Pharmacological doses of melatonin impede cognitive decline in tau-related Alzheimer models, once tauopathy is initiated, by restoring the autophagic flux.

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV-hTauP301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau-related models. Melatonin (10 µmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV-hTauP301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase-3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.

Clinical practice guideline on the management of vestibular schwannoma.

INTRODUCTION: Vestibular schwannoma (VS) is the most common tumour of the cerebellopontine angle. The greater accessibility to radiological tests has increased its diagnosis. Taking into account the characteristics of the tumour, the symptoms and the age of the patient, three therapeutic strategies have been proposed: observation, surgery or radiotherapy. Choosing the most appropriate for each patient is a frequent source of controversy. MATERIAL AND METHODS: This paper includes an exhaustive literature review of issues related to VS that can serve as a clinical guide in the management of patients with these lesions. The presentation has been oriented in the form of questions that the clinician usually asks himself and the answers have been written and/or reviewed by a panel of national and international experts consulted by the Otology Commission of the SEORL-CCC. RESULTS: A list has been compiled containing the 13 most controversial thematic blocks on the management of VS in the form of 50 questions, and answers to all of them have been sought through a systematic literature review (articles published on PubMed and Cochrane Library between 1992 and 2023 related to each thematic area). Thirty-three experts, led by the Otology Committee of SEORL-CCC, have analyzed and discussed all the answers. In Annex 1, 14 additional questions divided into 4 thematic areas can be found. CONCLUSIONS: This clinical practice guideline on the management of VS offers agreed answers to the most common questions that are asked about this tumour. The absence of sufficient prospective studies means that the levels of evidence on the subject are generally medium or low. This fact increases the interest of this type of clinical practice guidelines prepared by experts.

[Tumours of the upper cervical spine]. / Tumores vertebrales de la región cervical alta.

OBJECTIVE: Vertebral tumours arising in the upper cervical spine are rare. We present our experience in managing these neoplasms. MATERIAL AND METHODS: We retrospectively reviewed the case histories of patients treated at our institution between January 2000 and June 2011. RESULTS: There were 9 patients with tumours in C1-C2-C3: 2metastases, 3chordomas, 2plasmocytomas, 1chondrosarcoma and 1osteochondroma. All patients complained of neck pain at the time of diagnosis. Three patients underwent an anterior and posterior approach, 3 an exclusively posterior approach and 3 an exclusively anterior surgical approach. Tumour resection was intralesional in 7 cases. Chemo-radiotherapy was used as adjuvant therapy in patients with malignant tumours. CONCLUSIONS: Vertebral tumours in the upper cervical spine are usually malignant. Achieving en bloc resection is particularly challenging and is technically unfeasible in many cases. This worsens the prognosis and makes adjuvant treatment very important.

Serum Amyloid A1/Toll-Like Receptor-4 Axis, an Important Link between Inflammation and Outcome of TBI Patients.

Traumatic brain injury (TBI) is one of the leading causes of mortality and disability worldwide without any validated biomarker or set of biomarkers to help the diagnosis and evaluation of the evolution/prognosis of TBI patients. To achieve this aim, a deeper knowledge of the biochemical and pathophysiological processes triggered after the trauma is essential. Here, we identified the serum amyloid A1 protein-Toll-like receptor 4 (SAA1-TLR4) axis as an important link between inflammation and the outcome of TBI patients. Using serum and mRNA from white blood cells (WBC) of TBI patients, we found a positive correlation between serum SAA1 levels and injury severity, as well as with the 6-month outcome of TBI patients. SAA1 levels also correlate with the presence of TLR4 mRNA in WBC. In vitro, we found that SAA1 contributes to inflammation via TLR4 activation that releases inflammatory cytokines, which in turn increases SAA1 levels, establishing a positive proinflammatory loop. In vivo, post-TBI treatment with the TLR4-antagonist TAK242 reduces SAA1 levels, improves neurobehavioral outcome, and prevents blood-brain barrier disruption. Our data support further evaluation of (i) post-TBI treatment in the presence of TLR4 inhibition for limiting TBI-induced damage and (ii) SAA1-TLR4 as a biomarker of injury progression in TBI patients.

Impact of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients: a nationwide study in Spain.

OBJECTIVE: To assess the effect of the first wave of the SARS-CoV-2 pandemic on the outcome of neurosurgical patients in Spain. SETTINGS: The initial flood of COVID-19 patients overwhelmed an unprepared healthcare system. Different measures were taken to deal with this overburden. The effect of these measures on neurosurgical patients, as well as the effect of COVID-19 itself, has not been thoroughly studied. PARTICIPANTS: This was a multicentre, nationwide, observational retrospective study of patients who underwent any neurosurgical operation from March to July 2020. INTERVENTIONS: An exploratory factorial analysis was performed to select the most relevant variables of the sample. PRIMARY AND SECONDARY OUTCOME MEASURES: Univariate and multivariate analyses were performed to identify independent predictors of mortality and postoperative SARS-CoV-2 infection. RESULTS: Sixteen hospitals registered 1677 operated patients. The overall mortality was 6.4%, and 2.9% (44 patients) suffered a perioperative SARS-CoV-2 infection. Of those infections, 24 were diagnosed postoperatively. Age (OR 1.05), perioperative SARS-CoV-2 infection (OR 4.7), community COVID-19 incidence (cases/105 people/week) (OR 1.006), postoperative neurological worsening (OR 5.9), postoperative need for airway support (OR 5.38), ASA grade ≥3 (OR 2.5) and preoperative GCS 3-8 (OR 2.82) were independently associated with mortality. For SARS-CoV-2 postoperative infection, screening swab test <72 hours preoperatively (OR 0.76), community COVID-19 incidence (cases/105 people/week) (OR 1.011), preoperative cognitive impairment (OR 2.784), postoperative sepsis (OR 3.807) and an absence of postoperative complications (OR 0.188) were independently associated. CONCLUSIONS: Perioperative SARS-CoV-2 infection in neurosurgical patients was associated with an increase in mortality by almost fivefold. Community COVID-19 incidence (cases/105 people/week) was a statistically independent predictor of mortality. TRIAL REGISTRATION NUMBER: CEIM 20/217.

Early toll-like receptor 4 blockade reduces ROS and inflammation triggered by microglial pro-inflammatory phenotype in rodent and human brain ischaemia models.

BACKGROUND AND PURPOSE: Ischaemic stroke is a leading cause of death, disability, and a high unmet medical need. Post-reperfusion inflammation and an up-regulation of toll-like receptor 4 (TLR4), an upstream sensor of innate immunity, are associated with poor outcome in stroke patients. Here, we identified the therapeutic effect of targeting the LPS/TLR4 signal transduction pathway. EXPERIMENTAL APPROACH: We tested the effect of the TLR4 inhibitor, eritoran (E5564) in different in vitro ischaemia-related models: human organotypic cortex culture, rat organotypic hippocampal cultures, and primary mixed glia cultures. We explored the therapeutic window of E5564 in the transient middle cerebral artery occlusion model of cerebral ischaemia in mice. KEY RESULTS: In vivo, administration of E5564 1 and 4 hr post-ischaemia reduced the expression of different pro-inflammatory chemokines and cytokines, infarct volume, blood-brain barrier breakdown, and improved neuromotor function, an important clinically relevant outcome. In the human organotypic cortex culture, E5564 reduced the activation of microglia and ROS production evoked by LPS. CONCLUSION AND IMPLICATIONS: TLR4 signalling has a causal role in the inflammation associated with a poor post-stroke outcome. Importantly, its inhibition by eritoran (E5564) provides neuroprotection both in vitro and in vivo, including in human tissue, suggesting a promising new therapeutic approach for ischaemic stroke.

Surgical outcomes of traumatic cervical fractures in patients with ankylosing spondylitis. / Resultados quirúrgicos de fracturas cervicales traumáticas en pacientes con espondilitis anquilosante.

OBJECTIVE: Ankylosing spondylitis is an inflammatory rheumatic disease mainly affecting the axial skeleton. The rigid spine may secondarily develop osteoporosis, further increasing the risk of spinal fracture. In this study, we reviewed fractures in patients with ankylosing spondylitis that had been clinically diagnosed to better define the mechanism of injury, associated neurological deficit, predisposing factors, and management strategies. METHODS: Between January 2004 and December 2014, 6 patients with ankylosing spondylitis and neurological complications after injuries were treated. Neuroimaging evaluation was obtained in all patients by using plain radiography, CT scan, and MR imaging. The ASIA Impairment Scale was used in order to evaluate the neurologic status of the patients. Surgical decision was based on relationship of neurological involvement and spinal instability. RESULTS: A total of 6 cervical injuries were identified in a review of patients in whom ankylosing spondylitis had been diagnosed. Of these, 2 patients were associated with a hyperextension mechanism and 4 cases by flexion mechanism. Posttraumatic neurological deficits were demonstrated in all 6 cases and neurological improvement after surgery was observed in 4 of these cases. The two cases were not improved by the surgery was on a case by presenting a degree of Asia A and another patient who initially improved with surgery but died of pneumonia in the postoperative. CONCLUSIONS: Patients with ankylosing spondylitis are highly susceptible to spinal fracture and spinal cord injury even after only mild trauma. Initial CT or MR imaging of the whole spine is recommended even if the patient's symptoms are mild. The patient should also have early surgical stabilization to correct spinal deformity and avoid worsening of the patient's neurological status.