Publications by authors named "Alessandro Frati"

114 Publications

Traumatic internal carotid artery injuries: do we need a screening strategy? Literature review, case report, and forensic evaluation.

Curr Neuropharmacol 2021 Jul 12. Epub 2021 Jul 12.

IRCSS Neuromed Mediterranean Neurological Institute, Via Atinense 18, 86077 Pozzilli (IS), Italy.

Internal carotid artery dissection (ICAD) represents the cause of ictus cerebral in about 20% of all cases of cerebral infarction among the young adult population. ICAD could involve both the extracranial and intracranial internal carotid artery (ICA). It could be spontaneous (SICAD) or traumatic (TICAD). It has been estimated that carotid injuries could complicate the 0,32% of cases of general blunt trauma and the percentage seems to be higher in severe multiple traumas. TICAD is diagnosed when neurological symptoms have already occurred, and it could have devastating consequences, from permanent neurological impairment to death. Thus, even if it is a rare condition, a prompt diagnosis is essential. There are no specific guidelines regarding TICAD screening. TICAD is mainly correlated to motor vehicle accidents (94/227), specifically to car accidents (39/94), and to direct or indirect head and cervical trauma (76/227). Nevertheless, TICAD should be considered when a young adult or middle-aged patient presents after severe blunt trauma. Understanding which kind of traumatic event is most associated with TICAD could help clinicians direct their diagnostic process. Herein, a review of the literature concerning TICAD has been carried out to highlights its correlation with specific traumatic events. As well, a case report is presented to discuss TICAD forensic implications.
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http://dx.doi.org/10.2174/1570159X19666210712125929DOI Listing
July 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

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

Outcome Features Analysis in Intramedullary Tumors of the Cervicomedullary Junction: A Surgical Series.

J Neurol Surg A Cent Eur Neurosurg 2021 May 4;82(3):225-231. Epub 2021 Feb 4.

Department of Neurology and Psychiatry, Endovascular Neurosurgery/Interventional Neuroradiology, "Sapienza" University of Rome, Rome, Italy.

Object:  The aim of this study is to investigate the impact of surgery for different cervicomedullary lesions on symptomatic pattern expression and postoperative outcome. We focused on specific outcome features of the early and late postoperative assessments. The former relies on surgery-related transient and permanent morbidity and feasibility of radicality in eloquent areas, whereas the latter on long-term course in lower grade tumors and benign tumorlike lesions (cavernomas, etc.).

Material And Methods:  We retrospectively analyzed 28 cases of intramedullary tumors of the cervicomedullary junction surgically treated at our institution between 1990 and 2018. All cases were stratified for gender, histology, macroscopic appearance, location, surgical approach, and presence of a plane of dissection (POD). Mean follow-up was 5.6 years and it was performed via periodic magnetic resonance imaging (MRI) and functional assessments (Karnofsky Performance Scale [KPS] and modified McCormick [MC] grading system).

Results:  In all, 78.5% were low-grade tumors (or benign lesions) and 21.5% were high-grade tumors. Sixty-one percent underwent median suboccipital approach, 18% a posterolateral approach, and 21% a posterior cervical approach. Gross total resection was achieved in 54% of cases, near-total resection (>90%) in 14%, and subtotal resection (50-90%) in 32% of cases. Early postoperative morbidity was 25%, but late functional evaluation in 79% of the patients showed KPS > 70 and MC grade I; only 21% of cases showed KPS < 70 and MC grades II and III at late follow-up. Mean overall survival was 7 years in low-grade tumors or cavernomas and 11.7 months in high-grade tumors. Progression-free survival at the end of follow-up was 71% (evaluated mainly on low-grade tumors).

Conclusions:  The surgical goal should be to achieve maximal cytoreduction and minimal postoperative neurologic damage. Functional outcome is influenced by the presence of a POD, radicality, histology, preoperative status, and employment of advanced neuroimaging planning and intraoperative monitoring.
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http://dx.doi.org/10.1055/s-0040-1719080DOI Listing
May 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

Risk of Recurrence of Chronic Subdural Hematomas After Surgery: A Multicenter Observational Cohort Study.

Front Neurol 2020 24;11:560269. Epub 2020 Nov 24.

Neurosurgery Unit, Department of Neuroscience "Rita Levi Montalcini", University of Turin, Turin, Italy.

Chronic Subdural Hematoma (CSDH) is a common condition in the elderly population. Recurrence rates after surgical evacuation range from 5 to 30%. Factors predicting recurrence remain debated and unclear. To identify factors associated with increased risk of recurrence. Cases of CSDHs that underwent surgical treatment between 2005 and 2018 in the Neurosurgery Units of two major Italian hospitals were reviewed. Data extracted from a prospectively maintained database included demographics, laterality, antithrombotic therapy, history of trauma, corticosteroid therapy, preoperative and postoperative symptoms, type of surgical intervention, use of surgical drain, and clinical outcomes. A total of 1313 patients was analyzed. The overall recurrence rate was 10.1%. The risk of recurrence was not significantly different between patients with unilateral or bilateral CSDH (10.4 vs. 8.8%, = 0.39). The risk of recurrence was higher in patients that underwent surgical procedure without postoperative drainage (16.1 vs. 5.4%, < 0.01). No relationship was found between recurrence rates and therapy with antithrombotic drugs ( = 0.97). The risk of recurrence was increasingly higher considering craniostomy, craniectomy, and craniotomy (9.3, 11.3, and 18.9%, respectively, = 0.013). Lower recurrence rates following Dexamethasone therapy were recorded ( = 0.013). No association was found between the risk of recurrence of CSDH after surgical evacuation and age, use of antithrombotic medication, or laterality. Burr-hole craniostomy was found to be associated with lower recurrence rates, when compared to other surgical procedures. Placement of surgical drain and Dexamethasone therapy were significantly associated with reduced risk of recurrence of CSDHs.
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http://dx.doi.org/10.3389/fneur.2020.560269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7732444PMC
November 2020

First-in-man craniectomy and asportation of solitary cerebellar metastasis in COVID-19 patient: A case report.

Int J Surg Case Rep 2020 21;77:753-758. Epub 2020 Nov 21.

Department of Human Neurosciences, Division of Neurosurgery, Policlinico Umberto I University Hospital, Sapienza University of Rome, Rome, Italy.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak has an impact on the delivery of neurosurgical care, and it is changing the perioperative practice worldwide. We present the first case in the literature of craniectomy procedure and asportation of a solitary cerebellar metastasis of the oesophagus squamous carcinoma in a 77 years old woman COVID-19 positive. In these particular circumstances, we show that adequate healthcare resources and risk assessments are essential in the management of COVID-19 patients referred to emergency surgery.

Presentation Of Case: The case here presented was treated in 2019 for squamous carcinoma of the oesophagus. In April 2020, she presented a deterioration of her clinical picture consisting of dysphagia, abdominal pain, hyposthenia and ataxia. A Head CT scan was performed, which showed the presence of a solitary cerebellar metastasis. Her associated SARS-CoV-2 positivity status represented the principal clinical concern throughout her hospitalisation.

Discussion: The patient underwent a suboccipital craniectomy procedure with metastasis asportation. She tested positive for SARS-CoV-2 in the pre- and post-operative phases, but she was not admitted to the intensive care unit because she did not present any respiratory complications. Her vital parameters and inflammation indexes fell within the reference ranges, and she was kept in isolation for 16 days in our neurosurgical unit following strict COVID-19 measures. She was asymptomatic and not treated for any of the specific and non-specific symptoms of COVID-19.

Conclusion: This is the first case reported of solitary cerebellar metastasis of oesophagus carcinoma operated on a COVID-19 positive patient. It shows that asymptomatic COVID-19 positive patients can undergo major emergency surgeries without the risk of infecting the operating team if adequate Personal Protection Equipment (PPE) is used. The patient remained asymptomatic and did not develop the disease's active phase despite undergoing a stressful event such as a major emergency neurosurgical procedure. In the current crisis, a prophylactic COVID-19 screening test can identify asymptomatic patients undergoing major emergency surgery and adequate resource planning and Personal Protective Equipment (PPE) for healthcare workers can minimise the effect of the COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.ijscr.2020.11.102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7679517PMC
November 2020

The Multi-Faceted Effect of Curcumin in Glioblastoma from Rescuing Cell Clearance to Autophagy-Independent Effects.

Molecules 2020 Oct 20;25(20). Epub 2020 Oct 20.

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

The present review focuses on the multi-faceted effects of curcumin on the neurobiology glioblastoma multiforme (GBM), with a special emphasis on autophagy (ATG)-dependent molecular pathways activated by such a natural polyphenol. This is consistent with the effects of curcumin in a variety of experimental models of neurodegeneration, where the molecular events partially overlap with GBM. In fact, curcumin broadly affects various signaling pathways, which are similarly affected in cell degeneration and cell differentiation. The antitumoral effects of curcumin include growth inhibition, cell cycle arrest, anti-migration and anti-invasion, as well as chemo- and radio-sensitizing activity. Remarkably, most of these effects rely on mammalian target of rapamycin (mTOR)-dependent ATG induction. In addition, curcumin targets undifferentiated and highly tumorigenic GBM cancer stem cells (GSCs). When rescuing ATG with curcumin, the tumorigenic feature of GSCs is suppressed, thus counteracting GBM establishment and growth. It is noteworthy that targeting GSCs may also help overcome therapeutic resistance and reduce tumor relapse, which may lead to a significant improvement of GBM prognosis. The present review focuses on the multi-faceted effects of curcumin on GBM neurobiology, which represents an extension to its neuroprotective efficacy.
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http://dx.doi.org/10.3390/molecules25204839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587955PMC
October 2020

No prognostic differences between GBM-patients presenting with postoperative SMA-syndrome and GBM-patients involving cortico-spinal tract and primary motor cortex.

J Neurol Sci 2020 Dec 15;419:117188. Epub 2020 Oct 15.

Human Neurosciences Department Neurosurgery Division "Sapienza" University, Italy.

Background: The supplementary motor area (SMA) is involved in several aspects of motor control and its can be associated to a contralateral motor deficit and speech disorders. After the resection of low-grade gliomas, this syndrome is diffusely reported but it is rarely investigated in high-grade gliomas. SMA deficits may resolve completely or with minor sequelae within weeks. Whether this condition of transient deficit affects survival, was not previously investigated, and is not currently understood.

Objective: The study aimed to perform an accurate investigation concerning the real clinical and prognostic impact of the postoperative SMA syndrome in order to shed light over its relationship to survival parameters and postoperative functional status of the patients.

Methods: We performed a retrospective review of a series of 176 surgically treated patients suffering from Glioblastomas. Tumors classified as Group A: Involving the SMA and Group B: Lesion located outside and distal to the SMA but in anatomical relationship to primary motor cortices (PM1) or corticospinal tract (CST), in order to investigate differences concerning immunohistochemical and molecular profiles in regard to the survival parameters.

Results: Although lesions involving SMA demonstrated a significantly higher volume in respect to their general counterparts they did not significantly differ in concerns to the molecular patterns, pre and postoperative KPS scores and in PFS and OS findings.

Conclusions: In our cohort SMA-syndrome is reversible and therefore guarantees a satisfactory functional status at follow-up, apparently not compromising survival when compared to other lesions affecting the primary or cortical motor area -spinal tract.
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http://dx.doi.org/10.1016/j.jns.2020.117188DOI Listing
December 2020

How SARS-Cov-2 can involve the central nervous system. A systematic analysis of literature of the department of human neurosciences of Sapienza University, Italy.

J Clin Neurosci 2020 Sep 7;79:231-236. Epub 2020 Jul 7.

IRCCS - "Neuromed", Pozzilli, (IS), Italy; A.U.O. "Policlinico Umberto I", Neurosurgery Division, Sapienza University, Rome Human Neurosciences Department, Via del Policlinico, 155 - 00161 Rome, Italy.

Italy is currently one of the countries most affected by the global emergency of COVID-19, a lethal disease of a novel coronavirus renamed as SARS-CoV-2. SARS-CoV-2 shares highly homological sequence with the most studied SARS-CoV, and causes acute, highly deadly pneumonia (COVID-19) with clinical symptoms similar to those reported for SARS-CoV and MERS-CoV. Increasing evidence shows that these coronaviruses are not always confined to the respiratory tract and that they may also neuroinvasive and neurotropic, with potential neuropathological consequences in vulnerable populations. The aim of this study is to predict a likely CNS involvement by SARS-CoV-2 by studying the pathogenic mechanisms in common with other better known and studied coronaviruses with which it shares the same characteristics. Understanding the mechanisms of neuroinvasion and interaction of HCoV (including SARS-Cov-2) with the CNS is essential to evaluate potentially pathological short- and long-term consequences. Autopsies of the COVID-19 patients, detailed neurological investigation, and attempts to isolate SARS-CoV-2 from the endothelium of cerebral microcirculation, cerebrospinal fluid, glial cells, and neuronal tissue can clarify the role played by COVID-19 in CNS-involvement and in the ongoing mortalities as has been in the recent outbreak.
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http://dx.doi.org/10.1016/j.jocn.2020.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340069PMC
September 2020

mTOR Modulates Intercellular Signals for Enlargement and Infiltration in Glioblastoma Multiforme.

Cancers (Basel) 2020 Sep 2;12(9). Epub 2020 Sep 2.

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

Recently, exosomal release has been related to the acquisition of a malignant phenotype in glioblastoma cancer stem cells (GSCs). Remarkably, intriguing reports demonstrate that GSC-derived extracellular vesicles (EVs) contribute to glioblastoma multiforme (GBM) tumorigenesis via multiple pathways by regulating tumor growth, infiltration, and immune invasion. In fact, GSCs release tumor-promoting macrovesicles that can disseminate as paracrine factors to induce phenotypic alterations in glioma-associated parenchymal cells. In this way, GBM can actively recruit different stromal cells, which, in turn, may participate in tumor microenvironment (TME) remodeling and, thus, alter tumor progression. Vice versa, parenchymal cells can transfer their protein and genetic contents to GSCs by EVs; thus, promoting GSCs tumorigenicity. Moreover, GBM was shown to hijack EV-mediated cell-to-cell communication for self-maintenance. The present review examines the role of the mammalian Target of Rapamycin (mTOR) pathway in altering EVs/exosome-based cell-to-cell communication, thus modulating GBM infiltration and volume growth. In fact, exosomes have been implicated in GSC niche maintenance trough the modulation of GSCs stem cell-like properties, thus, affecting GBM infiltration and relapse. The present manuscript will focus on how EVs, and mostly exosomes, may act on GSCs and neighbor non tumorigenic stromal cells to modify their expression and translational profile, while making the TME surrounding the GSC niche more favorable for GBM growth and infiltration. Novel insights into the mTOR-dependent mechanisms regulating EV-mediated intercellular communication within GBM TME hold promising directions for future therapeutic applications.
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http://dx.doi.org/10.3390/cancers12092486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564864PMC
September 2020

Is Ki-67 index overexpression in IDH wild type glioblastoma a predictor of shorter Progression Free survival? A clinical and Molecular analytic investigation.

Clin Neurol Neurosurg 2020 11 3;198:106126. Epub 2020 Aug 3.

IRCCS "Neuromed" Pozzilli (IS), Italy.

Background: Ki-67 proliferation index is widely used for differentiating between high and low-grade gliomas, but differentiating between the same grade IV appears to be more problematic, and the point about its prognostic value for GBM patients remains unclear. To reduce the possibility to find a marked histological heterogeneity, and may contain areas that could be diagnosed as lower grade, in this study we considered a large group of patients with IDH wild-type Glioblastoma (IDH-WT GBM) and we have analyzed previously reported prognostic factors, in regards to their relationship with the Ki-67 expression index.

Methods: We explore the prognostic impact of ki-67 index status in 127 patients affected by IDH-WT GBM. We therefore analyzed clinical characteristics, tumor genetics, dimension and clinical outcomes. We selected a total of 127 patients affected by newly diagnosed IDH-WT GBM who underwent surgery, radiation, and chemotherapy in our Institution in the period ranging between January 2014 and December 2016 RESULTS: The volume of the lesion had a strong association with the Ki67 overexpression. In particular lesions whose volume was greater than 45  cm, presented a higher percentage of Ki67 expression demonstrating that greater tumors are more likely associated to higher values of Ki67 percentages. On a multivariate analysis, it was possible to outline that Ki67 was significant a predictor of shorter PFS independently from the age of the patients, the volume of the lesion and preoperative KPS.

Conclusions: There is a correlation between percentage staining of Ki-67 and OS in our cohort of patients with IDH-WT GBM. This is only the third observational study documenting a positive correlation between Ki-67 and overall survival in GBM and the first one demonstrates that percentage Ki-67 staining >20 % predicts poorer progression free survival in IDH-WT GBM.
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http://dx.doi.org/10.1016/j.clineuro.2020.106126DOI Listing
November 2020

Quantitative Ultrastructural Morphometry and Gene Expression of mTOR-Related Mitochondriogenesis within Glioblastoma Cells.

Int J Mol Sci 2020 Jun 27;21(13). Epub 2020 Jun 27.

I.R.C.C.S. Neuromed, via Atinense 18, 86077 Pozzilli (IS), Italy.

In glioblastoma (GBM) cells, an impairment of mitochondrial activity along with autophagy suppression occurs. Autophagy suppression in GBM promotes stemness, invasion, and poor prognosis. The autophagy deficit seems to be due, at least in part, to an abnormal up-regulation of the mammalian target of rapamycin (mTOR), which may be counteracted by pharmacological mTORC1 inhibition. Since autophagy activation is tightly bound to increased mitochondriogenesis, a defect in the synthesis of novel mitochondria is expected to occur in GBM cells. In an effort to measure a baseline deficit in mitochondria and promote mitochondriogenesis, the present study used two different GBM cell lines, both featuring mTOR hyperactivity. mTORC1 inhibition increases the expression of genes and proteins related to autophagy, mitophagy, and mitochondriogenesis. Autophagy activation was counted by RT-PCR of autophagy genes, LC3- immune-fluorescent puncta and immune-gold, as well as specific mitophagy-dependent BNIP3 stoichiometric increase in situ, within mitochondria. The activation of autophagy-related molecules and organelles after rapamycin exposure occurs concomitantly with progression of autophagosomes towards lysosomes. Remarkably, mitochondrial biogenesis and plasticity (increased mitochondrial number, integrity, and density as well as decreased mitochondrial area) was long- lasting for weeks following rapamycin withdrawal.
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http://dx.doi.org/10.3390/ijms21134570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370179PMC
June 2020

Histological, molecular, clinical and outcomes characteristics of Multiple Lesion Glioblastoma. A retrospective monocentric study and review of literature.

Neurocirugia (Astur : Engl Ed) 2021 May-Jun;32(3):114-123. Epub 2020 Jun 18.

Human Neurosciences Department Neurosurgery Division "Sapienza" University, Italy.

Background: Multiple lesion glioblastoma (M-GBM) represent a group of GBM patients in which there exist multiple foci of tumor enhancement. The prognosis is poorer than that of single-lesion GBM patients, but this actually is a controversial data. Is unknown whether multifocality has a genetic and molecular basis. Our specific aim is to identify the molecular characteristics of M-GBM by performing a comprehensive multidimensional analysis.

Methods: The surgical, radiological and clinical outcomes of patients that underwent surgery for GBM at our institution for 2 years have been retrospectively reviewed. We compared the overall survival (OS), progression free survival and extent of resection (EOR) between M-GBM tumors (type I) and S-GBM (single contrast-enhancing lesion, type II).

Results: A total of 177 patients were included in the final cohort, 12 patients had M-GBM and 165 patients had S-GBM. Although patients with M-GBM had higher tumor volumes and midline location, the EOR was not different between both type of lesions. Higher percentage of tumors with EGFR overexpression was detected in M-GBM. PFS and OS was significantly shorter in M-GBM.

Conclusions: Considering no differences in EOR, patients with M-GBM showed shorter PFS and OS in comparison with S-GBM. Evidences about the M-GBM origin as a multifocal lesion because its molecular profile are suggested.
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http://dx.doi.org/10.1016/j.neucir.2020.04.003DOI Listing
May 2021

Transoral Endoscopic Approach to Repair Early Pharyngeal Perforations After Anterior Cervical Spine Surgery without Failure of Instrumentation: Our Experience and Review of Literature.

World Neurosurg 2020 09 17;141:219-225. Epub 2020 Jun 17.

IRCCS Neuromed, Pozzilli, Italy.

Background: Pharyngoesophageal injury during anterior cervical spine surgery is a rare and potentially life-threatening complication; generally it is the result of intraoperative manipulation or hardware erosion and sometimes may be due to weakness of the pharyngoesophageal wall from pre-existing pathologic conditions, such as diabetes, gastritis, or obesity.

Case Description: We describe the management strategies in patients with an early postoperative hypopharyngeal perforation that occurred after anterior cervical spine surgery without failure of instrumentation, and we present a case treated endoscopically at our institution.

Conclusions: Appropriate treatment for pharyngoesophageal perforations is controversial and not investigated in detail. There is a lack of prospective studies comparing initial conservative versus surgical approaches to treatment. In addition, endoscopic management is growing as a therapeutic option, but no consensus concerning the indications for an endoscopic approach in the treatment of pharyngoesophageal injury in anterior cervical spine surgery is currently reached. A common theme proposed in the literature is that early recognition and aggressive investigation and treatment are essential to ensure a good outcome. A customized interdisciplinary surgical approach is essential for successful treatment. Use of the transoral endoscopic approach is a useful noninvasive method to treat this rare but potentially devastating complication.
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http://dx.doi.org/10.1016/j.wneu.2020.06.080DOI Listing
September 2020

A Forgotten Tale from the Great War: General Lorenzo Bonomo and the Birth of Italian War Neurosurgery.

World Neurosurg 2020 08 12;140:338-346. Epub 2020 Jun 12.

Rome Army Hospital Celio, Neurosurgery Division, Roma, Italy.

Little is known of the advances in battlefield medicine achieved in Italy before and during the Great War. Some deserve wider recognition; this is especially true for the field of neurosurgery. There are a limited number of historical records currently available, fewer still in English, and most of the systematic investigations on field surgery have been in the form of monographs within science history reviews, which obviously lack a strictly clinical perspective. Together with shell shock, the gunshot-related traumatic brain injury (GrTBI) is considered one of the typical, or signature, lesions of the Great War. It was intrinsically linked to trench and mountain warfare: to view the battlefield from a trench/hiding area, soldiers' heads and necks were repeatedly exposed, therefore making them the most likely target for snipers. Military physicians therefore focused their efforts in the clinical and experimental treatment of GrTBI. Among notable contributions of the military surgeons of the time, there is a volume of selected war-surgery lectures conserved in the archives of the Library of the Italian National Academy of Military Medicine. These lectures shed light over the work of General Dr. Lorenzo Bonomo. His incredibly advanced and modern ideas had unfortunately been forgotten. He pioneered research in the ballistic and forensic medical fields, building on first-hand experience, as he performed surgeries himself before the conflict and even while on the frontline, actively working to improve the chances of survival for the Italian troops fighting in the Great War.
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http://dx.doi.org/10.1016/j.wneu.2020.05.113DOI Listing
August 2020

Standard awake surgery versus hypnosis aided awake surgery for the management of high grade gliomas: A non-randomized cohort comparison controlled trial.

J Clin Neurosci 2020 Jul 11;77:41-48. Epub 2020 May 11.

IRCCS "Neuromed" - Pozzilli (IS), Italy.

Hypnosis could extend the time of Intraoperative Neuropsychological Testing and Brain Mapping in Awake Surgery. A clinical validation for the Hypnosis aided AS (HAs) is still ongoing and further evidences are required. The objective of the present study is to compare two homogeneous cohorts of patients undergoing AS, the first with the aid of the hypnosis and the second according to a standard AS (SAs) protocols. The clinical, radiological and surgical data of two comparable procedures cohorts were retrospectively examined for the present study. All surgeries in Group A were performed with a HAs protocol. Procedures belonging to Group B were performed with a SAs protocol. Endpoints: to compare 1. Incidence of complications in the immediate postoperative period, 2. Clinical and neurological status in the immediate postoperative period and 30 days after surgery, 3. Duration of surgical interventions, 4. Extent of Resection (EOR). The final cohort is composed of 15 procedures; 6 belonging to Group A and 9 to Group B. The different methods outline statistically comparable results from the clinical (Neurological outcomes) both in the postoperative period and one month after surgery and from the surgical point of view (comparable EOR). The incidence of complications is comparable either. The duration of the procedures was significantly longer in HAs group. Hypnosis is a promising approach to increasing the duration of intraoperative "testability" of patients at the price of a longer operative time. A specific professional is needed to induce hypnosis in the difficult intraoperative setting.
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http://dx.doi.org/10.1016/j.jocn.2020.05.047DOI Listing
July 2020

Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies.

Int J Mol Sci 2020 Apr 24;21(8). Epub 2020 Apr 24.

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

Alterations in autophagy and the ubiquitin proteasome system (UPS) are commonly implicated in protein aggregation and toxicity which manifest in a number of neurological disorders. In fact, both UPS and autophagy alterations are bound to the aggregation, spreading and toxicity of the so-called prionoid proteins, including alpha synuclein (α-syn), amyloid-beta (Aβ), tau, huntingtin, superoxide dismutase-1 (SOD-1), TAR-DNA-binding protein of 43 kDa (TDP-43) and fused in sarcoma (FUS). Recent biochemical and morphological studies add to this scenario, focusing on the coordinated, either synergistic or compensatory, interplay that occurs between autophagy and the UPS. In fact, a number of biochemical pathways such as mammalian target of rapamycin (mTOR), transcription factor EB (TFEB), Bcl2-associated athanogene 1/3 (BAG3/1) and glycogen synthase kinase beta (GSk3β), which are widely explored as potential targets in neurodegenerative proteinopathies, operate at the crossroad between autophagy and UPS. These biochemical steps are key in orchestrating the specificity and magnitude of the two degradation systems for effective protein homeostasis, while intermingling with intracellular secretory/trafficking and inflammatory pathways. The findings discussed in the present manuscript are supposed to add novel viewpoints which may further enrich our insight on the complex interactions occurring between cell-clearing systems, protein misfolding and propagation. Discovering novel mechanisms enabling a cross-talk between the UPS and autophagy is expected to provide novel potential molecular targets in proteinopathies.
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http://dx.doi.org/10.3390/ijms21083028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7215558PMC
April 2020

Letter: Neurosurgery and Coronavirus (COVID-19) Epidemic: Doing our Part.

Neurosurgery 2020 07;87(1):E48-E49

A.U.O. "Policlinico Umberto I" Neurosurgery Division Sapienza University, Rome Human Neurosciences Department Roma, Italy.

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http://dx.doi.org/10.1093/neuros/nyaa115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184435PMC
July 2020

mTOR-Related Cell-Clearing Systems in Epileptic Seizures, an Update.

Int J Mol Sci 2020 Feb 28;21(5). Epub 2020 Feb 28.

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

Recent evidence suggests that autophagy impairment is implicated in the epileptogenic mechanisms downstream of mTOR hyperactivation. This holds true for a variety of genetic and acquired epileptic syndromes besides malformations of cortical development which are classically known as mTORopathies. Autophagy suppression is sufficient to induce epilepsy in experimental models, while rescuing autophagy prevents epileptogenesis, improves behavioral alterations, and provides neuroprotection in seizure-induced neuronal damage. The implication of autophagy in epileptogenesis and maturation phenomena related to seizure activity is supported by evidence indicating that autophagy is involved in the molecular mechanisms which are implicated in epilepsy. In general, mTOR-dependent autophagy regulates the proliferation and migration of inter-/neuronal cortical progenitors, synapse development, vesicular release, synaptic plasticity, and importantly, synaptic clustering of GABA receptors and subsequent excitatory/inhibitory balance in the brain. Similar to autophagy, the ubiquitin-proteasome system is regulated downstream of mTOR, and it is implicated in epileptogenesis. Thus, mTOR-dependent cell-clearing systems are now taking center stage in the field of epilepsy. In the present review, we discuss such evidence in a variety of seizure-related disorders and models. This is expected to provide a deeper insight into the molecular mechanisms underlying seizure activity.
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http://dx.doi.org/10.3390/ijms21051642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7084443PMC
February 2020

Impact of early surgery of ruptured cerebral aneurysms on vasospasm and hydrocephalus after SAH: Our preliminary results.

Clin Neurol Neurosurg 2020 05 3;192:105714. Epub 2020 Feb 3.

S. Andrea Hospital, Neurosurgery, University of Rome "La Sapienza", Roma, Italy.

Objective: Timing of surgical treatment of ruptured intracranial aneurysms has undergone a drastic change in the last few decades with preference for early surgery Our paper focuses specifically on the prognostic importance of timing of surgery, since early surgery of ruptured aneurysms provides immediately good clinical results. We present a series of cases operated in early and ultra early surgery, evaluating the technical aspects, the efficacy, the safety and the clinical results.

Patients And Methods: We retrospectively reviewed the clinical records and radiological imaging of patients treated for ruptured intracranial aneurysms who underwent early and ultra early clipping between January 2011 and April 2017 at our Institution. We included patients treated within the first 12 h and subsequently we divided our series in two subgroups based on the timing of surgery comparing the "early surgery" group (within 12 h) with the "ultra early surgery" group (within 6 h).

Results: Seventy-six (76) patients undergoing either early or ultra-early surgery for ruptured intracranial aneurysms have been reported Either early or ultra-early surgery showed a statistically favorable impact on reducing the incidence of both postoperative vasospasm and hydrocephalus. Ultra-early surgery group had the best outcome at the statistical analyses. (good postoperative 1Y GOSE.) CONCLUSIONS: We strongly believe that patients affected by ruptured intracranial aneurysms excluding Hunt and Hess grade V patients) should be treated as soon as possible and hence it should be considered as an emergency surgery. This approach prevents immediately a second bleeding of the aneurysm, allows to treat any associated condition of intracranial hypertension including hematomas and hydrocephalus and to use safely aggressive medical therapy such as hypertension.
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http://dx.doi.org/10.1016/j.clineuro.2020.105714DOI Listing
May 2020

Retrospective and Randomized Analysis of Influence and Correlation of Clinical and Molecular Prognostic Factors in a Mono-Operative Series of 122 Patients with Glioblastoma Treated with STR or GTR.

Brain Sci 2020 Feb 9;10(2). Epub 2020 Feb 9.

Department of Neurological Sciences, Neurosurgey, "La Sapienza" University of Rome, 00161 Rome, Italy.

Glioblastoma is a solid, infiltrating, and the most frequent highly malignant primary brain tumor. Our aim was to find the correlation between sex, age, preoperative Karnofsky performance status (KPS), presenting with seizures, and extent of resection (EOR) with overall survival (OS), progression-free survival (PFS), and postoperative KPS, along with the prognostic value of IDH1, MGMT, ATRX, EGFR, and TP53 genes mutations and of Ki67 through the analysis of a single-operator series in order to avoid the biases of a multi-operator series, such as the lack of homogeneity in surgical and adjuvant nonsurgical treatments. A randomized retrospective analysis of 122 patients treated by a single first operator at Sapienza University of Rome was carried out. After surgery, patients followed standard Stupp protocol treatment. Exclusion criteria were: (1) patients with primary brainstem and spinal cord gliomas and (2) patients who underwent partial resections (resection < 90%) or a biopsy exclusively for diagnostic purposes. Statistical analysis with a simultaneous regression model was carried out through the use of SPSS 25 (IBM). Results showed statistically significant survival increase in four groups: (1) patients treated with gross total resection (GTR) ( < 0.030); (2) patients with mutation of IDH1 ( < 0.0161); (3) patients with methylated MGMT promoter ( < 0.005); (4) patients without EGFR amplification or EGFRvIII mutation ( < 0.035). Higher but not statistically significant survival rates were also observed in: patients <75 years, patients presenting with seizures at diagnosis, patients affected by lesions in noneloquent areas, as well as in patients with ATRX gene mutation and Ki-67 < 10%.
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http://dx.doi.org/10.3390/brainsci10020091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7071604PMC
February 2020

EGFR amplification is a real independent prognostic impact factor between young adults and adults over 45yo with wild-type glioblastoma?

J Neurooncol 2020 Jan 30;146(2):275-284. Epub 2019 Dec 30.

IRCCS "Neuromed", Pozzilli, IS, Italy.

Background: In 2019 a group of University of Pennsylvania (Hoffman et al., J Neurooncol 145: 321-328, 2019) aimed to explore the prognostic impact of expression of epidermal growth factor receptor (EGFR), one of the most common genetic alterations in WT-GBM, in young adults with IDH-WT GBM, suggesting an inferior outcomes in young adults (< 45yo) with newly diagnosed, IDH-WT GBM. At the same time, our group were considering the dimension of this subpopulation treated in our centre, and we performed the same analysis, comparing datas with affected elderly adults.

Methods: We explore the prognostic impact of EGFR expression status in young adults with IDH-WT GBM, and compare this impact with the affected elderly adults. We therefore analyzed clinical characteristics, tumor genetics, and clinical outcomes in a cohort of adults aged 18-45 years with newly diagnosed WT GBM. We selected a total of 146 patients affected by newly diagnosed IDH-WT GBM who underwent surgery, radiation, and chemotherapy in our Institution in the period ranging between January 2014 and December 2016. We focused primarily on the prognostic impact of EGFR expression.

Results: We confirmed through a Bivariate Analysis that the Age of the Patients, the Volume of the lesions, were statistically strongly associated with the survival parameters; The general OS of the cohort presented a breakthrough point between the patients who were respectively younger and older than 45 years, EGFR mutation was per se not associated to a survival reduction in all the cohort patients. When analyzing exclusively the Survival parameters of the patients whose age was under 40, it was possible to outline a non statistically significant trend towards a lesser OS in younger patients harboring an EGFR expression.

Conclusions: Once again the main difference in terms of OS in GBM is shown in a EOR and in Age. To our knowledge, ours is the second study (Hoffman et al., J Neurooncol 145: 321-328, 2019) to evaluate the prognostic impact of EGFR CN gain specifically in young adults with IDH-WT GBM and in the era of modern radiation and Temozolomide, but is the first one to compares this impact with a population of adults over 45, and correlates this date with clinical onset, dimension and localization of disease between this groups. We suggest other centers to evaluate this important finding with a larger number of patients and we are inclined to accept collaborations to increase the power of this study.
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http://dx.doi.org/10.1007/s11060-019-03364-zDOI Listing
January 2020

Long Term Survival in Patients Suffering from Glio-blastoma Multiforme: A Single-Center Observational Cohort Study.

Diagnostics (Basel) 2019 Nov 30;9(4). Epub 2019 Nov 30.

IRCCS "Neuromed" Pozzilli (IS), Università Sapienza of Rome, 00135 Roma, Italy.

Background: Glioblastomas (GBM) are generally burdened, to date, by a dismal prognosis, although long term survivors have a relatively significant incidence. Our specific aim was to determine the exact impact of many surgery-, patient- and tumor-related variables on survival parameters.

Methods: The surgical, radiological and clinical outcomes of patients have been retrospectively reviewed for the present study. All the patients have been operated on in our institution and classified according their overall survival in long term survivors (LTS) and short term survivors (STS). A thorough review of our surgical series was conducted to compare the oncologic results of the patients in regard to: (1) surgical-(2) molecular and (3) treatment-related features.

Results: A total of 177 patients were included in the final cohort. Extensive statistical analysis by means of univariate, multivariate and survival analyses disclosed a survival advantage for patients presenting a younger age, a smaller lesion and a better functional status at presentation. From the histochemical point of view, Ki67 (%) was the strongest predictor of better oncologic outcomes. A stepwise analysis of variance outlines the existence of eight prognostic subgroups according to the molecular patterns of Ki67 overexpression and epidermal growth factor receptor (EGFR), p53 and isocitrate dehydrogenase (IDH) mutations.

Conclusions: On the grounds of our statistical analyses we can affirm that the following factors were significant predictors of survival advantage: Karnofsky performance status (KPS), age, volume of the lesion, motor disorder at presentation and/or a Ki67 overexpression. In our experience, LTS is associated with a gross total resection (GTR) of tumor correlated with EGFR and p53 mutations with regardless of localization, and poorly correlated to dimension. We suppose that performing a standard molecular analysis (IDH, EGFR, p53 and Ki67) is not sufficient to predict the behavior of a GBM in regards to overall survival (OS), nor to provide a deeper understanding of the meaning of the different genetic alterations in the DNA of cancer cells. A fine molecular profiling is feasible to precisely stratify the prognosis of GBM patients.
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http://dx.doi.org/10.3390/diagnostics9040209DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6963741PMC
November 2019

Prion Protein in Glioblastoma Multiforme.

Int J Mol Sci 2019 Oct 15;20(20). Epub 2019 Oct 15.

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

The cellular prion protein (PrPc) is an evolutionarily conserved cell surface protein encoded by the gene. PrPc is ubiquitously expressed within nearly all mammalian cells, though most abundantly within the CNS. Besides being implicated in the pathogenesis and transmission of prion diseases, recent studies have demonstrated that PrPc contributes to tumorigenesis by regulating tumor growth, differentiation, and resistance to conventional therapies. In particular, PrPc over-expression has been related to the acquisition of a malignant phenotype of cancer stem cells (CSCs) in a variety of solid tumors, encompassing pancreatic ductal adenocarcinoma (PDAC), osteosarcoma, breast cancer, gastric cancer, and primary brain tumors, mostly glioblastoma multiforme (GBM). Thus, PrPc is emerging as a key in maintaining glioblastoma cancer stem cells' (GSCs) phenotype, thereby strongly affecting GBM infiltration and relapse. In fact, PrPc contributes to GSCs niche's maintenance by modulating GSCs' stem cell-like properties while restraining them from differentiation. This is the first review that discusses the role of PrPc in GBM. The manuscript focuses on how PrPc may act on GSCs to modify their expression and translational profile while making the micro-environment surrounding the GSCs niche more favorable to GBM growth and infiltration.
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http://dx.doi.org/10.3390/ijms20205107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6834196PMC
October 2019

Radiation-Induced Brain Aneurysms: Institutional Experience and State of the Art in the Contemporary Literature.

World Neurosurg 2020 Mar 9;135:339-351. Epub 2019 Oct 9.

IRCCS "Neuromed", Pozzilli, Isernia, Italy. Electronic address:

Background: Brain aneurysms (BAs) are the most common intracranial vascular condition, with an overall incidence of 1%-2%. Among the common causes of their initial formation and growth, the role of radiation therapy (RT) has been reported in some studies. The aim of the present study is to report the most relevant features of BA related to a previous cranial RT.

Methods: Data deriving from 1 patient treated for RT-induced BA in our institution were added to reports of another 66 BAs retrieved from the literature. The following parameters were evaluated: age, sex, location, primary lesion, clinical presentation, dosage/amount of radiation delivered, type of treatment for the BA, dimension, morphology, chemotherapy, comorbidities, risk factors, and number of BAs.

Results: The most commonly involved vessel was the internal carotid artery (34%). In general, the anterior circulation showed higher vulnerability compared with the posterior circulation and middle cerebral artery (56.7%). The average latency between RT and the first imaging showing the BA was 9.01 ± 6.85 years. Vessels coursing in the posterior cranial fossa showed a significant univariate association with lower X-ray dosages (P = 0.014) compared with the other locations. No statistically significant correlation between the continuous variables age, latency of BA appearance, RT delivered dose, and dimension of the BA was shown.

Conclusions: The apparent higher fragility of the vascular structures of the posterior cranial fossa was statistically outlined, and the X-ray dosage, the primary condition target of the RT, the age of the patients, and no statistically significant correlation were outlined. Biological factors could play a significant role.
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http://dx.doi.org/10.1016/j.wneu.2019.09.157DOI Listing
March 2020

The role of Locus Coeruleus in neuroinflammation occurring in Alzheimer's disease.

Brain Res Bull 2019 11 13;153:47-58. Epub 2019 Aug 13.

I.R.C.C.S. I.N.M. Neuromed, Pozzilli, Italy; Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy. Electronic address:

Alzheimer's Disease (AD) represents the main degenerative dementia. Its neuropathological hallmarks are β-amyloid plaques (APs) and neurofibrillary tangles (NFT), which lead to neuronal loss and brain atrophy. Recent data show that, early in the course of AD, hyperphosphorylated Tau proteins accumulate in Locus Coeruleus (LC) neuronal bodies. The fact that similar alterations have been found also in the entorhinal cortex suggests a causal relationship, although no final causal evidence exists. Later on, in the course of the disease, frank LC neuronal loss occurs, which is associated with marked cerebral NE reduction. In AD, neuroinflammation plays a pivotal role early in the process of APs deposition. LC degeneration is likely to play a key role in AD pathogenesis. In fact, NE modulates growth factors expression as well as integrity and functioning of the blood-brain barrier, and it also directly affects neuroinflammation. For instance, LC modulates microglia and astrocyte function, and this is evident following damage to LC, which induces astro- and micro-gliosis around APs, as well as interleukins secretion. These phenomena are dependent on the activation of beta-adrenergic receptors. The present review provides evidence about immune-mediated mechanisms through which LC may impact the course of AD. Some findings are consolidated in animal models. Should these data be confirmed in humans, adrenergic agents might represent potential therapeutic approaches acting on neuroinflammation to slow down the progression of AD.
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http://dx.doi.org/10.1016/j.brainresbull.2019.08.007DOI Listing
November 2019

Corrigendum to "Spinal dural tenting sutures in intradural tumor surgery: A technical insight" [J Clin Neurosci 61 (2019) 322-323].

J Clin Neurosci 2020 04 6;74:274. Epub 2019 Aug 6.

A.O.U. "Sant'Andrea", Neurosurgery Division, Sapienza University, Rome, NESMOS Department, Via di Grottarossa, 1035-1039, 00189 Roma, Italy.

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http://dx.doi.org/10.1016/j.jocn.2019.06.002DOI Listing
April 2020