Evaluation of multiple-flows exhaled nitric oxide and its clinical significance in severe asthmatic patients treated with biologics: a prospective real-life study.

BACKGROUND: Specific biomarkers, such as eosinophilia in peripheral blood or fractional exhaled nitric oxide (FeNO), can guide us in the choice of biologic therapy, allowing a more personalized approach. Although there are multiple evidences in the literature about the role of FeNO as a predictor of response to different biologic treatments, there are no data on the relationship between FeNO changes and clinical response to the four biologic drugs currently in use. OBJECTIVE: To evaluate and to compare the expression of multiple-flows FeNO parameters in a cohort of patients with severe asthma (SA) before and during the treatment with biologics to evaluate the performance of these biomarkers in predicting the achievement of clinical remission. METHODS: We prospectively enrolled 50 patients with severe asthma eligible for biologic therapy. Patients underwent clinical and functional monitoring at baseline (T0) and after 1, 6, and 12 months of treatment (T1, T6, T12), including multiple flows FeNO assessment. RESULTS: A statistically significant reduction of FeNO50 values and J'awNO was observed only in benralizumab and dupilumab subgroups. Among biomarkers, the reduction of FeNO 50 values at T1 was associated with a higher probability of achieving clinical remission at T12 (p = 0.003), which was also confirmed by ROC curve analysis (AUC 0.758, p = 0.002; sensitivity 60% and specificity 74% for a reduction of 16 ppb). CONCLUSION: These data confirm the potential of this biomarker in predicting clinical response to biologic treatment in patients with severe asthma in order to guide clinical decisions and evaluate a shift to other biologic therapy.

Multiple Sclerosis: Inflammatory and Neuroglial Aspects.

Multiple sclerosis (MS) represents the most common acquired demyelinating disorder of the central nervous system (CNS). Its pathogenesis, in parallel with the well-established role of mechanisms pertaining to autoimmunity, involves several key functions of immune, glial and nerve cells. The disease's natural history is complex, heterogeneous and may evolve over a relapsing-remitting (RRMS) or progressive (PPMS/SPMS) course. Acute inflammation, driven by infiltration of peripheral cells in the CNS, is thought to be the most relevant process during the earliest phases and in RRMS, while disruption in glial and neural cells of pathways pertaining to energy metabolism, survival cascades, synaptic and ionic homeostasis are thought to be mostly relevant in long-standing disease, such as in progressive forms. In this complex scenario, many mechanisms originally thought to be distinctive of neurodegenerative disorders are being increasingly recognized as crucial from the beginning of the disease. The present review aims at highlighting mechanisms in common between MS, autoimmune diseases and biology of neurodegenerative disorders. In fact, there is an unmet need to explore new targets that might be involved as master regulators of autoimmunity, inflammation and survival of nerve cells.

Apperceptive and Associative Forms of Phonagnosia.

PURPOSE OF REVIEW: Pronagnosia is a rare acquired or developmental pathological condition that consists of a selective difficulty to recognize familiar people by their voices. It can be distinguished into two different categories: apperceptive phonagnosia, which denotes a purely perceptual form of voice recognition disorder; and associative phonagnosia, in which patients have no perceptual defects, but cannot evaluate if the voice of a known person is or not familiar. The neural substrate of these two forms of voice recognition is still controversial, but it could concern different components of the core temporal voice areas and of extratemporal voice processing areas. This article reviews recent research on the neuropsychological and anatomo-clinical aspects of this condition. RECENT FINDINGS: Data obtained in group studies or single case reports of phonagnosic patients suggest that apperceptive phonagnosia might be due to disruption of the core temporal voice areas, bilaterally located in the posterior parts of the superior temporal gyrus, whereas associative phonagnosia might result from impaired access to structures where voice representations are stored, due to a disconnection of these areas from structures of the voice extended system. Although these results must be confirmed by further investigations, they represent an important step toward understanding the nature and neural substrate of apperceptive and associative forms of phonagnosia.

A Deep Learning Model for Correlation Analysis between Electroencephalography Signal and Speech Stimuli.

In recent years, the use of electroencephalography (EEG) has grown as a tool for diagnostic and brain function monitoring, being a simple and non-invasive method compared with other procedures like histological sampling. Typically, in order to extract functional brain responses from EEG signals, prolonged and repeated stimuli are needed because of the artifacts generated in recordings which adversely impact the stimulus-response analysis. To mitigate the artifact effect, correlation analysis (CA) methods are applied in the literature, where the predominant approaches focus on enhancing stimulus-response correlations through the use of linear analysis methods like canonical correlation analysis (CCA). This paper introduces a novel CA framework based on a neural network with a loss function specifically designed to maximize correlation between EEG and speech stimuli. Compared with other deep learning CA approaches (DCCAs) in the literature, this framework introduces a single multilayer perceptron (MLP) network instead of two networks for each stimulus. To validate the proposed approach, a comparison with linear CCA (LCCA) and DCCA was performed, using a dataset containing the EEG traces of subjects listening to speech stimuli. The experimental results show that the proposed method improves the overall Pearson correlation by 10.56% compared with the state-of-the-art DCCA method.

Cytokine profiles in the detection of severe lung involvement in hospitalized patients with COVID-19: The IL-8/IL-32 axis.

Coronavirus disease 2019 (COVID-19) is an infectious respiratory disorder caused by a new coronavirus called SARS-CoV-2. The pathophysiology of severe COVID-19 is associated with a "cytokine storm". IL-32 is a key modulator in the pathogenesis of various clinical conditions and is mostly induced by IL-8. IL-32 modulates important inflammatory pathways (including TNF-α, IL-6 and IL-1b), contributing to the pathogenesis of inflammatory diseases. Il-32 was never evaluated before in COVID-19 patients stratifying as mild-moderate and severe patients. A total of 64 COVID-19 patients, 27 healthy controls were consecutively enrolled in the study. Serum concentrations of biomarkers including IL-1ß, IL-10, IFN-γ, TNF-α and IL-6 were quantified by bead-based multiplex analysis and Serum concentration of IL-8 and IL-32 were determined by enzyme-linked immunosorbent assay (ELISA) kits. Interestingly, among the blood parameters, neutrophil and lymphocyte counts were significantly lower in severe COVID-19 patients than in the other, on the contrary, CRP was significantly higher in severe patients than in other groups. The cytokines that best distinguished controls from COVID-19 patients were IL-8 and IL-32, while IL-6 resulted the better variables for discriminate severe group. The best model performance for severe group was obtained by the combination of IL-32, IL-6, IFN-γ, and CRP serum concentration showing an AUC = 0.83. A cut off of 15 pg/ml of IL-6 greatly discriminate survivor from death patients. New insights related to the cytokine storm in COVID-19 patients, highlighting different severity of disease infection.

Accuracy of the clinical diagnosis of dementia with Lewy bodies (DLB) among the Italian Dementia Centers: a study by the Italian DLB study group (DLB-SINdem).

INTRODUCTION: Dementia with Lewy bodies (DLB) may represent a diagnostic challenge, since its clinical picture overlaps with other dementia. Two toolkits have been developed to aid the clinician to diagnose DLB: the Lewy Body Composite Risk Score (LBCRS) and the Assessment Toolkit for DLB (AT-DLB). We aim to evaluate the reliability of these two questionnaires, and their ability to enhance the interpretation of the international consensus diagnostic criteria. METHODS: LBCRS and AT-DLB were distributed to 135 Italian Neurological Centers for Cognitive Decline and Dementia (CDCDs), with the indication to administer them to all patients with dementia referred within the subsequent 3 months. We asked to subsequently apply consensus criteria for DLB diagnosis, to validate the diagnostic accuracy of the two toolkits. RESULTS: A total of 23 Centers joined the study; 1854 patients were enrolled. We found a prevalence of possible or probable DLB of 13% each (26% total), according to the consensus criteria. LBCRS toolkit showed good reliability, with a Cronbach alpha of 0.77, stable even after removing variables from the construct. AT-DLB toolkit Cronbach alpha was 0.52 and, after the subtraction of the "cognitive fluctuation" criterion, was only 0.31. Accuracy, sensitivity, and specificity were higher for LBCRS vs. AT-DLB. However, when simultaneously considered in the logistic models, AT-DLB showed a better performance (p < 0.001). Overall, the concordance between LBCRS positive and AT-DLB possible/probable was of 78.02% CONCLUSIONS: In a clinical setting, the LBCRS and AT-DLB questionnaires have good accuracy for DLB diagnosis.

EEG-Based Alzheimer's Disease Recognition Using Robust-PCA and LSTM Recurrent Neural Network.

The use of electroencephalography (EEG) has recently grown as a means to diagnose neurodegenerative pathologies such as Alzheimer's disease (AD). AD recognition can benefit from machine learning methods that, compared with traditional manual diagnosis methods, have higher reliability and improved recognition accuracy, being able to manage large amounts of data. Nevertheless, machine learning methods may exhibit lower accuracies when faced with incomplete, corrupted, or otherwise missing data, so it is important do develop robust pre-processing techniques do deal with incomplete data. The aim of this paper is to develop an automatic classification method that can still work well with EEG data affected by artifacts, as can arise during the collection with, e.g., a wireless system that can lose packets. We show that a recurrent neural network (RNN) can operate successfully even in the case of significantly corrupted data, when it is pre-filtered by the robust principal component analysis (RPCA) algorithm. RPCA was selected because of its stated ability to remove outliers from the signal. To demonstrate this idea, we first develop an RNN which operates on EEG data, properly processed through traditional PCA; then, we use corrupted data as input and process them with RPCA to filter outlier components, showing that even with data corruption causing up to 20% erasures, the RPCA was able to increase the detection accuracy by about 5% with respect to the baseline PCA.

Vasoactive neuropeptides and Alzheimer's disease: a systematic review focusing on calcitonin gene-related peptide.

Vasoactive peptides constitute a heterogenous family of mediators exerting various physiological functions, mostly studied for their vasotropic effects and role as peripheral neurotransmitters/neuromodulators, mainly involved in nociceptive transmission modulation. They have been divided into vasodilatory or vasoconstrictive peptides, according to their predominant effects on vascular tone. Recent research has shown in the Central Nervous System effects as transmitters and "growth factor-like" signals. Therefore, deregulation of their signaling systems has been thought to play a role in neural cell death and in the pathogenesis of neurodegenerative disorders, including Alzheimer's disease, since these peptides can regulate neuronal stress signaling, survival cascades, synaptic plasticity. This review considers evidence about the implication of neuropeptide systems in Alzheimer's disease while focusing mainly on calcitonin gene-related peptide-alpha. In vitro and in vivo studies have shown potential implications in its pathogenesis. It has been possibly proposed as a neuroprotective agent, considering not only its pleiotropic actions on blood vessels, neurovascular coupling, energy metabolism, but also its potential actions on neuronal, glial, and immune system stress signaling, which might also derive from its structural homology to amylin. Amylin signaling is thought to be disrupted in Alzheimer's disease, and amylin itself takes part in the composition of senile plaques. Calcitonin gene-related peptide-containing systems seem more closely related to Alzheimer's disease pathogenesis than other neuropeptidergic systems, and their regulation might represent an interesting mechanism in developing novel therapeutic approaches.

Insight in frontotemporal dementia and progressive supranuclear palsy.

INTRODUCTION: Progressive supranuclear palsy (PSP) and behavioural variant frontotemporal dementia - (bv-FTD) share common neuropsychological features except for online monitoring awareness. Therefore, the aim of our study is to explore if this assessment could be used in standard clinical practice. MATERIALS AND METHODS: We retrospectively analyse 93 subjects (27 FTD, 25 PSP, 42 healthy controls). Neuropsychological and instrumental examinations were performed for each patient. RESULTS: FTD patients made fewer self-corrections than PSP patients despite a similar number of total errors. We also performed ROC curves: the area under the curve (AUC) is 0.79. A model for a logistic regression was also developed: the only significant predictor is the number of self-corrections (p = 0.004 ß = 1244). DISCUSSION AND CONCLUSIONS: In conclusion, our findings show online awareness is more compromised in FTD patients than in PSP patients. This difference could be useful for making a differential diagnosis between the two diseases: for each extra point in number of self-corrections the probability of suffering from PSP increases by about three and a half times (OR 3.47).

Naming famous people through face and voice: a normative study.

OBJECTIVES: Within the large topic of naming disorders, an important and separated chapter belongs to proper names. Defects of proper naming could be a selective linguistic problem. Sometimes, it includes names belonging to various kinds of semantically unique entities, but other times, it has been observed for famous people proper names only. According to Bruce and Young's model, different stages allow to recognize, identify, and name famous people from their faces and voices, subsuming different anatomical pathways, both in right temporal lobe, and their different efficiency in this task. The present study aimed to report the normative data concerning the naming of the same famous people from voice and face. SUBJECTS AND METHODS: One hundred fifty-three normal subjects underwent a test in which they were requested to name famous people from their face and from their voice. The stimuli belonged to the previously published Famous People Recognition Battery. RESULTS: The mean percentage score on naming from face was 84.42 ± 12.03% (range 55.26-100%) and the mean percentage score on naming from voice was 66.04 ± 16.81% (range 28.13-100%). The difference observed in performance by face and by voice resulted significant (t|153 = 15.973; p < 0.001). Regression analyses showed that the percentage score obtained on naming from faces was predicted by education, whereas naming from voice was predicted by education and gender. DISCUSSION: Naming from voice is more difficult than from face, confirming a different difficulty of the two tasks. Education showed high predicting value for faces and less for voices, whereas gender contributed to predict results only for voices.

Famous people recognition through personal name: a normative study.

In this normative study, we investigated famous people recognition through personal name, using as stimuli the names of the same 40 Italian famous persons whose faces and voices had been utilized for the normative study of the Famous People Recognition Battery. For each famous people, we assessed name familiarity, person identification (when the name had been considered as familiar), and false alarms. The investigation was carried out on 143 normal subjects who varied in age and education. Name familiarity and semantic scores were affected by educational level, whereas age influenced false alarms. A comparison between results obtained with names in this research and with faces and voices of the same famous people in our previous study showed that familiarity scores were higher for personal names than those for faces and voices, which obtained the worst scores. Person identification scores were not significantly different from names and from faces, but both these scores were significantly higher than the semantic scores obtained by voices. Taken together, these results are inconsistent with the influential interactive activation and competition model of person recognition.

Recognition disorders for famous faces and voices: a review of the literature and normative data of a new test battery.

Several anatomo-clinical investigations have shown that familiar face recognition disorders not due to high level perceptual defects are often observed in patients with lesions of the right anterior temporal lobe (ATL). The meaning of these findings is, however, controversial, because some authors claim that these patients show pure instances of modality-specific 'associative prosopagnosia', whereas other authors maintain that in these patients voice recognition is also impaired and that these patients have a 'multimodal person recognition disorder'. To solve the problem of the nature of famous faces recognition disorders in patients affected by right ATL lesions, it is therefore very important to verify with formal tests if these patients are or are not able to recognize others by voice, but a direct comparison between the two modalities is hindered by the fact that voice recognition is more difficult than face recognition. To circumvent this difficulty, we constructed a test battery in which subjects were requested to recognize the same persons (well-known at the national level) through their faces and voices, evaluating familiarity and identification processes. The present paper describes the 'Famous People Recognition Battery' and reports the normative data necessary to clarify the nature of person recognition disorders observed in patients affected by right ATL lesions.

Relational and conjunctive binding functions dissociate in short-term memory.

Remembering complex events requires binding features within unified objects (conjunctions) and holding associations between objects (relations). Recent studies suggest that the two functions dissociate in long-term memory (LTM). Less is known about their functional organization in short-term memory (STM). The present study investigated this issue in patient AE affected by a stroke which caused damage to brain regions known to be relevant for relational functions both in LTM and in STM (i.e., the hippocampus). The assessment involved a battery of standard neuropsychological tasks and STM binding tasks. One STM binding task (Experiment 1) presented common objects and common colors forming either pairs (relations) or integrated objects (conjunctions). Free recall of relations or conjunctions was assessed. A second STM binding task used random polygons and non-primary colors instead (Experiment 2). Memory was assessed by selecting the features that made up the relations or the conjunctions from a set of single polygons and a set of single colors. The neuropsychological assessment revealed impaired delayed memory in AE. AE's pronounced relational STM binding deficits contrasted with his completely preserved conjunctive binding functions in both Experiments 1 and 2. Only 2.35% and 1.14% of the population were expected to have a discrepancy more extreme than that presented by AE in Experiments 1 and 2, respectively. Processing relations and conjunctions of very elementary nonspatial features in STM led to dissociating performances in AE. These findings may inform current theories of memory decline such as those linked to cognitive aging.

Metabolic syndrome and cerebrovascular impairment in Alzheimer's disease.

OBJECTIVE: Metabolic Syndrome (MeS) has inconstantly been associated with cognitive impairment. The aim of this study was to investigate the influence of MeS on cerebrovascular reactivity and the possible consequences on cognitive impairment in patients with Alzheimer's disease (AD). METHODS: A total of 162 AD patients were enrolled and grouped depending on the presence/absence of MeS. An ultrasound assessment of the neck vessels was performed to evaluate common carotid artery intima-media thickness (IMT). Cerebral hemodynamics was assessed by the transcranial Doppler-based breath-holding index (BHI) test. The relationship between BHI and MeS was explored first with a nested binary logistic model and then with a general linear model/adjusted model. Both models were corrected for sex, age, education, BMI, smoking attitude, and IMT treated as covariates. RESULTS: Pathologic BHI values were significantly more frequent among patients with MeS (risk ratio (RR):1.477; 95% CI: 1.177-1.848). MeS significantly improved the prediction of a pathologic BHI in the binary logistic model (odds ratio (OR):11.64; 95% CI: 1.001-135.304; p < 0.05). Moreover, AD patients affected by MeS had significantly lower mean Mini-Mental State Evaluation values than the unaffected ones (16.06; 95% CI: 14.96-17.15 vs 17.79; 95% CI: 17.05-18.53; p < 0.0001). CONCLUSIONS: Our data show an association between the presence of MeS and cerebral hemodynamics. The possibility that a cluster of potentially treatable vascular risk factors may influence AD patients' prognosis deserves consideration.

Impairment of homonymous processing in Alzheimer's disease.

An important issue in research on language is how concepts are represented and associated with each other in the brain. Many investigations have focused on language ambiguity and the phenomenon of homonymy in which a single lexical item, presenting the same form, is related to different meanings. Our study aims to test the hypothesis that weak association of meaning characterizing homonyms may be especially prone to brain damage. To verify this hypothesis a test of attribution of the meaning of homonymous words, the Humpty Dumpty (HD) test, was applied to 50 patients with Alzheimer's disease (AD) and 50 healthy subjects. Results show that AD patients are impaired in the HD test in an early phase of disease and that performance correlates with naming ability and phonological fluency. The data are in keeping with a growing body of literature that supports dual impairment to the semantic system in AD, i.e., to semantic knowledge and active processing and access to the semantic field. The evaluation of the ability to resolve homonymous ambiguity, using the HD test, may provide a useful and quick clinical tool to detect the anomalies of the semantic network linked to either a loss of the core system where meaning of words is stored or an impairment of the access to an intact semantic representation.

Visit-to-visit blood pressure variability in Alzheimer disease.

The aim of this study was to evaluate visit-to-visit blood pressure (BP) variability in a cohort of patients with Alzheimer disease (AD) and healthy controls. Patients with clinically diagnosed mild or moderate AD and cognitively normal controls matched for age and sex were recruited and followed up for 6 months. To characterize the BP status of each individual, mean, maximum and minimum values, SD, and coefficient of variation were obtained for both systolic BP (SBP) and diastolic BP (DBP). Seventy AD patients and 140 controls were enrolled. No meaningful differences were found in prevalence or treatments of various vascular risk factors. AD patients had higher maximum and lower minimum values and greater SD and coefficient of variation of both SBP and DBP. Group differences in mean values were significant only for SBP. In the multiple logistic regression analysis, adjusted for confounding variables, all the indices related to BP variability were significantly associated with AD. Our results show that AD patients have a greater variability of both SBP and DBP in comparison with age-matched cognitive normal controls, suggesting potential implication in the pathogenesis or progression of the disease.

Instrumental exams performance can be a contributing factor to the delay in diagnosis of migraine.

BACKGROUND: Diagnostic delay is a recognized drawback for a correct management of migraine patients. The aim of this study was to investigate the possible relationship among number and type of examinations performed and diagnostic delay in migraine diagnosis. METHODS: We enrolled 500 subjects referred to our Headache Center for a migraine without aura. We analyzed the relationship among diagnostic delay, number of examinations performed and performance of each single test by a Cox regression model and an ordinal logistic regression model. RESULTS: Each individual exam increased a diagnostic delay of at least 12 months (p < 0.05, Cox regression model). Brain CT as the first diagnostic approach had a reduced risk of delay of more than 5 years (OR 0.632, 95% CI 0.71-0.56, p < 0.05, ordinal regression model). CONCLUSIONS: The number of instrumental examinations seems to significantly influence the diagnostic delay. This aspect contributes to increase health care costs, the risk of pain chronicization and pharmacological treatment misuse.

Arithmetic knowledge in early semantic dementia.

The issue of whether arithmetic knowledge is invariably spared or impaired in semantic dementia is still under debate. The corpus of data mainly relies on single case-report descriptions. Relative to this issue, only one paper, by Julien et al. (Neuropsychologia 44(10): 2732-2744, 2008) explored in a systematic way arithmetic knowledge in an SD patient group. The present study is aimed to explore calculation in a group of eight patients affected by early semantic dementia (SD) using a neuropsychological battery devised to examine arithmetic knowledge (arithmetic signs recognition, arithmetic facts and written and mental calculation). These SD patients showed problems in recognition of arithmetic signs, difficulty in arithmetic facts and procedural errors in calculation. Still, the pattern of answers that the SD patients showed was not completely homogeneous and some individual variations were present. In contrast with most literature, the present study provides evidence for impairment of arithmetic knowledge in patients with early semantic dementia and contributes to the recent evidence that arithmetic knowledge cannot be considered an independent domain within the semantic system.

Percutaneous transluminal angioplasty for chronic cerebrospinal venous insufficiency in multiple sclerosis: dichotomy between subjective and objective outcome scores.

Some multiple sclerosis (MS) patients reported an improvement after percutaneous transluminal angioplasty (PTA) for chronic cerebrospinal venous insufficiency (CCSVI), despite the lack of correspondence with objective outcome scores. The objective was to assess neurologic and quality of life scores before and after PTA for CCSVI in an observational study after a self-decided approach. 44 consecutive MS patients (21/23 M/F; median age 43 years, SD 9.8) who underwent PTA were evaluated before endovascular treatment for CCSVI and after 12 months. Neurologic outcome was assessed with EDSS, the annualized relapse rate (ARR) and frequency of new lesions at MRI after PTA. Quality of life was evaluated through the MSQoL-54 questionnaire. No modification in the ARR (p = 0.829), worsening of disability status (p = 0.002) and new lesions at MRI in 29.6 % of patients were found, in contrast to an improvement both in physical and mental domains of MSQoL-54 (p = 0.003). Multiple logistic regression showed EDSS score before PTA to be predictor of an increase of >10 points in MSQoL-54 mental domain (OR 0.52, 95 % CI, 0.31-0.89, p = 0.018). Spontaneously performed approach to CCSVI does not improve clinical and MRI parameters, despite frequent subjective perception of quality of life improvement.

The Dynamic Interplay between Loss of Semantic Memory and Semantic Learning Capacity: Insight from Neologisms Learning in Semantic Variant Primary Progressive Aphasia.

Semantic Variant of Primary Progressive Aphasia (svPPA) has often been considered as a loss of knowledge stored in semantic memory, but might also be due to a general disruption of mechanisms allowing the acquisition, storage, and retrieval of semantic memories. In order to assess any parallelism in svPPA patients between loss of semantic knowledge and inability to acquire new semantic information, we administered a battery of semantic learning tasks to healthy individuals and svPPA patients, where they were requested to learn new conceptual representations and new word forms, and to associate the former with the latter. A strong relation was found between loss of semantic knowledge and disruption of semantic learning: (a) patients with severe svPPA had the lowest scores in the semantic learning tasks; (b) significant correlations were found between scores obtained in semantic learning tasks and scores obtained in semantic memory disorders in svPPA patients.