Publications by authors named "Francesco Fornai"

233 Publications

Protease Activated Receptor 1 and Its Ligands as Main Regulators of the Regeneration of Peripheral Nerves.

Biomolecules 2021 Nov 10;11(11). Epub 2021 Nov 10.

Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, Via A. Borelli 50, 00161 Rome, Italy.

In contrast with the brain and spinal cord, peripheral nerves possess a striking ability to regenerate after damage. This characteristic of the peripheral nervous system is mainly due to a specific population of glial cells, the Schwann cells. Schwann cells promptly activate after nerve injury, dedifferentiate assuming a repair phenotype, and assist axon regrowth. In general, tissue injury determines the release of a variety of proteases which, in parallel with the degradation of their specific targets, also activate plasma membrane receptors known as protease-activated receptors (PARs). PAR1, the prototypical member of the PAR family, is also known as thrombin receptor and is present at the Schwann cell plasma membrane. This receptor is emerging as a possible regulator of the pro-regenerative capacity of Schwann cells. Here, we summarize the most recent literature data describing the possible contribution of PAR1 and PAR1-activating proteases in regulating the regeneration of peripheral nerves.
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http://dx.doi.org/10.3390/biom11111668DOI Listing
November 2021

Locus Coeruleus magnetic resonance imaging in cognitively intact elderly subjects.

Brain Imaging Behav 2021 Nov 5. Epub 2021 Nov 5.

Neurology Unit, Pisa University Hospital, Pisa, Italy.

The locus coeruleus is the main noradrenergic nucleus of the brain and is often affected in neurodegenerative diseases. Recently, magnetic resonance imaging with specific T1-weighted sequences for neuromelanin has been used to evaluate locus coeruleus integrity in patients with these conditions. In some of these studies, abnormalities in locus coeruleus signal have also been found in healthy controls and related to ageing. However, this would be at variance with recent post-mortem studies showing that the nucleus is not affected during normal ageing. The present study aimed at evaluating locus coeruleus features in a well-defined cohort of cognitively healthy subjects who remained cognitively intact on a one-year follow-up. An ad-hoc semiautomatic analysis of locus coeruleus magnetic resonance was applied. Sixty-two cognitively intact subjects aged 60-80 years, without significant comorbidities, underwent 3 T magnetic resonance with specific sequences for locus coeruleus. A semi-automatic tool was used to estimate the number of voxels belonging to locus coeruleus and its intensity was obtained for each subject. Each subject underwent extensive neuropsychological testing at baseline and 12 months after magnetic resonance scan. Based on neuropsychological testing 53 subjects were cognitively normal at baseline and follow up. No significant age-related differences in locus coeruleus parameters were found in this cohort. In line with recent post-mortem studies, our in vivo study confirms that locus coeruleus magnetic resonance features are not statistically significantly affected by age between 60 and 80 years, the age range usually evaluated in studies on neurodegenerative diseases. A significant alteration of locus coeruleus features in a cognitively intact elderly subject might be an early sign of pathology.
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http://dx.doi.org/10.1007/s11682-021-00562-0DOI Listing
November 2021

Lactoferrin Protects against Methamphetamine Toxicity by Modulating Autophagy and Mitochondrial Status.

Nutrients 2021 Sep 25;13(10). Epub 2021 Sep 25.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Lactoferrin (LF) was used at first as a vehicle to deliver non-soluble active compounds to the body, including the central nervous system (CNS). Nonetheless, it soon became evident that, apart from acting as a vehicle, LF itself owns active effects in the CNS. In the present study, the effects of LF are assessed both in baseline conditions, as well as to counteract methamphetamine (METH)-induced neurodegeneration by assessing cell viability, cell phenotype, mitochondrial status, and specific autophagy steps. In detail, cell integrity in baseline conditions and following METH administration was carried out by using H&E staining, Trypan blue, Fluoro Jade B, and WST-1. Western blot and immuno-fluorescence were used to assess the expression of the neurofilament marker βIII-tubulin. Mitochondria were stained using Mito Tracker Red and Green and were further detailed and quantified by using transmission electron microscopy. Autophagy markers were analyzed through immuno-fluorescence and electron microscopy. LF counteracts METH-induced degeneration. In detail, LF significantly attenuates the amount of cell loss and mitochondrial alterations produced by METH; and mitigates the dissipation of autophagy-related proteins from the autophagy compartment, which is massively induced by METH. These findings indicate a protective role of LF in the molecular mechanisms of neurodegeneration.
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http://dx.doi.org/10.3390/nu13103356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8537867PMC
September 2021

Inhibition of Autophagy In Vivo Extends Methamphetamine Toxicity to Mesencephalic Cell Bodies.

Pharmaceuticals (Basel) 2021 Sep 29;14(10). Epub 2021 Sep 29.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Methamphetamine (METH) is a widely abused psychostimulant and a stress-inducing compound, which leads to neurotoxicity for nigrostriatal dopamine (DA) terminals in rodents and primates including humans. In vitro studies indicate that autophagy is a strong modulator of METH toxicity. In detail, suppressing autophagy increases METH toxicity, while stimulating autophagy prevents METH-induced toxicity in cell cultures. In the present study, the role of autophagy was investigated in vivo. In the whole brain, METH alone destroys meso-striatal DA axon terminals, while fairly sparing DA cell bodies within (SNpc). No damage to either cell bodies or axons from ventral tegmental area (VTA) is currently documented. According to the hypothesis that ongoing autophagy prevents METH-induced DA toxicity, we tested whether systemic injection of autophagy inhibitors such as asparagine (ASN, 1000 mg/Kg) or glutamine (GLN, 1000 mg/Kg), may extend METH toxicity to DA cell bodies, both within SNpc and VTA, where autophagy was found to be inhibited. When METH (5 mg/Kg × 4, 2 h apart) was administered to C57Bl/6 mice following ASN or GLN, a frank loss of cell bodies takes place within SNpc and a loss of both axons and cell bodies of VTA neurons is documented. These data indicate that, ongoing autophagy protects DA neurons and determines the refractoriness of cell bodies to METH-induced toxicity.
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http://dx.doi.org/10.3390/ph14101003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538796PMC
September 2021

The Autophagy-Related Organelle Autophagoproteasome Is Suppressed within Ischemic Penumbra.

Int J Mol Sci 2021 Sep 26;22(19). Epub 2021 Sep 26.

I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Italy.

The peri-infarct region, which surrounds the irreversible ischemic stroke area is named ischemic . This term emphasizes the borderline conditions for neurons placed within such a critical region. separates the ischemic core, where frank cell loss occurs, from the surrounding healthy brain tissue. Within such a brain region, nervous matter, and mostly neurons are impaired concerning metabolic conditions. The classic biochemical marker, which reliably marks is the over-expression of the heat shock protein 70 (HSP70). However, other proteins related to cell clearing pathways are modified within . Among these, autophagy proteins like LC3 increase in a way, which recapitulates Hsp70. In contrast, components, such as P20S, markedly decrease. Despite apparent discrepancies, the present study indicates remarkable overlapping between LC3 and P20S redistribution within . In fact, the amount of both proteins is markedly reduced within vacuoles. Specifically, a massive loss of LC3 + P20S immuno-positive vacuoles (autophagoproteasomes) is reported here. This represents the most relevant sub-cellular alteration here described in cell clearing pathways within . The functional significance of these findings remains to be determined and it will take a novel experimental stream to decipher the fine-tuning of such a phenomenon.
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http://dx.doi.org/10.3390/ijms221910364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508911PMC
September 2021

Perspective on mTOR-dependent Protection in Status Epilepticus.

Curr Neuropharmacol 2021 Oct 5. Epub 2021 Oct 5.

I.R.C.C.S. Neuromed, Pozzilli. Italy.

Background: The piriform cortex known as area tempestas owns a high propensity to trigger limbic epileptic seizures. Recent studies on human patients indicate that a resection containing the piriform cortex produces a marked improvement in patients suffering from intractable limbic seizures. This calls for looking back pharmacological and anatomical data on area tempestas. Within the piriform cortex status epilepticus can be induced by impairing desensitization of AMPA receptors. The mechanistic target of rapamycin complex1 (mTORC1) is a promising candidate.

Objective: The present perspective joins the novel role of the piriform cortex with recent evidence on the modulation of AMPA receptors under the influence of mTORC1. This is based on recent evidence and preliminary data, which lead to formulate an interaction between mTORC1 and AMPA receptors to mitigate the onset of long-lasting, self-sustaining, neurotoxic status epilepticus.

Methods: The perspective grounds its method on recent literature along with the actual experimental procedure to elicit status epilepticus from the piriform cortex and the method to administer the mTORC1 inhibitor rapamycin to mitigate seizure expression and brain damage.

Results: The available and present perspective converge to show that rapamycin may disrupt the seizure circuitry initiated in the piriform cortex to mitigate seizure duration, severity, and brain damage.

Conclusions: The perspective offered by this manuscript provides a novel scenario to understand refractory epilepsy and self-sustaining status epilepticus. This is expected to provide a beneficial outcome in patients suffering from temporal lobe epilepsy.

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http://dx.doi.org/10.2174/1570159X19666211005152618DOI Listing
October 2021

The Baseline Structure of the Enteric Nervous System and Its Role in Parkinson's Disease.

Life (Basel) 2021 Jul 22;11(8). Epub 2021 Jul 22.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy.

The gastrointestinal (GI) tract is provided with a peculiar nervous network, known as the enteric nervous system (ENS), which is dedicated to the fine control of digestive functions. This forms a complex network, which includes several types of neurons, as well as glial cells. Despite extensive studies, a comprehensive classification of these neurons is still lacking. The complexity of ENS is magnified by a multiple control of the central nervous system, and bidirectional communication between various central nervous areas and the gut occurs. This lends substance to the complexity of the microbiota-gut-brain axis, which represents the network governing homeostasis through nervous, endocrine, immune, and metabolic pathways. The present manuscript is dedicated to identifying various neuronal cytotypes belonging to ENS in baseline conditions. The second part of the study provides evidence on how these very same neurons are altered during Parkinson's disease. In fact, although being defined as a movement disorder, Parkinson's disease features a number of degenerative alterations, which often anticipate motor symptoms. Among these, the GI tract is often involved, and for this reason, it is important to assess its normal and pathological structure. A deeper knowledge of the ENS is expected to improve the understanding of diagnosis and treatment of Parkinson's disease.
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http://dx.doi.org/10.3390/life11080732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400095PMC
July 2021

Cohort Analysis of 67 Charcot-Marie-Tooth Italian Patients: Identification of New Mutations and Broadening of Phenotype Expression Produced by Rare Variants.

Front Genet 2021 19;12:682050. Epub 2021 Jul 19.

IRCCS Neuromed, Pozzilli, Italy.

Charcot-Marie-Tooth (CMT) disease is the most prevalent inherited motor sensory neuropathy, which clusters a clinically and genetically heterogeneous group of disorders with more than 90 genes associated with different phenotypes. The goal of this study is to identify the genetic features in the recruited cohort of patients, highlighting the role of rare variants in the genotype-phenotype correlation. We enrolled 67 patients and applied a diagnostic protocol including multiple ligation-dependent probe amplification for copy number variation (CNV) detection of locus, and next-generation sequencing (NGS) for sequencing of 47 genes known to be associated with CMT and routinely screened in medical genetics. This approach allowed the identification of 26 patients carrying a whole gene CNV of . In the remaining 41 patients, NGS identified the causative variants in eight patients in the genes , , , , , , , and (five new vs. three previously reported variants; three sporadic vs. five familial variants). Familial segregation analysis allowed to correctly interpret two variants, initially reported as "variants of uncertain significance" but re-classified as pathological. In this cohort is reported a patient carrying a novel familial mutation in the tail domain of [a protein domain previously associated with familial amyotrophic lateral sclerosis (ALS)], and a CMT patient carrying a mutation, previously reported in ALS. These data indicate that combined tools for gene association in medical genetics allow dissecting unexpected phenotypes associated with previously known or unknown genotypes, thus broadening the phenotype expression produced by either pathogenic or undefined variants. : ClinicalTrials.gov (NCT03084224).
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http://dx.doi.org/10.3389/fgene.2021.682050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329958PMC
July 2021

Prolonged and short epileptiform discharges have an opposite relationship with the sleep-wake cycle in patients with JME: Implications for EEG recording protocols.

Epilepsy Behav 2021 09 2;122:108226. Epub 2021 Aug 2.

Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Italy; Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy.

In a recent study, we found that during 20.55 ± 1.60 h of artifact-free ambulatory EEG recordings, epileptiform discharges (EDs) longer than 2.68 s occurred exclusively in patients with Juvenile Myoclonic Epilepsy (JME) who experienced seizure recurrence within a year after the EEG. Here we expanded this analysis, exploring whether long EDs (>2.68 s), and short ones, were uniformly distributed during the day. Lastly, we evaluated the temporal distribution of seizure relapses. By Friedman test, we demonstrated that hourly frequencies of both short and long EDs were dependent on the hours of day and sleep-wake cycle factors, with an opposite trend. Short EDs were found mostly during the night (with two peaks at 1 AM and 6 AM), and sleep, dropping at the wake onset (p < 0.001). Conversely, long EDs surged at the wake onset (0.001), remaining frequent during the whole wake period, when compared to sleep (p = 0.002). Of note, this latter pattern mirrored that of seizures, which occurred exclusively during the wake period, and in 9 out of 13 cases at the wake onset. We therefore suggested that short and long EDs could reflect distinct pathophysiological phenomena. Extended wake EEG recordings, possibly including the awakening, could be extremely useful in clinical practice, as well as in further studies, with the ambitious goal of predicting seizure recurrences.
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http://dx.doi.org/10.1016/j.yebeh.2021.108226DOI Listing
September 2021

Norepinephrine Protects against Methamphetamine Toxicity through β2-Adrenergic Receptors Promoting LC3 Compartmentalization.

Int J Mol Sci 2021 Jul 5;22(13). Epub 2021 Jul 5.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Norepinephrine (NE) neurons and extracellular NE exert some protective effects against a variety of insults, including methamphetamine (Meth)-induced cell damage. The intimate mechanism of protection remains difficult to be analyzed in vivo. In fact, this may occur directly on target neurons or as the indirect consequence of NE-induced alterations in the activity of trans-synaptic loops. Therefore, to elude neuronal networks, which may contribute to these effects in vivo, the present study investigates whether NE still protects when directly applied to Meth-treated PC12 cells. Meth was selected based on its detrimental effects along various specific brain areas. The study shows that NE directly protects in vitro against Meth-induced cell damage. The present study indicates that such an effect fully depends on the activation of plasma membrane β2-adrenergic receptors (ARs). Evidence indicates that β2-ARs activation restores autophagy, which is impaired by Meth administration. This occurs via restoration of the autophagy flux and, as assessed by ultrastructural morphometry, by preventing the dissipation of microtubule-associated protein 1 light chain 3 (LC3) from autophagy vacuoles to the cytosol, which is produced instead during Meth toxicity. These findings may have an impact in a variety of degenerative conditions characterized by NE deficiency along with autophagy impairment.
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http://dx.doi.org/10.3390/ijms22137232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8269332PMC
July 2021

Translational evidence for lithium-induced brain plasticity and neuroprotection in the treatment of neuropsychiatric disorders.

Transl Psychiatry 2021 07 5;11(1):366. Epub 2021 Jul 5.

IRCCS Neuromed, Via Atinense 18, 86077, Pozzilli (IS), Italy.

Increasing evidence indicates lithium (Li) efficacy in neuropsychiatry, pointing to overlapping mechanisms that occur within distinct neuronal populations. In fact, the same pathway depending on which circuitry operates may fall in the psychiatric and/or neurological domains. Li restores both neurotransmission and brain structure unveiling that psychiatric and neurological disorders share common dysfunctional molecular and morphological mechanisms, which may involve distinct brain circuitries. Here an overview is provided concerning the therapeutic/neuroprotective effects of Li in different neuropsychiatric disorders to highlight common molecular mechanisms through which Li produces its mood-stabilizing effects and to what extent these overlap with plasticity in distinct brain circuitries. Li mood-stabilizing effects are evident in typical bipolar disorder (BD) characterized by a cyclic course of mania or hypomania followed by depressive episodes, while its efficacy is weaker in the opposite pattern. We focus here on neural adaptations that may underlie psychostimulant-induced psychotic development and to dissect, through the sensitization process, which features are shared in BD and other psychiatric disorders, including schizophrenia. The multiple functions of Li highlighted here prove its exceptional pharmacology, which may help to elucidate its mechanisms of action. These may serve as a guide toward a multi-drug strategy. We propose that the onset of sensitization in a specific BD subtype may predict the therapeutic efficacy of Li. This model may help to infer in BD which molecular mechanisms are relevant to the therapeutic efficacy of Li.
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http://dx.doi.org/10.1038/s41398-021-01492-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257731PMC
July 2021

Behavioural and biochemical responses to methamphetamine are differentially regulated by mGlu2 and mGlu3 metabotropic glutamate receptors in male mice.

Neuropharmacology 2021 09 1;196:108692. Epub 2021 Jul 1.

IRCCS Neuromed, Pozzilli, Italy; Department of Physiology and Pharmacology, University Sapienza, Roma, Italy. Electronic address:

Group II metabotropic glutamate receptors (mGlu2 and mGlu3 receptors) shape mechanisms of methamphetamine addiction, but the individual role played by the two subtypes is unclear. We measured methamphetamine-induced conditioned place preference (CPP) and motor responses to single or repeated injections of methamphetamine in wild-type, mGlu2, and mGlu3mice. Only mGlu3mice showed methamphetamine preference in the CPP test. Motor response to the first methamphetamine injection was dramatically reduced in mGlu2mice, unless these mice were treated with the mGlu5 receptor antagonist, MTEP. In contrast, methamphetamine-induced sensitization was increased in mGlu3mice compared to wild-type mice. Only mGlu3mice sensitized to methamphetamine showed increases in phospho-ERK1/2 levels in the nucleus accumbens (NAc) and free radical formation in the NAc and medial prefrontal cortex. These changes were not detected in mGlu2mice. We also measured a series of biochemical parameters related to the mechanism of action of methamphetamine in naïve mice to disclose the nature of the differential behavioural responses of the three genotypes. We found a reduced expression and activity of dopamine transporter (DAT) and vesicular monoamine transporter-2 in the NAc and striatum of mGlu2and mGlu3mice, whereas expression of the DAT adaptor, syntaxin 1A, was selectively increased in the striatum of mGlu3mice. Methamphetamine-stimulated dopamine release in striatal slices was largely reduced in mGlu2, but not in mGlu3, mice. These findings suggest that drugs that selectively enhance mGlu3 receptor activity or negatively modulate mGlu2 receptors might be beneficial in the treatment of methamphetamine addiction and associated brain damage.
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http://dx.doi.org/10.1016/j.neuropharm.2021.108692DOI Listing
September 2021

Stoichiometric Analysis of Shifting in Subcellular Compartmentalization of HSP70 within Ischemic Penumbra.

Molecules 2021 Jun 11;26(12). Epub 2021 Jun 11.

I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, IS, Italy.

The heat shock protein (HSP) 70 is considered the main hallmark in preclinical studies to stain the peri-infarct region defined area penumbra in preclinical models of brain ischemia. This protein is also considered as a potential disease modifier, which may improve the outcome of ischemic damage. In fact, the molecule HSP70 acts as a chaperonine being able to impact at several level the homeostasis of neurons. Despite being used routinely to stain area penumbra in light microscopy, the subcellular placement of this protein within area penumbra neurons, to our knowledge, remains undefined. This is key mostly when considering studies aimed at deciphering the functional role of this protein as a determinant of neuronal survival. The general subcellular placement of HSP70 was grossly reported in studies using confocal microscopy, although no direct visualization of this molecule at electron microscopy was carried out. The present study aims to provide a direct evidence of HSP70 within various subcellular compartments. In detail, by using ultrastructural morphometry to quantify HSP70 stoichiometrically detected by immuno-gold within specific organelles we could compare the compartmentalization of the molecule within area penumbra compared with control brain areas. The study indicates that two cell compartments in control conditions own a high density of HSP70, cytosolic vacuoles and mitochondria. In these organelles, HSP70 is present in amount exceeding several-fold the presence in the cytosol. Remarkably, within area penumbra a loss of such a specific polarization is documented. This leads to the depletion of HSP70 from mitochondria and mostly cell vacuoles. Such an effect is expected to lead to significant variations in the ability of HSP70 to exert its physiological roles. The present findings, beyond defining the neuronal compartmentalization of HSP70 within area penumbra may lead to a better comprehension of its beneficial/detrimental role in promoting neuronal survival.
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http://dx.doi.org/10.3390/molecules26123578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230775PMC
June 2021

Autophagy as a gateway for the effects of methamphetamine: From neurotransmitter release and synaptic plasticity to psychiatric and neurodegenerative disorders.

Prog Neurobiol 2021 09 23;204:102112. Epub 2021 Jun 23.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma, 55, 56126, Pisa, PI, Italy; IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli, IS, Italy. Electronic address:

As a major eukaryotic cell clearing machinery, autophagy grants cell proteostasis, which is key for neurotransmitter release, synaptic plasticity, and neuronal survival. In line with this, besides neuropathological events, autophagy dysfunctions are bound to synaptic alterations that occur in mental disorders, and early on, in neurodegenerative diseases. This is also the case of methamphetamine (METH) abuse, which leads to psychiatric disturbances and neurotoxicity. While consistently altering the autophagy machinery, METH produces behavioral and neurotoxic effects through molecular and biochemical events that can be recapitulated by autophagy blockade. These consist of altered physiological dopamine (DA) release, abnormal stimulation of DA and glutamate receptors, as well as oxidative, excitotoxic, and neuroinflammatory events. Recent molecular insights suggest that METH early impairs the autophagy machinery, though its functional significance remains to be investigated. Here we discuss evidence suggesting that alterations of DA transmission and autophagy are intermingled within a chain of events underlying behavioral alterations and neurodegenerative phenomena produced by METH. Understanding how METH alters the autophagy machinery is expected to provide novel insights into the neurobiology of METH addiction sharing some features with psychiatric disorders and parkinsonism.
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http://dx.doi.org/10.1016/j.pneurobio.2021.102112DOI Listing
September 2021

The Italian law on body donation: A position paper of the Italian College of Anatomists.

Ann Anat 2021 Nov 15;238:151761. Epub 2021 Jun 15.

Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.

In Italy, recent legislation (Law No. 10/2020) has tuned regulations concerning the donation of one's postmortem body and tissues for study, training, and scientific research purposes. This study discusses several specific issues to optimise the applicability and effectiveness of such an important, novel regulatory setting. Critical issues arise concerning the learners, the type of training and teaching activities that can be planned, the position of academic anatomy institutes, the role of family members in the donation process, the time frame of the donation process, the eligibility of partial donation, or the simultaneous donation of organs and tissues to patients awaiting transplantation. In particular, a universal time limit for donations (i.e., one year) makes it impossible to plan the long-term use of specific body parts, which could be effectively preserved for the advanced teaching and training of medical students and surgeons. The abovementioned conditions lead to the limited use of corpses, thus resulting in the inefficiency of the whole system of body donation. Overall, the donors' scope for the donation of their body could be best honoured by a more flexible and tuneable approach that can be used on a case-by-case basis. Furthermore, it is deemed necessary to closely monitor the events scheduled for corpses in public nonacademic institutions or private enterprises. This paper presents useful insights from Italian anatomists with the hope of providing inspiration for drafting the regulations. In conclusion, this paper focuses on the critical issues derived from the recently introduced Italian law on the donation and use of the body after death and provides suggestions to lawmakers for future implementations.
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http://dx.doi.org/10.1016/j.aanat.2021.151761DOI Listing
November 2021

An attempt to dissect a peripheral marker based on cell pathology in Parkinson's disease.

J Neural Transm (Vienna) 2021 10 9;128(10):1599-1610. Epub 2021 Jun 9.

I.R.C.C.S Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy.

Peripheral markers in Parkinson's disease (PD) represent a hot issue to provide early diagnosis and assess disease progression. The gold standard marker of PD should feature the same reliability as the pathogenic alteration, which produces the disease itself. PD is foremost a movement disorder produced by a loss of nigrostriatal dopamine innervation, in which striatal dopamine terminals are always markedly reduced in PD patients to an extent, which never overlaps with controls. Similarly, a reliable marker of PD should possess such a non-overlapping feature when compared with controls. In the present study, we provide a novel pathological hallmark, the autophagosome, which in each PD patient was always suppressed compared with each control subject. Autophagosomes were counted as microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive vacuoles at ultrastructural morphometry within peripheral (blood) blood mononuclear cells (PBMC). This also provides the gold standard to assess the autophagy status. Since autophagy may play a role in the pathogenesis of PD, autophagosomes may be a disease marker, while participating in the biology of the disease. Stoichiometric measurement of α-synuclein despite significantly increased in PD patients, overlapped between PD and control patients. Although the study need to be validated in large populations, the number of autophagy vacuoles is neither related with therapy (the amount was similarly suppressed in a few de novo patients), nor the age in PD or controls.
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http://dx.doi.org/10.1007/s00702-021-02364-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528800PMC
October 2021

A Large Family with p.Arg554His Mutation in : Clinical Features and Genotype/Phenotype Correlation in Female Carriers.

Genes (Basel) 2021 05 19;12(5). Epub 2021 May 19.

IRCCS Neuromed, 86077 Pozzilli, Italy.

X-linked adrenoleukodystrophy (X-ALD, OMIM #300100) is the most common peroxisomal disorder clinically characterized by two main phenotypes: adrenomyeloneuropathy (AMN) and the cerebral demyelinating form of X-ALD (cerebral ALD). The disease is caused by defects in the gene for the adenosine triphosphate (ATP)-binding cassette protein, subfamily D () that encodes the peroxisomal transporter of very-long-chain fatty acids (VLCFAs). The defective function of protein prevents β-oxidation of VLCFAs, which thus accumulate in tissues and plasma, to represent the hallmark of the disease. As in many X-linked diseases, it has been routinely expected that female carriers are asymptomatic. Nonetheless, recent findings indicate that most female carriers become symptomatic, with a motor disability that typically appears between the fourth and fifth decade. In this paper, we report a large family in which affected males died during the first decade, while affected females develop, during the fourth decade, progressive lower limb weakness with spastic or ataxic-spastic gait, tetra-hyperreflexia with sensory alterations. Clinical and genetic evaluations were performed in nine subjects, eight females (five affected and three healthy) and one healthy male. All affected females were carriers of the c.1661G>A (p.Arg554His, rs201568579) mutation. This study strengthens the relevance of clinical symptoms in female carriers of mutations, which leads to a better understanding of the role of the genetic background and the genotype-phenotype correlation. This indicates the relevance to include genes in genetic panels for gait disturbance in women.
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http://dx.doi.org/10.3390/genes12050775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160645PMC
May 2021

Rapamycin Ameliorates Defects in Mitochondrial Fission and Mitophagy in Glioblastoma Cells.

Int J Mol Sci 2021 May 20;22(10). Epub 2021 May 20.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Glioblastoma (GBM) cells feature mitochondrial alterations, which are documented and quantified in the present study, by using ultrastructural morphometry. Mitochondrial impairment, which roughly occurs in half of the organelles, is shown to be related to mTOR overexpression and autophagy suppression. The novelty of the present study consists of detailing an mTOR-dependent mitophagy occlusion, along with suppression of mitochondrial fission. These phenomena contribute to explain the increase in altered mitochondria reported here. Administration of the mTOR inhibitor rapamycin rescues mitochondrial alterations. In detail, rapamycin induces the expression of genes promoting mitophagy (, , , ) and mitochondrial fission (, ). This occurs along with over-expression of , an early gene placed upstream in the autophagy pathway. The topographic stoichiometry of proteins coded by these genes within mitochondria indicates that, a remarkable polarization of proteins involved in fission and mitophagy within mitochondria including LC3 takes place. Co-localization of these proteins within mitochondria, persists for weeks following rapamycin, which produces long-lasting mitochondrial plasticity. Thus, rapamycin restores mitochondrial status in GBM cells. These findings add novel evidence about mitochondria and GBM, while fostering a novel therapeutic approach to restore healthy mitochondria through mTOR inhibition.
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http://dx.doi.org/10.3390/ijms22105379DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161366PMC
May 2021

Morphology, clearing efficacy, and mTOR dependency of the organelle autophagoproteasome.

Eur J Histochem 2021 Jun 1;65(s1). Epub 2021 Jun 1.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa; IRCCS Neuromed, Pozzilli (IS).

The interplay between autophagy (ATG) and ubiquitin proteasome (UP) cell-clearing systems was recently evidenced at biochemical and morphological levels, where subunits belonging to both pathways co-localize within a novel organelle named autophagoproteasome (APP). We previously documented that APP occurs at baseline conditions, while it is hindered by neurotoxicant administration. This is bound to the activity of the mechanistic target of rapamycin (mTOR), since APP is stimulated by mTOR inhibition, which in turn, is correlated with cell protection. In this brief report, we provide novel, morphological and biochemical evidence on APP, suggesting the presence of active UP subunits within ATG vacuoles. Although a stream of interpretation considers such a merging as a catabolic pathway to clear inactive UP subunits, our data further indicate that UP-ATG merging may rather provide an empowered catalytic organelle.
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http://dx.doi.org/10.4081/ejh.2021.3220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200839PMC
June 2021

Ultrastructural characterization of peripheral denervation in a mouse model of Type III spinal muscular atrophy.

J Neural Transm (Vienna) 2021 06 17;128(6):771-791. Epub 2021 May 17.

I.R.C.C.S. Neuromed, Via Atinense 18, 86077, Pozzilli, IS, Italy.

Spinal muscular atrophy (SMA) is a heritable, autosomal recessive neuromuscular disorder characterized by a loss of the survival of motor neurons (SMN) protein, which leads to degeneration of lower motor neurons, and muscle atrophy. Despite SMA being nosographically classified as a motor neuron disease, recent advances indicate that peripheral alterations at the level of the neuromuscular junction (NMJ), involving the muscle, and axons of the sensory-motor system, occur early, and may even precede motor neuron loss. In the present study, we used a mouse model of slow progressive (type III) SMA, whereby the absence of the mouse SMN protein is compensated by the expression of two human genes (heterozygous SMN1A2G, and SMN2). This leads to late disease onset and prolonged survival, which allows for dissecting slow degenerative steps operating early in SMA pathogenesis. In this purely morphological study carried out at transmission electron microscopy, we extend the examination of motor neurons and proximal axons towards peripheral components, including distal axons, muscle fibers, and also muscle spindles. We document remarkable ultrastructural alterations being consistent with early peripheral denervation in SMA, which may shift the ultimate anatomical target in neuromuscular disease from the spinal cord towards the muscle. This concerns mostly mitochondrial alterations within distal axons and muscle, which are quantified here through ultrastructural morphometry. The present study is expected to provide a deeper knowledge of early pathogenic mechanisms in SMA.
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http://dx.doi.org/10.1007/s00702-021-02353-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205903PMC
June 2021

The connections of Locus Coeruleus with hypothalamus: potential involvement in Alzheimer's disease.

J Neural Transm (Vienna) 2021 05 3;128(5):589-613. Epub 2021 May 3.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126, Pisa, Italy.

The hypothalamus and Locus Coeruleus (LC) share a variety of functions, as both of them take part in the regulation of the sleep/wake cycle and in the modulation of autonomic and homeostatic activities. Such a functional interplay takes place due to the dense and complex anatomical connections linking the two brain structures. In Alzheimer's disease (AD), the occurrence of endocrine, autonomic and sleep disturbances have been associated with the disruption of the hypothalamic network; at the same time, in this disease, the occurrence of LC degeneration is receiving growing attention for the potential roles it may have both from a pathophysiological and pathogenetic point of view. In this review, we summarize the current knowledge on the anatomical and functional connections between the LC and hypothalamus, to better understand whether the impairment of the former may be responsible for the pathological involvement of the latter, and whether the disruption of their interplay may concur to the pathophysiology of AD. Although only a few papers specifically explored this topic, intriguingly, some pre-clinical and post-mortem human studies showed that aberrant protein spreading and neuroinflammation may cause hypothalamus degeneration and that these pathological features may be linked to LC impairment. Moreover, experimental studies in rodents showed that LC plays a relevant role in modulating the hypothalamic sleep/wake cycle regulation or neuroendocrine and systemic hormones; in line with this, the degeneration of LC itself may partly explain the occurrence of hypothalamic-related symptoms in AD.
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http://dx.doi.org/10.1007/s00702-021-02338-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8105225PMC
May 2021

Neuroprotective Effects of Curcumin in Methamphetamine-Induced Toxicity.

Molecules 2021 Apr 24;26(9). Epub 2021 Apr 24.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Curcumin (CUR), a natural polyphenol extracted from rhizome of the , has received great attention for its multiple potential health benefits as well as disease prevention. For instance, CUR protects against toxic agents acting on the human body, including the nervous system. In detail, CUR possesses, among others, strong effects as an autophagy activator. The present study indicates that CUR counteracts methamphetamine (METH) toxicity. Such a drug of abuse is toxic by disturbing the autophagy machinery. We profited from an unbiased, low variable cell context by using rat pheochromocytoma PC12 cell line. In such a system, a strong protection was exerted by CUR against METH toxicity. This was associated with increased autophagy flux, merging of autophagosomes with lysosomes and replenishment of autophagy vacuoles with LC3, which instead is moved out from the vacuoles by METH. This is expected to enable the autophagy machinery. In fact, while in METH-treated cells the autophagy substrates α-synuclein accumulates in the cytosol, CUR speeds up α-synuclein clearance. Under the effects of CUR LC3 penetrate in autophagy vacuoles to commit them to cell clearance and promotes the autophagy flux. The present data provide evidence that CUR counteracts the neurotoxic effects induced by METH by promoting autophagy.
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http://dx.doi.org/10.3390/molecules26092493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8123176PMC
April 2021

Uncoupling Protein 2 as a pathogenic determinant and therapeutic target in cardiovascular and metabolic diseases.

Curr Neuropharmacol 2021 Apr 20. Epub 2021 Apr 20.

IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Is, Italy.

Uncoupling protein 2 (UCP2) is a mitochondrial protein that acts as an anion carrier. It is involved in the regulation of several processes including mitochondrial membrane potential, generation of reactive oxygen species within the inner mitochondrial membrane and calcium homeostasis. UCP2 expression can be regulated at different levels: genetic (gene variants), transcriptional [by peroxisome proliferator-activated receptors (PPARs) and microRNAs], and post-translational. Experimental evidence indicates that activation of UCP2 expression through the AMPK/PPAR-α axis exerts a protective effect toward renal damage and stroke occurrence in an animal model of ischemic stroke (IS) associated with hypertension. UCP2 plays a key role in heart diseases (myocardial infarction and cardiac hypertrophy) and metabolic disorders (obesity and diabetes). In humans, UCP2 genetic variants (-866G/A and Ala55Val) associate with an increased risk of type 2 diabetes mellitus and of IS development. Over the last few years, many agents that modulate UCP2 expression have been identified. Some of them are natural compounds of plant origin such as Brassica oleracea, curcumin, berberine and resveratrol. Other molecules, currently used in clinical practice, include anti-diabetic (gliptin) and chemotherapeutic (doxorubicin and taxol) drugs. This evidence highlights the relevant role of UCP2 for the treatment of a wide range of diseases, which affect the national health systems of the Western countries. We will review current knowledge on the physiological and pathological implications of UCP2 with particular regard to cardiovascular and metabolic disorders and will focus on the available therapeutic approaches affecting UCP2 level for the treatment of human diseases.
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http://dx.doi.org/10.2174/1570159X19666210421094204DOI Listing
April 2021

Prolonged epileptic discharges predict seizure recurrence in JME: Insights from prolonged ambulatory EEG.

Epilepsia 2021 05 18;62(5):1184-1192. Epub 2021 Mar 18.

Department of Clinical and Experimental Medicine, Neurological Clinic, University of Pisa, Pisa, Italy.

Objective: Markers of seizure recurrence are needed to personalize antiseizure medication (ASM) therapy. In the clinical practice, EEG features are considered to be related to the risk of seizure recurrence for genetic generalized epilepsies (GGE). However, to our knowledge, there are no studies analyzing systematically specific EEG features as indices of ASM efficacy in GGE. In this study, we aimed at identifying EEG indicators of ASM responsiveness in Juvenile Myoclonic Epilepsy (JME), which, among GGE, is characterized by specific electroclinical features.

Methods: We compared the features of prolonged ambulatory EEG (paEEG, 22 h of recording) of JME patients experiencing seizure recurrence within a year ("cases") after EEG recording, with those of patients with sustained seizure freedom for at least 1 year after EEG ("controls"). We included only EEG recordings of patients who had maintained the same ASM regimen (dosage and type) throughout the whole time period from the EEG recording up to the outcome events (which was seizure recurrence for the "cases", or 1-year seizure freedom for "controls"). As predictors, we evaluated the total number, frequency, mean and maximum duration of epileptiform discharges (EDs) and spike density (i.e. total EDs duration/artifact-free EEG duration) recorded during the paEEG. The same indexes were assessed also in standard EEG (stEEG), including activation methods.

Results: Both the maximum length and the mean duration of EDs recorded during paEEG significantly differed between cases and controls; when combined in a binary logistic regression model, the maximum length of EDs emerged as the only valid predictor. A cut-off of EDs duration of 2.68 seconds discriminated between cases and controls with a 100% specificity and a 93% sensitivity. The same indexes collected during stEEG lacked both specificity and sensitivity.

Significance: The occurrence of prolonged EDs in EEG recording might represent an indicator of antiepileptic drug failure in JME patients.
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http://dx.doi.org/10.1111/epi.16875DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251928PMC
May 2021

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition).

Autophagy 2021 Jan 8;17(1):1-382. Epub 2021 Feb 8.

University of Crete, School of Medicine, Laboratory of Clinical Microbiology and Microbial Pathogenesis, Voutes, Heraklion, Crete, Greece; Foundation for Research and Technology, Institute of Molecular Biology and Biotechnology (IMBB), Heraklion, Crete, Greece.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.
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http://dx.doi.org/10.1080/15548627.2020.1797280DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996087PMC
January 2021

Glymphatic System as a Gateway to Connect Neurodegeneration From Periphery to CNS.

Front Neurosci 2021 9;15:639140. Epub 2021 Feb 9.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy.

The classic concept of the absence of lymphatic vessels in the central nervous system (CNS), suggesting the immune privilege of the brain in spite of its high metabolic rate, was predominant until recent times. On the other hand, this idea left questioned how cerebral interstitial fluid is cleared of waste products. It was generally thought that clearance depends on cerebrospinal fluid (CSF). Not long ago, an anatomically and functionally discrete paravascular space was revised to provide a pathway for the clearance of molecules drained within the interstitial space. According to this model, CSF enters the brain parenchyma along arterial paravascular spaces. Once mixed with interstitial fluid and solutes in a process mediated by aquaporin-4, CSF exits through the extracellular space along venous paravascular spaces, thus being removed from the brain. This process includes the participation of perivascular glial cells due to a sieving effect of their end-feet. Such draining space resembles the peripheral lymphatic system, therefore, the term "glymphatic" (glial-lymphatic) pathway has been coined. Specific studies focused on the potential role of the glymphatic pathway in healthy and pathological conditions, including neurodegenerative diseases. This mainly concerns Alzheimer's disease (AD), as well as hemorrhagic and ischemic neurovascular disorders; other acute degenerative processes, such as normal pressure hydrocephalus or traumatic brain injury are involved as well. Novel morphological and functional investigations also suggested alternative models to drain molecules through perivascular pathways, which enriched our insight of homeostatic processes within neural microenvironment. Under the light of these considerations, the present article aims to discuss recent findings and concepts on nervous lymphatic drainage and blood-brain barrier (BBB) in an attempt to understand how peripheral pathological conditions may be detrimental to the CNS, paving the way to neurodegeneration.
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http://dx.doi.org/10.3389/fnins.2021.639140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7900543PMC
February 2021

Autophagy status as a gateway for stress-induced catecholamine interplay in neurodegeneration.

Neurosci Biobehav Rev 2021 04 23;123:238-256. Epub 2021 Jan 23.

IRCCS Neuromed, Via Atinense 18, Pozzilli, IS, Italy. Electronic address:

The catecholamine-containing brainstem nuclei locus coeruleus (LC) and ventral tegmental area (VTA) are critically involved in stress responses. Alterations of catecholamine systems during chronic stress may contribute to neurodegeneration, including cognitive decline. Stress-related catecholamine alterations, while contributing to anxiety and depression, might accelerate neuronal degeneration by increasing the formation of toxic dopamine and norepinephrine by-products. These, in turn, may impair proteostasis within a variety of cortical and subcortical areas. In particular, the molecular events governing neurotransmission, neuroplasticity, and proteostasis within LC and VTA affect a variety of brain areas. Therefore, we focus on alterations of autophagy machinery in these nuclei as a relevant trigger in this chain of events. In fact, these catecholamine-containing areas are mostly prone to autophagy-dependent neurodegeneration. Thus, we propose a dynamic hypothesis according to which stress-induced autophagy alterations within the LC-VTA network foster a cascade towards early neurodegeneration within these nuclei.
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http://dx.doi.org/10.1016/j.neubiorev.2021.01.015DOI Listing
April 2021

Response to levetiracetam or lamotrigine in subjects with Juvenile Myoclonic Epilepsy previously treated with valproic acid: A single center retrospective study.

Epilepsy Behav 2021 02 8;115:107706. Epub 2021 Jan 8.

Neurology Unit of Pisa University Hospital, University of Pisa, Pisa, Italy; Department of Translational Research and of New Surgical and Medical Technologies, University of Pisa, Pisa, Italy. Electronic address:

Background: Valproic acid (VPA) is the most effective medication in juvenile myoclonic epilepsy (JME) but, due to its teratogenic potential, levetiracetam (LEV) and lamotrigine (LTG) are preferred in women of childbearing age. The aim of this study was to compare the effectiveness and tolerability of LEV and LTG monotherapy in patients with a previous good seizure control in VPA monotherapy, in which VPA was withdrawn because of teratogenic potential or adverse drug effects.

Methods: We retrospectively analyzed 65 patients with JME which had been followedup at the Epilepsy Center of Pisa University Hospital, identifying 28 subjects who had been successfully treated with VPA monotherapy and who were shifted to another monotherapy. The second monotherapy was LEV for 14 subjects and LTG for the remaining 14 ones. Drug efficacy was measured in terms of seizure freedom for more than twelve months after reaching the minimum effective or the highest tolerated dose.

Results: In terms of seizure control, our analysis showed a significantly better outcome for LEV compared to LTG (14.3% and 71.4% of seizure relapse, respectively, p = 0.006) monotherapy. Such a higher efficacy was confirmed in those subjects with seizure relapse on LTG, who achieved good seizure control after switching to LEV monotherapy (89% of cases). Concerning tolerability, none of the patients reported severe side effects.

Conclusion: Although obtained in a small case series, our analysis showed a significant better efficacy of LEV compared to LTG in monotherapy, in patients with JME with a good response to VPA, concerning both myoclonic and generalized tonic-clonic seizures.
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http://dx.doi.org/10.1016/j.yebeh.2020.107706DOI Listing
February 2021

The Role of Cellular Prion Protein in Promoting Stemness and Differentiation in Cancer.

Cancers (Basel) 2021 Jan 6;13(2). Epub 2021 Jan 6.

Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Via Roma 55, 56126 Pisa, Italy.

Cellular prion protein (PrP) is seminal to modulate a variety of baseline cell functions to grant homeostasis. The classic role of such a protein was defined as a chaperone-like molecule being able to rescue cell survival. Nonetheless, PrP also represents the precursor of the deleterious misfolded variant known as scrapie prion protein (PrP). This variant is detrimental in a variety of prion disorders. This multi-faceted role of PrP is greatly increased by recent findings showing how PrP in its folded conformation may foster tumor progression by acting at multiple levels. The present review focuses on such a cancer-promoting effect. The manuscript analyzes recent findings on the occurrence of PrP in various cancers and discusses the multiple effects, which sustain cancer progression. Within this frame, the effects of PrP on stemness and differentiation are discussed. A special emphasis is provided on the spreading of PrP and the epigenetic effects, which are induced in neighboring cells to activate cancer-related genes. These detrimental effects are further discussed in relation to the aberrancy of its physiological and beneficial role on cell homeostasis. A specific paragraph is dedicated to the role of PrP beyond its effects in the biology of cancer to represent a potential biomarker in the follow up of patients following surgical resection.
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http://dx.doi.org/10.3390/cancers13020170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7825291PMC
January 2021

Locus Coeruleus Magnetic Resonance Imaging in Neurological Diseases.

Curr Neurol Neurosci Rep 2020 12 12;21(1). Epub 2020 Dec 12.

Neurology Unit, Pisa University Hospital, Pisa, Italy.

Purpose Of Review: Locus coeruleus (LC) is the main noradrenergic nucleus of the brain, and its degeneration is considered to be key in the pathogenesis of neurodegenerative diseases. In the last 15 years,MRI has been used to assess LC in vivo, both in healthy subjects and in patients suffering from neurological disorders. In this review, we summarize the main findings of LC-MRI studies, interpreting them in light of preclinical and histopathological data, and discussing its potential role as diagnostic and experimental tool.

Recent Findings: LC-MRI findings were largely in agreement with neuropathological evidences; LC signal showed to be not significantly affected during normal aging and to correlate with cognitive performances. On the contrary, a marked reduction of LC signal was observed in patients suffering from neurodegenerative disorders, with specific features. LC-MRI is a promising tool, which may be used in the future to explore LC pathophysiology as well as an early biomarker for degenerative diseases.
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http://dx.doi.org/10.1007/s11910-020-01087-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732795PMC
December 2020
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