors have no conflicts of interest to declare.

Competing Interests: Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Mesobot , an autonomous underwater vehicle, addresses specific unmet needs for observing and sampling a variety of phenomena in the ocean's midwaters. The midwater hosts a vast biomass, has a role in regulating climate, and may soon be exploited commercially, yet our scientific understanding of it is incomplete. Mesobot has the ability to survey and track slow-moving animals and to correlate the animals' movements with critical environmental measurements. Mesobot will complement existing oceanographic assets such as towed, remotely operated, and autonomous vehicles; shipboard acoustic sensors; and net tows. Its potential to perform behavioral studies unobtrusively over long periods with substantial autonomy provides a capability that is not presently available to midwater researchers. The 250-kilogram marine robot can be teleoperated through a lightweight fiber optic tether and can also operate untethered with full autonomy while minimizing environmental disturbance. We present recent results illustrating the vehicle's ability to automatically track free-swimming hydromedusae ( Solmissus sp.) and larvaceans ( Bathochordaeus stygius ) at depths of 200 meters in Monterey Bay, USA. In addition to these tracking missions, the vehicle can execute preprogrammed missions collecting image and sensor data while also carrying substantial auxiliary payloads such as cameras, sonars, and samplers., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Lysosomal storage disorders characterized by altered metabolism of heparan sulfate, including Mucopolysaccharidosis (MPS) III and MPS-II, exhibit lysosomal dysfunctions leading to neurodegeneration and dementia in children. In lysosomal storage disorders, dementia is preceded by severe and therapy-resistant autistic-like symptoms of unknown cause. Using mouse and cellular models of MPS-IIIA, we discovered that autistic-like behaviours are due to increased proliferation of mesencephalic dopamine neurons originating during embryogenesis, which is not due to lysosomal dysfunction, but to altered HS function. Hyperdopaminergia and autistic-like behaviours are corrected by the dopamine D1-like receptor antagonist SCH-23390, providing a potential alternative strategy to the D2-like antagonist haloperidol that has only minimal therapeutic effects in MPS-IIIA. These findings identify embryonic dopaminergic neurodevelopmental defects due to altered function of HS leading to autistic-like behaviours in MPS-II and MPS-IIIA and support evidence showing that altered HS-related gene function is causative of autism.

Purpose: To investigate whether a telemedicine service (TMS) carried out during the Covid-19 pandemic impacted on management of patients with differentiated thyroid cancer (DTC)., Methods: We retrospectively reviewed the number and the findings of outpatient visits in DTC subjects referred between March 11, 2020, and May 31, 2020, during the Covid-19 pandemic at the Radiometabolic Unit of the University of Naples Federico II. Office visits scheduled in March and May 2020 were converted in teleconsultation reaching all patients planned for an in-ward access to advise them to use the TMS for all clinical necessity. The number and the findings of DTC patients evaluated by in-ward access in the corresponding period of 2019 were also assessed for direct comparison., Results: The number of outpatient visits performed by TMS during the pandemic (n = 445) and by in-ward access in the corresponding period of 2019 (n = 525) was comparable with only 15% of outpatient evaluations missed., Conclusions: Our findings demonstrate the utility of telemedicine tools to avoid the potential negative impact of interruption or postponement of diagnostic and/or therapeutic procedures. Therefore, investments in medical network system development, including the implementation of telehealth approaches, should be encouraged at national and international levels.

The Therapeutic Alliance (TA) between patient and health provider (therapist or clinician) is one of the most relevant factors for the success of a therapy. In the case of people suffering from Autism Spectrum Disorder (ASD), the alliance is extended to all the people involved in their care (i.e., teachers, therapists, clinicians, relatives). In this paper, we propose a multimedia application named Thea for empowering the TA of children with ASD by improving the communication among the TA members, sharing guidelines, multimedia contents, and strategies to comply with challenging behaviors and progress with particular attention towards end-users who are occasional smart-users. A detailed process for empowering the TA members by enhancing the informed interaction among all of them is proposed and implemented. A vocal assistant also supports patients/caregivers and therapists in documenting their activity with the person with ASD by recording videos in a free-hand modality. After a contextual analysis based on Thematic Analysis Template, Thea has been implemented using a user-centered development approach. We performed three iterations involving the end-users. A user study is performed at the third iteration. Results of the user study revealed a positive attitude towards the application. In particular, the perception of empowerment of participants increased after the tool had been used. We also highlighted the guidelines and tools that may be adopted for empowering different kinds of patients. The first results seem to suggest that the use of Thea may increase the belief of the caregivers of a person with ASD to be able to better take care of her, in a more controlled and informed way., (© The Author(s) 2021.)

Introduction : The automatic interaction between a cue and a memory trace can give rise to the vivid recollection of a purely sensory past experience. But are humans able to reach back intentionally to purely sensory experiences in the absence of any exogenous or endogenous cue? In the present study, we propose an alternative hypothesis, claiming that the retrieval of associated semantic memories, stored in the left hemisphere and acting as endogenous cues, is a prerequisite for intentionally recollecting sensory experience stored in the right hemisphere during mental time travels (MTT). Methods : To investigate this issue, we administered an MTT task to 26 epileptic patients (16 males and 10 females) who had undergone right or left temporal lobectomy and to 28 age and education matched controls. The task was devised so as to require the recollection of purely visual memories in the absence of external cues. Participants also performed two conventional recognition tasks with visual and verbal materials. The three between-subjects memory tasks were analyzed separately with the Kruskal-Wallis test and the Wilcoxon rank-sum test in order to investigate differences across groups. According to our hypothesis, we expected side asymmetries in the patients' performance on the two recognition tasks but not the MTT task. Results : While patients showed the well-known hemispheric asymmetry for visual and verbal material in the (external-cue dependent) recognition tasks, no side asymmetries emerged in the purely visual MTT task. Conclusions : In keeping with the view that visual memories cannot be targeted directly by a strategic search process, the lack of any side asymmetry in our MTT task can be interpreted as a trade-off between left-sided strategic search for associated semantic memories and right-sided storage of visual ones.

Autophagy agonists have been proposed to slow down neurodegeneration. Spermidine, a polyamine that acts as an autophagy agonist, is currently under clinical trial for the treatment of age-related memory decline. How Spermidine and other autophagy agonists regulate memory and synaptic plasticity is under investigation. We set up a novel mouse model of mild cognitive impairment (MCI), in which middle-aged (12-month-old) mice exhibit impaired memory capacity, lysosomes engulfed with amyloid fibrils (β-amyloid and α-synuclein) and impaired task-induced GluA1 hippocampal post-translation modifications. Subchronic treatment with Spermidine as well as the autophagy agonist TAT-Beclin 1 rescued memory capacity and GluA1 post-translational modifications by favouring the autophagy/lysosomal-mediated degradation of amyloid fibrils. These findings provide new mechanistic evidence on the therapeutic relevance of autophagy enhancers which, by improving the degradation of misfolded proteins, slow down age-related memory decline., (© 2020 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

The presence of α-synuclein aggregates in the retina of Parkinson's disease patients has been associated with vision impairment. In this study we sought to determine the effects of α-synuclein overexpression on the survival and function of dopaminergic amacrine cells (DACs) in the retina. Adult mice were intravitreally injected with an adeno-associated viral (AAV) vector to overexpress human wild-type α-synuclein in the inner retina. Before and after systemic injections of levodopa (L-DOPA), retinal responses and visual acuity-driven behavior were measured by electroretinography (ERG) and a water maze task, respectively. Amacrine cells and ganglion cells were counted at different time points after the injection. α-synuclein overexpression led to an early loss of DACs associated with a decrease of light-adapted ERG responses and visual acuity that could be rescued by systemic injections of L-DOPA. The data show that α-synuclein overexpression affects dopamine neurons in the retina. The approach provides a novel accessible method to model the underlying mechanisms implicated in the pathogenesis of synucleinopathies and for testing novel treatments.

Cardiac amyloidosis is a restrictive infiltrative cardiomyopathy burdened by high mortality. The two more common forms are immunoglobulin light-chain amyloidosis and transthyretin-related amyloidosis with different prognoses and treatments. However, distinguishing between them is challenging. Appropriate utilization of the different available imaging techniques in the evaluation of patients with known or suspected cardiac amyloidosis is mandatory. We report two cases with cardiac amyloidosis of different etiology and with distinct imaging patterns. In the first case, the negative 99m Tc-diphosphonate imaging was useful to support the diagnosis of cardiac amyloid light-chain; the second case emphasized the utility of whole-body scintigraphy in recognizing transthyretin-related cardiac amyloidosis and the potential role of cadmium-zinc-telluride SPECT imaging for the evaluation of segmental distribution of cardiac disease. Both cases support the growing interest in looking for noninvasive methods to type cardiac amyloidosis in the place of invasive myocardial biopsy highlighting both possibilities and limitations of available imaging techniques in diagnosis and treatment monitoring.

Lysosomal storage diseases (LSDs) are inherited disorders caused by lysosomal deficiencies and characterized by dysfunction of the autophagy-lysosomal pathway (ALP) often associated with neurodegeneration. No cure is currently available to treat neuropathology in LSDs. By studying a mouse model of mucopolysaccharidosis (MPS) type IIIA, one of the most common and severe forms of LSDs, we found that multiple amyloid proteins including α-synuclein, prion protein (PrP), Tau, and amyloid β progressively aggregate in the brain. The amyloid deposits mostly build up in neuronal cell bodies concomitantly with neurodegeneration. Treating MPS-IIIA mice with CLR01, a "molecular tweezer" that acts as a broad-spectrum inhibitor of amyloid protein self-assembly reduced lysosomal enlargement and re-activates autophagy flux. Restoration of the ALP was associated with reduced neuroinflammation and amelioration of memory deficits. Together, these data provide evidence that brain deposition of amyloid proteins plays a gain of neurotoxic function in a severe LSD by affecting the ALP and identify CLR01 as new potent drug candidate for MPS-IIIA and likely for other LSDs., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: A link between depression and insecure attachment has long been postulated. Although many studies examined the relationship between depressive symptoms and attachment, relatively few studies were performed on patients diagnosed with depression. Also, research on patients with bipolar disorder is scarce., Objective: We aimed at testing the association between attachment insecurity and unipolar and bipolar depression., Methods: We studied 21 patients with bipolar disorder, current episode depressed, and three age- and sex-matched groups, each consisting of 21 individuals: patients with major depressive disorder, recurrent episode; patients with epilepsy; non-clinical participants. The Experience in Close Relationships questionnaire was used to assess adult attachment style., Results: Patients with both bipolar and unipolar depression displayed significantly higher scores on attachment-related avoidance as compared with patients with epilepsy and non-clinical participants. Also, patients with bipolar depression scored significantly higher on attachment-related anxiety than all other groups. In both psychiatric groups, attachment dimensions were not significantly correlated with global clinical severity or severity of depression., Conclusion: Despite some study limitations, our results are consistent with some previous studies and provide support to Bowlby's seminal hypothesis that attachment insecurity may predispose to depression. Attachment theory may provide a valuable theoretical framework for future research and for guiding treatment., (© 2019 Bentham Science Publishers.)

Mucopolysaccharidosis type IIIA (MPS-IIIA) is a lysosomal storage disorder (LSD) caused by inherited defect of sulfamidase, a lysosomal sulfatase. MPS-IIIA is one of the most common and severe forms of LSDs with CNS involvement. Presently there is no cure. Here we have developed a new gene delivery approach for the treatment of MPS-IIIA based on the use of a modified version of sulfamidase expression cassette. This cassette encodes both a chimeric sulfamidase containing an alternative signal peptide (sp) to improve enzyme secretion and sulfatase-modifying factor 1 (SUMF1) to increase sulfamidase post-translational activation rate. We demonstrate that improved secretion and increased activation of sulfamidase act synergistically to enhance enzyme biodistribution in wild-type (WT) pigs upon intrathecal adeno-associated virus serotype 9 (AAV9)-mediated gene delivery. Translating such gene delivery strategy to a mouse model of MPS-IIIA results in a rescue of brain pathology, including memory deficit, as well as improvement in somatic tissues. These data may pave the way for developing effective gene delivery replacement protocols for the treatment of MPS-IIIA patients., (© 2019 The Authors.)

Parkinson's disease is a progressive neurodegenerative disorder characterized by altered striatal dopaminergic signalling that leads to motor and cognitive deficits. Parkinson's disease is also characterized by abnormal presence of soluble toxic forms of α-synuclein that, when clustered into Lewy bodies, represents one of the pathological hallmarks of the disease. However, α-synuclein oligomers might also directly affect synaptic transmission and plasticity in Parkinson's disease models. Accordingly, by combining electrophysiological, optogenetic, immunofluorescence, molecular and behavioural analyses, here we report that α-synuclein reduces N-methyl-d-aspartate (NMDA) receptor-mediated synaptic currents and impairs corticostriatal long-term potentiation of striatal spiny projection neurons, of both direct (D1-positive) and indirect (putative D2-positive) pathways. Intrastriatal injections of α-synuclein produce deficits in visuospatial learning associated with reduced function of GluN2A NMDA receptor subunit indicating that this protein selectively targets this subunit both in vitro and ex vivo. Interestingly, this effect is observed in spiny projection neurons activated by optical stimulation of either cortical or thalamic glutamatergic afferents. We also found that treatment of striatal slices with antibodies targeting α-synuclein prevents the α-synuclein-induced loss of long-term potentiation and the reduced synaptic localization of GluN2A NMDA receptor subunit suggesting that this strategy might counteract synaptic dysfunction occurring in Parkinson's disease., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The aim of this observational cross-sectional study with retrospective review of the data is to evaluate the efficacy of using technetium-99m-octreotide (Tc-99m-OCT) in imaging neuroendocrine tumors (NETs) in our tertiary care hospital. A total of 58 patients had Tc-99m-OCT were identified in our database, from January 2013 to December 2016. Forty-one patients (age range of 15-75 years) meet our inclusion criteria, namely histopathology proven NETs, Tc-99m-OCT scan, computed tomography (CT), or magnetic resonance imaging (MRI) done in our institute for correlation. Twenty-three patients had true positive Tc-99m-OCT scan. In addition to the primary tumors, the octreotide scan revealed metastasis in the lung, liver, and retroperitoneal lymph nodes. The smallest lesion detected on octreotide scan was a 4-mm pulmonary nodule that was missed on lung window CT scan. The Tc-99m-OCT had 17 true negative, one false negative, and no false positive. The CT and MRI scans had 18 true positive, 17 true negative, 5 false negative, and one false positive. The overall sensitivity, specificity, accuracy, positive, and negative predictive values of Tc-99m-OCT scan were 96%, 100%, 97%, 100%, and 94%, respectively. Whereas those of CT and MRI were 78%, 94%, 85%, 94%, and 77%, respectively. Our diagnostic accuracy of Tc-99m-OCT is high. We recommend that, in addition to the conventional radiological investigations, Tc-99m-OCT scan, or other somatostatin receptor imaging (SSR) is a mandate for better and accurate staging of patients with NETs., Competing Interests: There are no conflicts of interest.

Memory capacity (MC) refers to the limited capacity of working memory and is defined as the number of elements that an individual can remember for a short retention interval. MC is impaired in many human pathologies, such as schizophrenia and ageing. Fronto-striatal dopamine regulates working memory, through its action on dopamine D1- and D2-like receptors. Human and rodent studies have suggested that MC is improved by D2 dopamine receptor agonists. Although D1 receptors have been crucially involved in the maintenance of working memory during delay, their role in regulating the capacity of WM remains poorly explored. In this study, we tested the effects of systemic injection of the D1-like and D2-like receptor antagonists, SCH 23390 and Haloperidol respectively, on MC in mice. For this, we used a modified version of the object recognition task, the Different/Identical Objects Task (DOT/IOT), which allows the evaluation of MC in rodents. The results showed a negative interaction between the dose of both drugs and the number of objects that could be remembered. The doses of SCH 23390 and Haloperidol that impaired novel object discrimination in the highest memory load condition were about 4 and 3 time lower, respectively, of those impairing performance in the lowest memory load condition. However, while SCH 23390 specifically impaired memory load capacity, the effects of Haloperidol were associated to impairment in exploratory behaviors. These findings may help to predict the cognitive side effects induced by Haloperidol in healthy subjects., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Limbic encephalitis (LE) is an autoimmune condition characterized by amnestic syndrome, psychiatric features and seizures. Early diagnosis and prompt treatment are crucial to avoid long-term sequelae, including psycho-cognitive deficits and persisting seizures. The aim of our study was to analyze the characteristics of 33 LE patients in order to identify possible prognostic factors associated with the development of chronic epilepsy., Methods: This is a retrospective cohort study including adult patients diagnosed with LE in the period 2010-2017 and followed up for ≥12 months. Demographics, seizure semiology, EEG pattern, MRI features, CSF/serum findings were reviewed., Results: All 33 LE patients (19 M/14F, mean age 61.2 years) presented seizures. Thirty subjects had memory deficits; 22 presented behavioural/mood disorders. Serum and/or CSF auto-antibodies were detected in 12 patients. In 31 subjects brain MRI at onset showed typical alterations involving temporal lobes. All patients received immunotherapy. At follow-up, 13/33 had developed chronic epilepsy; predisposing factors included delay in diagnosis (p = .009), low seizure frequency at onset (p = .02), absence of amnestic syndrome (p = .02) and absence/rarity of inter-ictal epileptic discharges on EEG (p = .06)., Conclusions: LE with paucisymptomatic electro-clinical presentation seemed to be associated to chronic epilepsy more than LE presenting with definite and severe "limbic syndrome"., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: The purpose of this study was to report long-term seizure outcome in patients who underwent frontal lobe epilepsy (FLE) surgery., Method: This retrospective study included 44 consecutive subjects who underwent resective surgery for intractable FLE at IRCCS NEUROMED (period 2001-2014), followed up for at least 2 years (mean: 8.7 years). All patients underwent noninvasive presurgical evaluation and/or invasive electroencephalography (EEG) monitoring when nonconcordant data were obtained or epileptogenic zone was hypothesized to be close to the eloquent cortex. Electroclinical, neuroimaging, surgical data, and histology were compared to seizure outcome., Results: Mean epilepsy duration was 19 years; mean age at surgery was 31.6 years. Preoperative magnetic resonance imaging (MRI) showed a frontal lesion in 86.4 % of cases. Scalp video-electroencephalography (VEEG) monitoring detected a focal ictal onset in 90% of cases. Twenty-seven patients (61.4%) underwent invasive recordings. Resections involved dorsolateral (47.7%), medial (9%), orbital (13.6%), and rolandic (13.6%) region. Lobectomy within functional boundaries was performed in the remaining 7 cases (16%). Transient and permanent neurological deficits were observed in 2 and 3 cases, respectively. Histology revealed focal cortical dysplasia (45.5%), World Health Organization (WHO) I-II grade tumors (15.9%), gliosis (22.7%), vascular malformations (4.5%), Rasmussen encephalitis (6.8%), and normal tissue (4.5%). At last observation 68.1% of patients were in Engel's class I, 11.4% in class II, 9% in class III, and 11.4% in class IV. A favorable outcome was associated with focal ictal scalp EEG onset (p = 0.0357)., Conclusion: Surgery is a safe treatment option in drug-resistant FLE with a satisfying long-term outcome. These data highlight the importance of an appropriate selection of potential surgical candidates., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Amnestic syndromes are acknowledged to be associated to bilateral hippocampal damage., Materials and Methods: We briefly report the case of a young man who underwent anterior left temporal lobectomy for a medically refractory temporal lobe epilepsy due to hippocampal sclerosis with an excellent seizure and neuropsychological outcome. Approximately 10 years later, he presented with a subacute severe global amnesia and neuroimaging findings of a damage involving the contralateral mesial temporal lobe structures., Results: A diagnosis of a possible autoimmune encephalitis was made., Conclusions: Due to its peculiarities (compared with other cases of bilateral temporal lesions, the damage occurred on two distinct occasions), this case might contribute to shed light on the issue of the possible contralateral reorganization of memory processes subserved by the mesial temporal lobe structures chronically involved in epileptogenesis.

Nigro-striatal dopamine transmission is central to a wide range of neuronal functions, including skill learning, which is disrupted in several pathologies such as Parkinson's disease. The synaptic plasticity mechanisms, by which initial motor learning is stored for long time periods in striatal neurons, to then be gradually optimized upon subsequent training, remain unexplored. Addressing this issue is crucial to identify the synaptic and molecular mechanisms involved in striatal-dependent learning impairment in Parkinson's disease. In this study, we took advantage of interindividual differences between outbred rodents in reaching plateau performance in the rotarod incremental motor learning protocol, to study striatal synaptic plasticity ex vivo. We then assessed how this process is modulated by dopamine receptors and the dopamine active transporter, and whether it is impaired by overexpression of human α-synuclein in the mesencephalon; the latter is a progressive animal model of Parkinson's disease. We found that the initial acquisition of motor learning induced a dopamine active transporter and D1 receptors mediated long-term potentiation, under a protocol of long-term depression in striatal medium spiny neurons. This effect disappeared in animals reaching performance plateau. Overexpression of human α-synuclein reduced striatal dopamine active transporter levels, impaired motor learning, and prevented the learning-induced long-term potentiation, before the appearance of dopamine neuronal loss. Our findings provide evidence of a reorganization of cellular plasticity within the dorsolateral striatum that is mediated by dopamine receptors and dopamine active transporter during the acquisition of a skill. This newly identified mechanism of cellular memory is a form of metaplasticity that is disrupted in the early stage of synucleinopathies, such as Parkinson's disease, and that might be relevant for other striatal pathologies, such as drug abuse., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Purpose: In line with the growing attention on non-motor symptoms and disturbance of affective and emotional processing in Parkinson's disease, we aimed to study the different aspects of facial emotion expression evaluation in a group of Parkinson's disease without cognitive decline in treatment with common antiparkinsonian drugs, matched for sex, age and education with healthy subjects., Materials and Methods: The study was conducted on 30 patients (13 male; mean age: 63.3 ± 6.7; mean age of disease onset: 56.5 ± 7.1; mean duration of the disease: 6.7 ± 2.6) with a diagnosis of Parkinson's disease and receiving dopaminergic therapy, as compared with 30 healthy controls. Different tasks of facial expression evaluation were used. All patients were assessed for neuropsychological and psychological profiles during optimized medication-on condition., Results: The total number of errors in facial emotion recognition task is higher (p < 0.001) in patients than controls and it is due to errors in identifying sadness (p < 0.001), anger (p = 0.01) and fear (p < 0.001). No differences in the total amount of activation, valence and intensity ratings were found. The difference between patients and controls in emotion recognition appears to be independent by the severity of depressive symptoms., Conclusions: The present study provides further evidence of altered non-verbal emotional information processing in Parkinson's disease patients, suggesting that nigrostriatal dopaminergic depletion leads also to emotional information processing dysfunction. The consequences of these emotional encoding disturbances in daily living and their relationship to mood and behavioural disorders remain to be clarified.

Purpose: To assess the clinical significance of temporal pole abnormalities (temporopolar blurring, TB, and temporopolar atrophy, TA) detected by using 3 Tesla MRI in the preoperative workup in patients with temporal lobe epilepsy due to hippocampal sclerosis (TLE-HS) who underwent surgery., Methods: We studied 78 consecutive patients with TLE-HS who underwent surgery and were followed up for at least 2 years. Based on findings of pre-surgical 3 Tesla MRI, patients were subdivided in subgroups according to the presence of TB or TA. Subgroups were compared on demographic, clinical, neuropsychological data and seizure outcome., Results: TB was found in 39 (50%) patients, while TA was found in 32 (41%) patients, always ipsilateral to HS, with a considerable degree of overlap (69%) between TB and TA (p=0.01). Patients with temporopolar abnormalities did not significantly differ from those without TB or TA with regard to sex, age, age of epilepsy onset, duration of epilepsy, history of febrile convulsions or birth complications, side of surgery, seizure frequency at surgery, presence of GTCSs, and, in particular, seizure outcome. On the other hand, TB patients show a less frequent family history of epilepsy (p<.05) while age at epilepsy onset showed a trend to be lower in the TB group (p=.09). Patients with temporopolar atrophy did not significantly differ from those without TA on any variable, except for age at epilepsy onset, which was significantly lower for the TA group (p<.05). History of birth complications and longer duration of epilepsy also showed a trend to be associated with TA (p=.08). Multivariate analysis corroborated the association between temporopolar abnormalities and absence of family history of epilepsy and history of birth complications., Conclusions: High-field 3 T MRI in the preoperative workup for epilepsy surgery confirms that temporopolar abnormalities are frequent findings in TLE-HS patients and may be helpful to lateralize the epileptogenic zone. Their presence did not influence seizure outcome., (Copyright © 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Lysosomal storage disorders (LSDs) are inherited diseases characterized by lysosomal dysfunction and often showing a neurodegenerative course. There is no cure to treat the central nervous system in LSDs. Moreover, the mechanisms driving neuronal degeneration in these pathological conditions remain largely unknown. By studying mouse models of LSDs, we found that neurodegeneration develops progressively with profound alterations in presynaptic structure and function. In these models, impaired lysosomal activity causes massive perikaryal accumulation of insoluble α-synuclein and increased proteasomal degradation of cysteine string protein α (CSPα). As a result, the availability of both α-synuclein and CSPα at nerve terminals strongly decreases, thus inhibiting soluble NSF attachment receptor (SNARE) complex assembly and synaptic vesicle recycling. Aberrant presynaptic SNARE phenotype is recapitulated in mice with genetic ablation of one allele of both CSPα and α-synuclein. The overexpression of CSPα in the brain of a mouse model of mucopolysaccharidosis type IIIA, a severe form of LSD, efficiently re-established SNARE complex assembly, thereby ameliorating presynaptic function, attenuating neurodegenerative signs, and prolonging survival. Our data show that neurodegenerative processes associated with lysosomal dysfunction may be presynaptically initiated by a concomitant reduction in α-synuclein and CSPα levels at nerve terminals. They also demonstrate that neurodegeneration in LSDs can be slowed down by re-establishing presynaptic functions, thus identifying synapse maintenance as a novel potentially druggable target for brain treatment in LSDs., (© 2016 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Vagal nerve stimulation (VNS) is a palliative treatment option for drug-resistant epilepsy. The aim of this study was to describe the clinical and demographic features of selected patients scheduled for VNS and to evaluate the long-term efficacy of VNS in seizure control., Materials and Methods: Between 2006 and 2013, 32 consecutive epileptic patients (14 male and 18 female) were enrolled at our Institute for VNS implantation. In all cases resective surgery had previously been excluded by the use of a noninvasive presurgical study protocol. Mean age was 32 years (range 18-50), and mean epilepsy duration 23 years (range 11-39). All subjects were followed-up for at least 2 years (mean 6 years, range 2-9) after VNS implantation. Patients were considered responders when a reduction of seizures of more than 50 % was reported., Results: All patients had complex partial seizures, in 81 % of the patients with secondary generalization and in 56 % with drop attacks. Neurological examination revealed focal deficits in 19 % of the patients. Brain magnetic resonance imaging (MRI) was positive in 47 % of the patients. No surgical complications were observed in this series. Three patients were lost to follow-up. Twelve patients were classified as responders. Among the others, 1 patient experienced side effects (snoring and groaning during sleep) and the device was removed., Conclusions: Our data confirm that VNS is a safe procedure and a valid palliative treatment option for drug-resistant epileptic patients not suitable for resective surgery.

Introduction: Deep brain stimulation (DBS) is currently considered a promising neuromodulation therapy for refractory epilepsy not suitable for resective surgery. Several anatomical targets and different stimulation approaches have been proposed in order to obtain satisfactory seizures reduction. As expected, according with different patterns of neural pathways involvement, the efficacy of each anatomical target stimulation in reducing seizure frequency varies among the different epileptic syndromes., Evidence Acquisition: We reviewed the current literature on this topic to provide an overview of the clinical efficacy of the main stimulation targets (anterior nucleus of the thalamus [ANT], hippocampus formation [HF] and centromedian nucleus of the thalamus [CMT]) related to the different epileptic syndromes. We also summarized the available data concerning side effects, neuropsychological outcome, quality of life and future perspective of DBS in intractable epilepsy., Evidence Synthesis: Encouraging results were reported for each target stimulation. However, only in ANT and responsive neurostimulation (RNS) the efficacy and safety were tested on large series of patients and achieving class I evidence level., Conslusions: We concluded that responsive stimulation could be more appropriate in focal epilepsy, while ANT stimulation could be properly performed also in multifocal seizures with predominant limbic involvement. Despite the small samples size, HF stimulation reduces seizure frequency in (bi) temporal lobe epilepsy, as well as CMT stimulation is able to reduce, seizure frequency, in generalized epilepsy.

Purpose: To assess the clinical significance of temporal pole abnormalities (temporopolar blurring, TB, and temporopolar atrophy, TA) in patients with temporal lobe epilepsy (TLE) and hippocampal sclerosis (HS) with a long post-surgical follow-up., Methods: We studied 60 consecutive patients with TLE-HS and 1.5 preoperative MRI scans who underwent surgery and were followed up for at least 5 years (mean follow-up 7.3 years). Based on findings of pre-surgical MRI, patients were classified according to the presence of TB or TA. Groups were compared on demographic, clinical, neuropsychological data, and seizure outcome., Results: TB was found in 37 (62%) patients, while TA was found in 35 (58%) patients, always ipsilateral to HS, with a high degree of overlap (83%) between TB and TA (p<0.001). Patients with TB did not differ from those without TB with regard to history of febrile convulsions, GTCSs, age of epilepsy onset, side of surgery, seizure frequency, seizure outcome, and neuropsychological outcome. On the other hand, they were significantly older, had a longer duration of epilepsy, and displayed lower preoperative scores on several neuropsychological tests. Similar findings were observed for TA. Multivariate analysis corroborated the association between temporopolar abnormalities and age at onset, age at surgery (for TB only), and lower preoperative scores on some neuropsychological tests., Conclusions: Temporopolar abnormalities are frequent in patients with TLE-HS. Our data support the hypothesis that TB and TA are caused by seizure-related damages. These abnormalities did not influence seizure outcome, even after a long-term post-surgical follow-up., (Copyright © 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

Purpose: To assess the incidence and the prognostic value of acute postoperative seizures (APOS) in patients surgically treated for drug-resistant temporal lobe epilepsy due to hippocampal sclerosis (TLE-HS)., Methods: We studied 139 consecutive patients with TLE-HS who underwent epilepsy surgery and were followed up for at least 5 years (mean duration of follow-up 9.1 years, range 5-15). Medical charts were reviewed to identify APOS, defined as ictal events with the exception of auras occurring within the first 7 days after surgery. Seizure outcome was determined at annual intervals. Patients who were in Engel Class Ia at the last contact were classified as having a favorable outcome., Results: Seizure outcome was favorable in 99 patients (71%). Six patients (4%) experienced APOS and in all cases their clinical manifestations were similar to the habitual preoperative seizures. All patients with APOS had unfavorable long-term outcome, as compared with 35 (26%) of 133 in whom APOS did not occur (p<0.001)., Conclusions: Our study suggests that APOS, despite being relatively uncommon in patients undergoing resective surgery for TLE-HS, are associated with a worse long-term seizure outcome. Given some study limitations, our findings should be regarded as preliminary and need confirmation from future larger, prospective, multicenter studies., (Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

We investigated different aspects of facial expression evaluation in a homogeneous cohort of 42 seizure-free patients with 5 or more years of follow-up after temporal lobectomy (TL), with the aim of further characterizing the impairment in emotion and social cognition among patients. A group of healthy subjects matched for sex, age, and education served as controls. Four tasks of facial expression evaluation were used: (a) facial expression recognition, (b) rating of the intensity of facial expression, and (c) rating of valence (pleasantness) and (d) rating of arousal induced by facial expressions. Patients had a worse performance in the recognition task for all negative emotions, while no differences in intensity ratings were found. They also reported lower arousal ratings than controls for faces showing fear, anger, disgust, and neutral expressions, as well as lower valence ratings for all facial expressions except those showing happiness. Longer epilepsy duration before TL was negatively associated with ratings of arousal and intensity and positively associated with valence ratings for fearful facial expressions. This study showed that patients who become seizure-free after TL present long-term deficits in several aspects of facial expression evaluation. Longitudinal, prospective studies are needed to evaluate if social cognition improves or declines after TL., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: To test if postoperative prolonged awake and sleep EEG monitoring predict long-term seizure outcome in patients operated for drug-resistant temporal lobe epilepsy due to hippocampal sclerosis (TLE-HS)., Methods: This longitudinal study includes 107 patients with MTLE-HS who underwent anterior temporal lobectomy (ATL), were followed for at least 5 years (mean 8.3, range 5-12), had postoperative EEG after 2 months and at least one prolonged video-EEG monitoring during both wakefulness and sleep after 12 and 24 months. At each follow-up visit, the presence of interictal epileptiform discharges (IED) was determined, and seizure outcome was evaluated., Results: Sixty-six patients (62%) remained free from auras and seizures throughout the follow-up period. Twenty-six (24%), 22 (21%), and 16 (16%) patients had IED at the 2-month, 12-month, and 24-month follow-up, respectively. The presence of IED at each time point was found to be associated with seizure or aura recurrence. Sleep recording contributed to the identification of patients with IED, as half of patients with IED displayed anomalies in sleep EEG only. In multivariate analysis, the presence of IED 2 months after surgery was found to be associated with seizure or aura recurrence independent of pre-operative factors consistently reported as outcome predictors in the literature., Conclusions: The presence of IED in serial postoperative EEG including sleep recording may predict long-term seizure outcome after ATL for TLE-HS. Serial postoperative EEGs may contribute to outcome prediction and help making decision about medication withdrawal in patients operated for TLE-HS., (Copyright © 2014 Elsevier B.V. All rights reserved.)