Publications by authors named "Valerio Frazzini"

21 Publications

  • Page 1 of 1

A self-supervised learning strategy for postoperative brain cavity segmentation simulating resections.

Int J Comput Assist Radiol Surg 2021 Jun 13. Epub 2021 Jun 13.

School of Biomedical Engineering & Imaging Sciences, King's College London, London, UK.

Purpose: Accurate segmentation of brain resection cavities (RCs) aids in postoperative analysis and determining follow-up treatment. Convolutional neural networks (CNNs) are the state-of-the-art image segmentation technique, but require large annotated datasets for training. Annotation of 3D medical images is time-consuming, requires highly trained raters and may suffer from high inter-rater variability. Self-supervised learning strategies can leverage unlabeled data for training.

Methods: We developed an algorithm to simulate resections from preoperative magnetic resonance images (MRIs). We performed self-supervised training of a 3D CNN for RC segmentation using our simulation method. We curated EPISURG, a dataset comprising 430 postoperative and 268 preoperative MRIs from 430 refractory epilepsy patients who underwent resective neurosurgery. We fine-tuned our model on three small annotated datasets from different institutions and on the annotated images in EPISURG, comprising 20, 33, 19 and 133 subjects.

Results: The model trained on data with simulated resections obtained median (interquartile range) Dice score coefficients (DSCs) of 81.7 (16.4), 82.4 (36.4), 74.9 (24.2) and 80.5 (18.7) for each of the four datasets. After fine-tuning, DSCs were 89.2 (13.3), 84.1 (19.8), 80.2 (20.1) and 85.2 (10.8). For comparison, inter-rater agreement between human annotators from our previous study was 84.0 (9.9).

Conclusion: We present a self-supervised learning strategy for 3D CNNs using simulated RCs to accurately segment real RCs on postoperative MRI. Our method generalizes well to data from different institutions, pathologies and modalities. Source code, segmentation models and the EPISURG dataset are available at https://github.com/fepegar/resseg-ijcars .
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http://dx.doi.org/10.1007/s11548-021-02420-2DOI Listing
June 2021

Agitation and Dementia: Prevention and Treatment Strategies in Acute and Chronic Conditions.

Front Neurol 2021 16;12:644317. Epub 2021 Apr 16.

Department of Neuroscience, Imaging and Clinical Sciences, University G. d'Annunzio of Chieti-Pescara, Chieti, Italy.

Agitation is a behavioral syndrome characterized by increased, often undirected, motor activity, restlessness, aggressiveness, and emotional distress. According to several observations, agitation prevalence ranges from 30 to 50% in Alzheimer's disease, 30% in dementia with Lewy bodies, 40% in frontotemporal dementia, and 40% in vascular dementia (VaD). With an overall prevalence of about 30%, agitation is the third most common neuropsychiatric symptoms (NPS) in dementia, after apathy and depression, and it is even more frequent (80%) in residents of nursing homes. The pathophysiological mechanism underlying agitation is represented by a frontal lobe dysfunction, mostly involving the anterior cingulate cortex (ACC) and the orbitofrontal cortex (OFC), respectively, meaningful in selecting the salient stimuli and subsequent decision-making and behavioral reactions. Furthermore, increased sensitivity to noradrenergic signaling has been observed, possibly due to a frontal lobe up-regulation of adrenergic receptors, as a reaction to the depletion of noradrenergic neurons within the locus coeruleus (LC). Indeed, LC neurons mainly project toward the OFC and ACC. These observations may explain the abnormal reactivity to weak stimuli and the global arousal found in many patients who have dementia. Furthermore, agitation can be precipitated by several factors, e.g., the sunset or low lighted environments as in the sundown syndrome, hospitalization, the admission to nursing residencies, or changes in pharmacological regimens. In recent days, the global pandemic has increased agitation incidence among dementia patients and generated higher distress levels in patients and caregivers. Hence, given the increasing presence of this condition and its related burden on society and the health system, the present point of view aims at providing an extensive guide to facilitate the identification, prevention, and management of acute and chronic agitation in dementia patients.
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http://dx.doi.org/10.3389/fneur.2021.644317DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8085397PMC
April 2021

Sleep scoring based on video-electroencephalography monitoring in an Epileptology Unit: Comparison with polysomnography.

J Sleep Res 2021 Apr 6:e13332. Epub 2021 Apr 6.

Department of Clinical Neurophysiology, AP-HP, Hôpital Pitié-Salpêtrière-Charles Foix, Paris, France.

The aim of the study was to compare the performance of video- electroencephalography (EEG) monitoring and standard polysomnography for sleep scoring in an Epileptology Unit. We calculated the level of agreement between two methods of sleep scoring, using either 27-electrode video-EEG or polysomnography for 1 night in 22 patients admitted to our Epileptology Unit. Independent experts manually scored sleep using the American Academy of Sleep Medicine 2017 guidelines. We evaluated the number of sleep cycles and their distribution on hypnogram, total sleep time, sleep efficiency, sleep and rapid eye movement sleep-onset latency, wake after sleep-onset, and sleep stages. We then extracted sub-samples of recordings to examine the agreement in microarousal and rapid eye movement scoring. We used Bland and Altman plots and Cohen's kappa test to measure agreement. Bland and Altman plots showed at least 95% agreement for all studied sleep parameters with the exception of wake after sleep onset, where there was an 11 min difference. Cohen's kappa test showed an agreement for the recognition of microarousal (0.89) and of rapid eye movements (0.96) in sub-samples. Video-EEG represents an acceptable alternative tool for sleep architecture study in patients admitted to an Epileptology Unit.
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http://dx.doi.org/10.1111/jsr.13332DOI Listing
April 2021

Disturbances of brain cholesterol metabolism: A new excitotoxic process associated with status epilepticus.

Neurobiol Dis 2021 Jul 24;154:105346. Epub 2021 Mar 24.

Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, INSERM U 1127, CNRS UMR 7225, Paris, France; AP-HP, Hôpital Pitié-Salpêtrière, DMU Neurosciences 6, Epileptology Unit and Clinical Neurophysiology Department, Paris, France; Sorbonne Université, 75006 Paris, France; Center of Reference for Rare Epilepsies, Pitié-Salpêtrière Hospital, Paris, France. Electronic address:

The understanding of the excitotoxic processes associated with a severe status epilepticus (SE) is of major importance. Changes of brain cholesterol homeostasis is an emerging candidate for excitotoxicity. We conducted an overall analysis of the cholesterol homeostasis both (i) in fluids and tissues from patients with SE: blood (n = 63, n = 87 controls), CSF (n = 32, n = 60 controls), and post-mortem brain tissues (n = 8, n = 8 controls) and (ii) in a mouse model of SE induced by an intrahippocampal injection of kainic acid. 24-hydroxycholesterol levels were decreased in kainic acid mouse hippocampus and in human plasma and post-mortem brain tissues of patients with SE when compared with controls. The decrease of 24-hydroxycholesterol levels was followed by increased cholesterol levels and by an increase of the cholesterol synthesis. Desmosterol levels were higher in human CSF and in mice and human hippocampus after SE. Lanosterol and dihydrolanosterol levels were higher in plasma from SE patients. Our results suggest that a CYP46A1 inhibition could occur after SE and is followed by a brain cholesterol accumulation. The excess of cholesterol is known to be excitotoxic for neuronal cells and may participate to neurological sequelae observed after SE. This study highlights a new pathophysiological pathway involved in SE excitotoxicity.
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http://dx.doi.org/10.1016/j.nbd.2021.105346DOI Listing
July 2021

Association of Clinical, Biological, and Brain Magnetic Resonance Imaging Findings With Electroencephalographic Findings for Patients With COVID-19.

JAMA Netw Open 2021 03 1;4(3):e211489. Epub 2021 Mar 1.

Sorbonne Université, Paris Brain Institute, Institut du Cerveau, Institut National de la Santé et de la Recherche Médicale U 1127, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7225, Paris, France.

Importance: There is evidence of central nervous system impairments associated with coronavirus disease 2019 (COVID-19) infection, including encephalopathy. Multimodal monitoring of patients with COVID-19 may delineate the specific features of COVID-19-related encephalopathy and guide clinical management.

Objectives: To investigate clinical, biological, and brain magnetic resonance imaging (MRI) findings in association with electroencephalographic (EEG) features for patients with COVID-19, and to better refine the features of COVID-19-related encephalopathy.

Design, Setting, And Participants: This retrospective cohort study conducted in Pitié-Salpêtrière Hospital, Paris, France, enrolled 78 hospitalized adults who received a diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) and underwent EEG between March 30 and June 11, 2020.

Exposures: Detection of SARS-CoV-2 from a nasopharyngeal specimen using a reverse transcription-polymerase chain reaction assay or, in the case of associated pneumonia, on a computed tomography scan of the chest.

Main Outcomes And Measures: Data on the clinical and paraclinical features of the 78 patients with COVID-19 were retrieved from electronic patient records.

Results: Of 644 patients who were hospitalized for COVID-19, 78 (57 men [73%]; mean [SD] age, 61 [12] years) underwent EEG. The main indications for EEG were delirium, seizure-like events, and delayed awakening in the intensive care unit after stopping treatment with sedatives. Sixty-nine patients showed pathologic EEG findings, including metabolic-toxic encephalopathy features, frontal abnormalities, periodic discharges, and epileptic activities. Of 57 patients who underwent brain MRI, 41 showed abnormalities, including perfusion abnormalities, acute ischemic lesions, multiple microhemorrhages, and white matter-enhancing lesions. Fifty-five patients showed biological abnormalities, including dysnatremia, kidney failure, and liver dysfunction, the same day as the EEG. The results of cerebrospinal fluid analysis were negative for SARS-Cov-2 for all tested patients. Nine patients who had no identifiable cause of brain injury outside COVID-19 were further isolated; their brain injury was defined as COVID-19-related encephalopathy. They represented 1% (9 of 644) of patients with COVID-19 requiring hospitalization. Six of these 9 patients had movement disorders, 7 had frontal syndrome, 4 had brainstem impairment, 4 had periodic EEG discharges, and 3 had MRI white matter-enhancing lesions.

Conclusions And Relevance: The results from this cohort of patients hospitalized with COVID-19 suggest there are clinical, EEG, and MRI patterns that could delineate specific COVID-19-related encephalopathy and guide treatment strategy.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.1489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961310PMC
March 2021

Acting Before; A Combined Strategy to Counteract the Onset and Progression of Dementia.

Curr Alzheimer Res 2020 ;17(9):790-804

Behavioral Neurology and Molecular Neurology Units, Center for Advanced Studies and Technology, CAST, University G. d'Annunzio of Chieti-Pescara, Pescara, Italy.

Brain aging and aging-related neurodegenerative disorders are posing a significant challenge for health systems worldwide. To date, most of the therapeutic efforts aimed at counteracting dementiarelated behavioral and cognitive impairment have been focused on addressing putative determinants of the disease, such as β-amyloid or tau. In contrast, relatively little attention has been paid to pharmacological interventions aimed at restoring or promoting the synaptic plasticity of the aging brain. The review will explore and discuss the most recent molecular, structural/functional, and behavioral evidence that supports the use of non-pharmacological approaches as well as cognitive-enhancing drugs to counteract brain aging and early-stage dementia.
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http://dx.doi.org/10.2174/1567205017666201203085524DOI Listing
January 2020

Interictal Heart Rate Variability Analysis Reveals Lateralization of Cardiac Autonomic Control in Temporal Lobe Epilepsy.

Front Neurol 2020 14;11:842. Epub 2020 Aug 14.

Department of Neurology, "SS Annunziata" Hospital, Chieti, Italy.

The temporal lobe, a critical hub for cognition, also plays a central role in the regulation of autonomic cardiovascular functions. Lesions in this area are usually associated with abnormalities in the regulation of heart rate (HR) and blood pressure (BP). The analysis of the heart rate variability (HRV) is useful to evaluate the cardiac parasympathetic nervous system activity. This study aims at comparing HRV changes occurring in two groups of patients suffering from Temporal Lobe Epilepsy (TLE). To that aim, we evaluated patients differentiated by the right or left location of the epileptic foci. Fifty-two adult patients with a diagnosis of TLE were enrolled. Each patient underwent a 20-min EEG + EKG recording in resting state. According to the localization of epileptic focus, patients were divided into two subgroups: right TLE (R-TLE) and left TLE (L-TLE). HRV parameters were calculated with a short-lasting analysis of EKG recordings. Time-domain and frequency domain-related, as well as non-linear analysis, parameters, were compared between the two groups. Compared to the R-TLE group, L-TLE subjects showed a significant decrease in low frequency (LF) ( < 0.01) and low frequency/high-frequency ratio (LF/HF) ( < 0.001) as well as increased HF values ( < 0.01), a parameter indicative of the presence of an increased cardiac vagal tone. These results were also confirmed in the subgroup analysis that took into account the seizure types, responses to antiepileptic drugs, seizure frequencies, and etiology. The main finding of the study is that, compared to R-TLE, L-TLE is associated with increased cardiac vagal tone. These results indicate that patients with TLE exhibit a lateralized cardiac autonomic control. L-TLE patients may have a lower risk of developing cardiac dysfunctions and less susceptible to develop Sudden Death for Epilepsy (SUDEP).
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http://dx.doi.org/10.3389/fneur.2020.00842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456848PMC
August 2020

Focal status epilepticus in anti-Hu encephalitis.

Autoimmun Rev 2019 Nov 11;18(11):102388. Epub 2019 Sep 11.

AP-HP, Epilepsy Unit, Rare Epilepsies Referral Center, Pitié-Salpêtrière Hospital and Sorbonne Université, Paris, France; ICM, Brain and Spine Institute, INSERM UMRS1127, CNRS UMR7225, Sorbonne Université, Pitié-Salpêtrière Hospital, Paris, France. Electronic address:

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http://dx.doi.org/10.1016/j.autrev.2019.102388DOI Listing
November 2019

An Uncommon Case of Hyperammonemic Encephalopathy.

Neurocrit Care 2019 10;31(2):439-442

Department of Neuroscience, Imaging and Clinical Sciences, "G.d'Annunzio" University, Chieti-Pescara, and Neurology Clinics, SS Annunziata Hospital, Chieti-Pescara, Italy.

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http://dx.doi.org/10.1007/s12028-019-00715-6DOI Listing
October 2019

The pharmacological perturbation of brain zinc impairs BDNF-related signaling and the cognitive performances of young mice.

Sci Rep 2018 06 27;8(1):9768. Epub 2018 Jun 27.

Center of Excellence on Aging and Translational Medicine - CeSI-MeT, Chieti, Italy.

Zinc (Zn) is a pleiotropic modulator of the neuronal and brain activity. The disruption of intraneuronal Zn levels triggers neurotoxic processes and affects neuronal functioning. In this study, we investigated how the pharmacological modulation of brain Zn affects synaptic plasticity and cognition in wild-type mice. To manipulate brain Zn levels, we employed the Zn (and copper) chelator 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol, CQ). CQ was administered for two weeks to 2.5-month-old (m.o.) mice, and effects studied on BDNF-related signaling, metalloproteinase activity as well as learning and memory performances. CQ treatment was found to negatively affect short- and long-term memory performances. The CQ-driven perturbation of brain Zn was found to reduce levels of BDNF, synaptic plasticity-related proteins and dendritic spine density in vivo. Our study highlights the importance of choosing "when", "where", and "how much" in the modulation of brain Zn levels. Our findings confirm the importance of targeting Zn as a therapeutic approach against neurodegenerative conditions but, at the same time, underscore the potential drawbacks of reducing brain Zn availability upon the early stages of development.
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http://dx.doi.org/10.1038/s41598-018-28083-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021411PMC
June 2018

Single-unit activities during the transition to seizures in deep mesial structures.

Ann Neurol 2017 Dec 15;82(6):1022-1028. Epub 2017 Dec 15.

Institut du Cerveau et de la Moelle épinière, ICM, INSERM UMRS 1127, CNRS UMR 7225, Pitié-Salpêtrière Hospital, F-75013, Paris, France.

Focal seizures are assumed to arise from a hypersynchronous activity affecting a circumscribed brain region. Using microelectrodes in seizure-generating deep mesial regions of 9 patients, we investigated the firing of hundreds of single neurons before, during, and after ictal electroencephalogram (EEG) discharges. Neuronal spiking activity at seizure initiation was highly heterogeneous and not hypersynchronous. Furthermore, groups of neurons showed significant changes in activity minutes before the seizure with no concomitant changes in the corresponding macroscopic EEG recordings. Altogether, our findings suggest that only limited subsets of neurons in epileptic depth regions initiate the seizure-onset and that ictogenic mechanisms operate in submillimeter-scale microdomains. Ann Neurol 2017 Ann Neurol 2017;82:1022-1028.
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http://dx.doi.org/10.1002/ana.25111DOI Listing
December 2017

Medium-chain plasma acylcarnitines, ketone levels, cognition, and gray matter volumes in healthy elderly, mildly cognitively impaired, or Alzheimer's disease subjects.

Neurobiol Aging 2016 07 15;43:1-12. Epub 2016 Mar 15.

Molecular Neurology Unit, Center of Excellence on Aging and Translational Medicine (Ce.S.I.-MeT), "G. d'Annunzio" University of Chieti-Pescara, Chieti, Italy; Department of Neurology, and Institute for Memory Impairments and Neurological Disorders, University of California-Irvine, Irvine, CA, USA; Department of Pharmacology, and Institute for Memory Impairments and Neurological Disorders, University of California-Irvine, Irvine, CA, USA. Electronic address:

Aging, amyloid deposition, and tau-related pathology are key contributors to the onset and progression of Alzheimer's disease (AD). However, AD is also associated with brain hypometabolism and deficits of mitochondrial bioenergetics. Plasma acylcarnitines (ACCs) are indirect indices of altered fatty acid beta-oxidation, and ketogenesis has been found to be decreased on aging. Furthermore, in elderly subjects, alterations in plasma levels of specific ACCs have been suggested to predict conversion to mild cognitive impairment (MCI) or AD. In this study, we assayed plasma profiles of ACCs in a cohort of healthy elderly control, MCI subjects, and AD patients. Compared with healthy controls or MCI subjects, AD patients showed significant lower plasma levels of several medium-chain ACCs. Furthermore, in AD patients, these lower concentrations were associated with lower prefrontal gray matter volumes and the presence of cognitive impairment. Interestingly, lower levels of medium-chain ACCs were also found to be associated with lower plasma levels of 2-hydroxybutyric acid. Overall, these findings suggest that altered metabolism of medium-chain ACCs and impaired ketogenesis can be metabolic features of AD.
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http://dx.doi.org/10.1016/j.neurobiolaging.2016.03.005DOI Listing
July 2016

Olanzapine-related repetitive focal seizures with lingual dystonia.

Epileptic Disord 2016 Mar;18(1):83-6

SS Annunziata Hospital of Chieti- Neurology, Chieti, Abruzzo, Italy.

Olanzapine-related seizures have rarely been reported despite associated proconvulsant risk factors described in the literature: myoclonic status, increased frequency of seizures, tonic-clonic seizures, as well as fatal status epilepticus. We present a psychiatric patient who developed repetitive focal motor seizures and lingual dystonia when olanzapine was added for psychomotor agitation and aggressiveness. Olanzapine was immediately suspended and the seizures progressively disappeared. A control EEG showed no paroxysmal discharges. Olanzapine shares some pharmacological similarities with clozapine, a neuroleptic with a high risk of dose-dependent seizures. This adverse effect should be taken into account, and olanzapine should be used with caution if concomitant circumstances decrease the seizure threshold. [Published with video sequence online].
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http://dx.doi.org/10.1684/epd.2016.0805DOI Listing
March 2016

Effects of non-pharmacological or pharmacological interventions on cognition and brain plasticity of aging individuals.

Front Syst Neurosci 2014 2;8:153. Epub 2014 Sep 2.

Molecular Neurology Unit, Center of Excellence on Aging, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy ; Department of Neuroscience, Imaging and Clinical Sciences, University "G. d'Annunzio" Chieti-Pescara, Chieti, Italy ; Departments of Neurology and Pharmacology, Institute for Memory Impairments and Neurological Disorders, University of California-Irvine Irvine, CA, USA.

Brain aging and aging-related neurodegenerative disorders are major health challenges faced by modern societies. Brain aging is associated with cognitive and functional decline and represents the favourable background for the onset and development of dementia. Brain aging is associated with early and subtle anatomo-functional physiological changes that often precede the appearance of clinical signs of cognitive decline. Neuroimaging approaches unveiled the functional correlates of these alterations and helped in the identification of therapeutic targets that can be potentially useful in counteracting age-dependent cognitive decline. A growing body of evidence supports the notion that cognitive stimulation and aerobic training can preserve and enhance operational skills in elderly individuals as well as reduce the incidence of dementia. This review aims at providing an extensive and critical overview of the most recent data that support the efficacy of non-pharmacological and pharmacological interventions aimed at enhancing cognition and brain plasticity in healthy elderly individuals as well as delaying the cognitive decline associated with dementia.
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http://dx.doi.org/10.3389/fnsys.2014.00153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4151335PMC
September 2014

Characterisation of element profile changes induced by long-term dietary supplementation of zinc in the brain and cerebellum of 3xTg-AD mice by alternated cool and normal plasma ICP-MS.

Metallomics 2012 Dec 14;4(12):1321-32. Epub 2012 Nov 14.

School of Engineering, Architecture, and Motor Science, Kore University, Via della Cooperazione, 94100 Enna, Italy.

Metal dyshomeostasis plays a crucial role in promoting several neurodegenerative diseases including Alzheimer's disease (AD), a condition that has been linked to deregulation of brain levels of Al, Fe, Mn, Cu, and Zn. Thus, quantitative multi-element profiling of brain tissues from AD models can be of great value in assessing the pathogenic role of metals as well as the value of therapeutic interventions aimed at restoring metal homeostasis in the brain. In this study, we employed low resolution inductively coupled plasma mass spectrometry (ICP-MS) to evaluate levels of ultra-trace, trace, and major elements in brains and cerebella of 3xTg-AD mice, a well characterized transgenic (Tg) AD model. This method is based on alternated cool and hot plasma ICP-MS. The essay fulfilled analytical requirements for the quantification of 14 elements in the Central Nervous System (CNS) of our Tg model. Quantification of Li, Al, Cr, and Co, a procedure that requires a pre-concentration step, was validated by high resolution ICP-MS. Changes in element profiles occurring in 3xTg-AD mice were compared to the ones observed in wild type (WT) mice. We also investigated variations in element profiles in 3xTg-AD mice receiving a long-term (17 months) dietary supplementation of Zn. Our data indicate that, compared to WT animals, 3xTg-AD mice displayed signs of altered brain metal homeostasis. We also found that long-term Zn administration promoted decreased brain levels of some metals (K, Ca, and Fe) and restored levels of Al, Cr, and Co to values found in WT mice.
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http://dx.doi.org/10.1039/c2mt20162cDOI Listing
December 2012

Combination training in aging individuals modifies functional connectivity and cognition, and is potentially affected by dopamine-related genes.

PLoS One 2012 28;7(8):e43901. Epub 2012 Aug 28.

Department of Neuroscience and Imaging, University G d'Annunzio Chieti-Pescara, Chieti, Italy.

Background: Aging is a major co-risk factor in many neurodegenerative diseases. Cognitive enrichment positively affects the structural plasticity of the aging brain. In this study, we evaluated effects of a set of structured multimodal activities (Combination Training; CT) on cognitive performances, functional connectivity, and cortical thickness of a group of healthy elderly individuals. CT lasted six months.

Methodology: Neuropsychological and occupational performances were evaluated before and at the end of the training period. fMRI was used to assess effects of training on resting state network (RSN) functional connectivity using Independent Component Analysis (ICA). Effects on cortical thickness were also studied. Finally, we evaluated whether specific dopamine-related genes can affect the response to training.

Principal Findings: Results of the study indicate that CT improves cognitive/occupational performances and reorganizes functional connectivity. Intriguingly, individuals responding to CT showed specific dopamine-related genotypes. Indeed, analysis of dopamine-related genes revealed that carriers of DRD3 ser9gly and COMT Val158Met polymorphisms had the greatest benefits from exposure to CT.

Conclusions And Significance: Overall, our findings support the idea that exposure to a set of structured multimodal activities can be an effective strategy to counteract aging-related cognitive decline and also indicate that significant capability of functional and structural changes are maintained in the elderly.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0043901PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3429431PMC
February 2013

Effects of dietary supplementation of carnosine on mitochondrial dysfunction, amyloid pathology, and cognitive deficits in 3xTg-AD mice.

PLoS One 2011 Mar 15;6(3):e17971. Epub 2011 Mar 15.

Molecular Neurology Unit, Center of Excellence on Aging (Ce.S.I.), University G. d'Annunzio, Chieti-Pescara, Italy.

Background: The pathogenic road map leading to Alzheimer's disease (AD) is still not completely understood; however, a large body of studies in the last few years supports the idea that beside the classic hallmarks of the disease, namely the accumulation of amyloid-β (Aβ) and neurofibrillary tangles, other factors significantly contribute to the initiation and the progression of the disease. Among them, mitochondria failure, an unbalanced neuronal redox state, and the dyshomeostasis of endogenous metals like copper, iron, and zinc have all been reported to play an important role in exacerbating AD pathology. Given these factors, the endogenous peptide carnosine may be potentially beneficial in the treatment of AD because of its free-radical scavenger and metal chelating properties.

Methodology: In this study, we explored the effect of L-carnosine supplementation in the 3xTg-AD mouse, an animal model of AD that shows both Aβ- and tau-dependent pathology.

Principal Findings: We found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions. No effects were found on tau pathology and we only observed a trend toward the amelioration of cognitive deficits.

Conclusions And Significance: Our data indicate that carnosine can be part of a combined therapeutic approach for the treatment of AD.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017971PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3058055PMC
March 2011

Zinc pre-treatment enhances NMDAR-mediated excitotoxicity in cultured cortical neurons from SOD1(G93A) mouse, a model of amyotrophic lateral sclerosis.

Neuropharmacology 2011 Jun 5;60(7-8):1200-8. Epub 2010 Nov 5.

Molecular Neurobiology Unit, Santa Lucia Foundation, Department of Neuroscience, University of "Tor Vergata", Rome, Italy.

Zn²+ is co-released at glutamatergic synapses throughout the central nervous system and acts as a neuromodulator for glutamatergic neurotransmission, as a key modulator of NMDA receptor functioning. Zn²+ is also implicated in the neurotoxicity associated with several models of acute brain injury and neurodegeneration. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting motor neurons in the spinal cord and cortex. In this study, we have investigated the modulatory role exerted by Zn²+ in NMDA-mediated neurotoxicity in either near-pure or mixed cortical cultured neurons obtained from either mice over-expressing the G93A mutant form of Cu/Zn superoxide dismutase (SOD1) human gene, a gene linked to familial ALS, or wild type (WT) mice. To that aim, SOD1(G93A) or WT cultures were exposed to either NMDA by itself or to Zn²+ prior to a toxic challenge with NMDA, and neuronal loss evaluated 24 h later. While we failed to observe any significant difference between NMDA and Zn²+/NMDA-mediated toxicity in mixed SOD1(G93A) or WT cortical cultures, different vulnerability to these toxic paradigms was found in near-pure neuronal cultures. In the WT near-pure neuronal cultures, a brief exposure to sublethal concentrations of Zn²+-enhanced NMDA receptor-mediated cell death, an effect that was far more pronounced in the SOD1(G93A) cultures. This increased excitotoxicity in SOD1(G93A) near-pure neuronal cultures appears to be mediated by a significant increase in NMDA-dependent rises of intraneuronal Ca²+ levels as well as enhanced production of cytosolic reactive oxygen species, while the injurious process seems to be unrelated to activation of nNOS or ERK1/2 pathways. This article is part of a Special Issue entitled 'Trends in neuropharmacology: in memory of Erminio Costa'.
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http://dx.doi.org/10.1016/j.neuropharm.2010.11.001DOI Listing
June 2011

The thiol-modifying agent N-ethylmaleimide elevates the cytosolic concentration of free Zn(2+) but not of Ca(2+) in murine cortical neurons.

Cell Calcium 2010 Jul 25;48(1):37-43. Epub 2010 Jul 25.

UMR CNRS 5249, Grenoble, France.

The membrane permeant alkylating agent N-ethylmaleimide (NEM) regulates numerous biological processes by reacting with thiol groups. Among other actions, NEM influences the cytosolic concentration of free Ca(2+) ([Ca(2+)]i). Depending on the cell type and the concentration used, NEM can promote the release of Ca(2+), affect its extrusion, stimulate or block its entry. However, most of these findings were obtained in experiments that employed fluorescent Ca(2+) probes and one major disadvantage of such experimental setting derives from the lack of specificity of the probes as all the so-called "Ca(2+)-sensitive" indicators also bind metals like Zn(2+) or Mn(2+) with higher affinities than Ca(2+). In this study, we examined the effects of NEM on the [Ca(2+)]i homeostasis of murine cortical neurons. We performed live-cell Ca(2+) and Zn(2+) imaging experiments using the fluorescent probes Fluo-4, FluoZin-3 and RhodZin-3 and found that NEM does not affect the neuronal [Ca(2+)]i homeostasis but specifically increases the cytosolic and mitochondrial concentration of free Zn(2+)([Zn(2+)]i). In addition, NEM triggers some neuronal loss that is prevented by anti-oxidants such as N-acetylcysteine or glutathione. NEM-induced toxicity is dependent on changes in [Zn(2+)]i levels as chelation of the cation with the cell-permeable heavy metal chelator, N,N,N'N'-tetrakis(-)[2-pyridylmethyl]-ethylenediamine (TPEN), promotes neuroprotection of cortical neurons exposed to NEM. Our data indicate that NEM affects [Zn(2+)]i but not [Ca(2+)]i homeostasis and shed new light on the physiological actions of this alkylating agent on central nervous system neurons.
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http://dx.doi.org/10.1016/j.ceca.2010.06.004DOI Listing
July 2010

Altered oxidant-mediated intraneuronal zinc mobilization in a triple transgenic mouse model of Alzheimer's disease.

Exp Gerontol 2008 May 12;43(5):488-92. Epub 2007 Nov 12.

Department of Basic and Applied Medical Science, CeSI-Center for Excellence on Aging, University G. d'Annunzio, Chieti, 66013, Italy.

Alzheimer's disease (AD) is responsible for the most common form of dementia among elderly people. Signature features of the AD brain are intra/extracellular deposits of beta-amyloid (Abeta) and neurofibrillary tangles composed of hyperphosphorylated tau. Recent evidence indicates that in AD altered Zn(2+) homeostasis can play an important role in the development of the disease as the cation promotes Abeta oligomerization and plaque formation. In this study, we investigated whether intraneuronal Zn(2+) homeostasis is affected by known "pro-AD factors" such as mutant forms of the amyloid precursor (APP), presenilin-1 (PS1), and tau proteins. Oxidative stress is a potent trigger for mobilization of intracellular free Zn(2+) ([Zn(2+)](i)) and we therefore evaluated ROS-driven [Zn(2+)](i) rises in neurons obtained from triple transgenic AD mice (3xTg-AD) that express mutant APP, PS1 and tau. In this study, [Zn(2+)](i) rises triggered by prolonged exposure to the membrane-permeant oxidizing agent 2,2'-dithiodipyridine were found to be significantly higher in 3xTg-AD neurons when compared to control cultures, suggesting that neuronal expression of pro-AD factors can facilitate altered Zn(2+) homeostasis.
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http://dx.doi.org/10.1016/j.exger.2007.10.018DOI Listing
May 2008

Mild acidosis enhances AMPA receptor-mediated intracellular zinc mobilization in cortical neurons.

Mol Med 2007 Jul-Aug;13(7-8):356-61

Department of Basic and Applied Medical Science, Molecular Neurology Unit, CeSI-Center for Excellence on Aging, University G. d'Annunzio, Chieti, Italy.

Overactivation of glutamate receptors and subsequent deregulation of the intraneuronal calcium ([Ca2+]i) levels are critical components of the injurious pathways initiated by cerebral ischemia. Another hallmark of stroke is parenchymal acidosis, and we have previously shown that mild acidosis can act as a switch to decrease NMDAR-dependent neuronal loss while potentiating the neuronal loss mediated by AMPARs. Potentiation of AMPAR-mediated neuronal death in an acidotic environment was originally associated only with [Ca2+]i dyshomeostasis, as assessed by Ca2+ imaging; however, intracellular dyshomeostasis of another divalent cation, Zn2+, has recently emerged as another important co-factor in ischemic neuronal injury. Rises in [Zn2+]i greatly contribute to the fluorescent changes of Ca2+-sensitive fluorescent probes, which also have great affinity for Zn2+. We therefore revisited our original findings (Mcdonald et al., 1998) and investigated if AMPAR-mediated fura-2 signals we observed could also be partially due to [Zn2+]i increases. Fura-2 loaded neuronal cultures were exposed to the AMPAR agonist, kainate, in a physiological buffer at pH 7.4 and then washed either at pH 7.4 or pH 6.2. A delayed recovery of fura-2 signals was observed at both pHs. Interestingly this impaired recovery phase was found to be sensitive to chelation of intracellular Zn2+. Experiments with the Zn2+ sensitive (and Ca2+-insensitive) fluorescent probe FluoZin-3 confirmed the idea that AMPAR activation increases [Zn2+]i, a phenomenon that is potentiated by mild acidosis. Additionally, our results show that selective Ca2+ imaging mandates the use of intracellular heavy metal chelators to avoid confounding effects of endogenous metals such as Zn2+.
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http://dx.doi.org/10.2119/2007–00047.FrazziniDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1952667PMC
October 2007
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