Induced Pluripotent Stem Cells and Organoids in Advancing Neuropathology Research and Therapies.

This review delves into the groundbreaking impact of induced pluripotent stem cells (iPSCs) and three-dimensional organoid models in propelling forward neuropathology research. With a focus on neurodegenerative diseases, neuromotor disorders, and related conditions, iPSCs provide a platform for personalized disease modeling, holding significant potential for regenerative therapy and drug discovery. The adaptability of iPSCs, along with associated methodologies, enables the generation of various types of neural cell differentiations and their integration into three-dimensional organoid models, effectively replicating complex tissue structures in vitro. Key advancements in organoid and iPSC generation protocols, alongside the careful selection of donor cell types, are emphasized as critical steps in harnessing these technologies to mitigate tumorigenic risks and other hurdles. Encouragingly, iPSCs show promising outcomes in regenerative therapies, as evidenced by their successful application in animal models.

Influence of Zika virus on the cytotoxicity, cell adhesion, apoptosis and inflammatory markers of glioblastoma cells.

Glioblastoma (GBM) is one of the most common types of brain tumor in adults. Despite the availability of treatments for this disease, GBM remains one of the most lethal and difficult types of tumors to treat, and thus, a majority of patients die within 2 years of diagnosis. Infection with Zika virus (ZIKV) inhibits cell proliferation and induces apoptosis, particularly in developing neuronal cells, and thus could potentially be considered an alternative for GBM treatment. In the present study, two GBM cell lines (U-138 and U-251) were infected with ZIKV at different multiplicities of infection (0.1, 0.01 and 0.001), and cell viability, migration, adhesion, induction of apoptosis, interleukin levels and CD14/CD73 cell surface marker expression were analyzed. The present study demonstrated that ZIKV infection promoted loss of cell viability and increased apoptosis in U-138 cells, as measured by MTT and triplex assay, respectively. Changes in cell migration, as determined by wound healing assay, were not observed; however, the GBM cell lines exhibited an increase in cell adhesion when compared with non-tumoral cells (Vero). The Luminex immunoassay showed a significant increase in the expression levels of IL-4 specifically in U-251 cells (MOI 0.001) following exposure to ZIKV. There was no significant change in the expression levels of IFN-γ upon ZIKV infection in the cell lines tested. Furthermore, a marked increase in the percentage of cells expressing the CD14 surface marker was observed in both GBM cell lines compared with in Vero cells; and significantly increased CD73 expression was observed particularly in U-251 cells, when compared with uninfected cells. These findings indicate that ZIKV infection could lead to reduced cell viability, elevated CD73 expression, improved cellular adherence, and higher rates of apoptosis in glioblastoma cells. Further studies are required to explore the potential use of ZIKV in the treatment of GBM.

The cortical thickness of tricenarian cocaine users assembles features of an octogenarian brain.

It has been suggested that substance use disorders could lead to accelerated biological aging, but only a few neuroimaging studies have investigated this hypothesis so far. In this cross-sectional study, structural neuroimaging was performed to measure cortical thickness (CT) in tricenarian adults with cocaine use disorder (CUD, n1 = 30) and their age-paired controls (YC, n1 = 30), and compare it with octogenarian elder controls (EC, n1 = 20). We found that CT in the right fusiform gyrus was similar between CUD and EC, thinner than the expected values of YC. We also found that regarding CT of the right inferior temporal gyrus, right inferior parietal cortex, and left superior parietal cortex, the CUD group exhibited parameters that fell in between EC and YC groups. Finally, CT of the right pars triangularis bordering with orbitofrontal gyrus, right superior temporal gyrus, and right precentral gyrus were reduced in CUD when contrasted with YC, but those areas were unrelated to CT of EC. Despite the 50-year age gap between our age groups, CT of tricenarian cocaine users assembles features of an octogenarian brain, reinforcing the accelerated aging hypothesis in CUD.

Epileptogenesis and drug-resistant in focal cortical dysplasias: Update on clinical, cellular, and molecular markers.

Focal cortical dysplasia (FCD) is a cortical malformation in brain development and is considered as one of the major causes of drug-resistant epilepsiesin children and adults. The pathogenesis of FCD is yet to be fully understood. Imaging markers such as MRI are currently the surgeons major obstacle due to the difficulty in delimiting the precise dysplasic area and a mosaic brain where there is epileptogenic tissue invisible to MRI. Also increased gene expression and activity may be responsible for the alterations in cell proliferation, migration, growth, and survival. Altered expressions were found, particularly in the PI3K/AKT/mTOR pathway. Surgery is still considered the most effective treatment option, due to drug-resistance, and up to 60 % of patients experience complete seizure control, varying according to the type and location of FCD. Both genetic and epigenetic factors may be involved in the pathogenesis of FCD, and there is no conclusive evidence whether these alterations are inherited or have an environmental origin.

Short-term consumption of highly processed diets varying in macronutrient content impair the sense of smell and brain metabolism in mice.

OBJECTIVE: Food processing greatly contributed to increased food safety, diversity, and accessibility. However, the prevalence of highly palatable and highly processed food in our modern diet has exacerbated obesity rates and contributed to a global health crisis. While accumulating evidence suggests that chronic consumption of such foods is detrimental to sensory and neural physiology, it is unclear whether its short-term intake has adverse effects. Here, we assessed how short-term consumption (<2 months) of three diets varying in composition and macronutrient content influence olfaction and brain metabolism in mice. METHODS: The diets tested included a grain-based standard chow diet (CHOW; 54% carbohydrate, 32% protein, 14% fat; #8604 Teklad Rodent diet , Envigo Inc.), a highly processed control diet (hpCTR; 70% carbohydrate, 20% protein, 10% fat; #D12450B, Research Diets Inc.), and a highly processed high-fat diet (hpHFD; 20% carbohydrate, 20% protein, 60% fat; #D12492, Research Diets Inc.). We performed behavioral and metabolic phenotyping, electro-olfactogram (EOG) recordings, brain glucose metabolism imaging, and mitochondrial respirometry in different brain regions. We also performed RNA-sequencing (RNA-seq) in the nose and across several brain regions, and conducted differential expression analysis, gene ontology, and network analysis. RESULTS: We show that short-term consumption of the two highly processed diets, but not the grain-based diet, regardless of macronutrient content, adversely affects odor-guided behaviors, physiological responses to odorants, transcriptional profiles in the olfactory mucosa and brain regions, and brain glucose metabolism and mitochondrial respiration. CONCLUSIONS: Even short periods of highly processed food consumption are sufficient to cause early olfactory and brain abnormalities, which has the potential to alter food choices and influence the risk of developing metabolic disease.

Exploring CD39 and CD73 Expression as Potential Biomarkers in Prostate Cancer.

Prostate cancer (PC) is the most diagnosed tumor in males and ranks as the second leading cause of male mortality in the western world. The CD39 and CD73 enzymes play a crucial role in cancer regulation by degrading nucleotides and forming nucleosides. This study aimed to investigate the expression of the CD39 and CD73 enzymes as potential therapeutic targets for PC. The initial part of this study retrospectively analyzed tissue samples from 23 PC patients. Using the TissueFAXSTM cytometry platform, we found significantly higher levels of CD39-labeling its intensity compared to CD73. Additionally, we observed a correlation between the Gleason score and the intensity of CD39 expression. In the prospective arm, blood samples were collected from 25 patients at the time of diagnosis and after six months of treatment to determine the expression of CD39 and CD73 in the serum extracellular vesicles (EVs) and to analyze nucleotide hydrolysis. Notably, the expression of CD39 in the EVs was significantly increased compared to the CD73 and/or combined CD39/CD73 expression levels at initial collection. Furthermore, our results demonstrated positive correlations between ADP hydrolysis and the transurethral resection and Gleason score. Understanding the role of ectonucleotidases is crucial for identifying new biomarkers in PC.

WNT pathway in focal cortical dysplasia compared to perilesional nonlesional tissue in refractory epilepsies.

BACKGROUND: Focal cortical dysplasia (FCD) is a malformation of cortical development that causes medical refractory seizures, and one of the main treatments may be surgical resection of the affected area of the brain. People affected by FCD may present with seizures of variable severity since childhood. Despite many medical treatments available, only surgery can offer cure. The pathophysiology of the disease is not yet understood; however, it is known that several gene alterations may play a role. The WNT/ß-catenin pathway is closely related to the control and balance of cell proliferation and differentiation in the central nervous system. The aim of this study was to explore genes related to the WNT/ß-catenin pathway in lesional and perilesional brain tissue in patients with FCD type II. METHODS: Dysplastic and perilesional tissue from the primary dysplastic lesion of patients with FCD type IIa were obtained from two patients who underwent surgical treatment. The analysis of the relative expression of genes was performed by a qRT-PCR array (super array) containing 84 genes related to the WNT pathway. RESULTS: Our results suggest the existence of molecular alteration in some genes of the WNT pathway in tissue with dysplastic lesions and of perilesional tissue. We call this tissue of normal-appearing adjacent cortex (NAAC). Of all genes analyzed, a large number of genes show similar behavior between injured, perilesional and control tissues. However, some genes have similar characteristics between the perilesional and lesional tissue and are different from the control brain tissue, presenting the perilesional tissue as a molecularly altered material. CONCLUSION: Our results suggest that the perilesional area after surgical resection of tissue with cortical dysplasia presents molecular changes that may play a role in the recurrence of seizures in these patients. The perilesional tissue should receive expanded attention beyond the somatic mutations described and associated with FCD, such as mTOR, for example, to new signaling pathways that may play a crucial role in seizure recurrence.

Clinical validation and diagnostic accuracy of 99mTc-EDDA/HYNIC-TOC compared to 111In-DTPA-octreotide in patients with neuroendocrine tumours: the LACOG 0214 study.

99mTc-EDDA/HYNIC-TOC is an easily available and cheaper radionuclide that could be used for somatostatin-receptor-based imaging of neuroendocrine tumours (NETs). We aimed to evaluate the diagnostic performance of 99mTc-EDDA/HYNIC-TOC compared to111In-DTPA-octreotide in patients (pts) with NETs. We performed a prospective diagnostic study including pts with biopsy-confirmed NET and at least one visible lesion at conventional imaging. Two independent nuclear medicine physicians evaluated pts who underwent 99mTc and 111In scans and images. The primary outcome was comparative diagnostic accuracy of 99mTc and 111In. Secondary outcomes include safety. Nine pts were included and performed 14 paired scans. Overall, 126 lesions were identified. 99mTc demonstrated superior sensitivity both when all images were analysed (93.7, 95% CI 88.1% - 96.8% versus 74.8%, 95% CI 66.6 - 81.6%, p < 0.001) and when liver-specific images were analysed (97.8%, 95% CI 92.7% - 99.5% versus 85.1%, 95% CI 76.6% - 91.0%, p < 0.001). 99mTc was also associated with a lower negative likelihood ratio (LR) (0.002, 95% CI 0.009 - 0.1 versus 0.19, 95% CI 0.12 - 0.42, p = 0.009) when evaluating hepatic lesions. Adverse events happened in 3 pts after 111In and in 2 pts after 99mTc, all grade 1. The 99mTc demonstrated a higher sensitivity overall and a better negative LR in liver-specific images compared to 111In in pts with NETs. Our findings suggest that 99mTc is an alternative to 111In and is especially useful in ruling out liver metastases. NCT02691078.

Fructose supplementation shifts rat brain metabolism in experimental migraine.

AIMS: We have previously demonstrated that fructose supplementation (FS), given in a scheme used for inducing metabolic syndrome (MS), elicited pain relief in the nitroglycerin (NTG)-elicited rat migraine model. Herein, we evaluated whether FS could reestablish the impaired metabolic pathways in NTG-injected rats. MAIN METHODS: Male Wistar rats (N = 40) were divided into two groups for receiving 10 % FS or tap water. After 45 days, they were subdivided into NTG-injected (10 mg/kg; 15 days) or controls. After the fourth NTG injection, 18F-fluorodeoxyglucose ([18F] FDG) micro-PET scanning was accomplished. The day after, euthanasia was performed, and blood was collected for glycemia and LDH analysis. The levels of energy molecules, TBARS, PGC-1α, and MCTS1 were evaluated in the brain cortices. The activated satellite glial cells (SGC) were assessed in the trigeminal ganglion (TG). KEY FINDINGS: There were no variations of glycemia or LDH serum levels. NTG-injected rats showed a significant increase in glucose uptake in the hypothalamus (HT) vs. NTG-free rats. The FS-NTG group showed increased metabolism in the superior colliculus (SC) vs. the NTG group. Moreover, the glucose uptake was amplified in the inferior colliculus (IC) of the FS-NTG vs. FS group. The cortical inosine levels were significantly higher in FS-NTG rats vs. NTG or FS groups, with no changes in TBARS or MCTS1 levels, despite a minor decrease of PGC1-α contents in the FS+NTG group. Finally, there was a significant increase of activated SGC around TG in the FS-NTG rats. SIGNIFICANCE: We provide novel evidence linking nutrition and metabolism with migraine.

Guillain-Barré syndrome associated with COVID-19: A systematic review.

With the outbreak of coronavirus disease 2019 (COVID-19), the whole world was impacted by a pandemic. With the passage of time and knowledge about the dynamics and viral propagation of this disease, the short-, medium- and long-term repercussions are still being discovered. During this period, it has been learned that various manifestations of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can affect the nervous system. In recent months, a variety of studies and case reports have proposed an association between COVID-19 and Guillain-Barré syndrome (GBS). The present work aims to systematically review the publications available to date to verify the relationship between these two pathologies and the characteristics of post-COVID GBS. There were 156 studies included in this work, resulting in a total of 436 patients. The findings show a mean age of the patients of 61,38 years and a male majority. The GBS symptoms began on average 19 days after the onset of COVID-19 infection. Regarding GBS, the main manifestations found included generalized weakness, reflex reduction, facial paresis/paralysis and hypoesthesia. As expected, the most common result in cerebrospinal fluid (CSF) analysis was albuminocytological dissociation. A pattern of blood analysis findings common to all patients was not observed due to non-standardization of case reports. Regarding electrodiagnostic studies, acute inflammatory demyelinating polyneuropathy (AIDP) appeared as the most common subtype of GBS in this study. There have been reports, to a lesser extent, of acute motor axonal neuropathy (AMAN), acute sensorimotor axonal neuropathy (AMSAN), the pharyngeal-cervical-brachial variant (PCB), and Miller-Fisher syndrome (MFS). The GBS treatment used was mainly intravenous immunoglobulin (IVIG) and plasma exchange (PLEX). Therefore, the present study reports a high prevalence of hospitalization and intensive care units ICU admissions, conjecturing a relationship between the development of GBS and the severity of COVID-19. Despite the severity, most patients showed improvement in GBS symptoms after treatment, and their residual symptoms did not include motor involvement. Therefore, the development of GBS seems to be related to COVID-19 infection, as reported by the present systematic review.

When to test for COVID-19 using real-time reverse transcriptase polymerase chain reaction: a systematic review.

OBJECTIVES: The aim of this study was to evaluate the time in days between symptom onset and first positive real-time reverse transcriptase polymerase chain reaction (RT-PCR) result for COVID-19. METHODS: This systematic review was conducted in the MEDLINE (PubMed), Embase, and Scopus databases using the following descriptors: "COVID-19", "SARS-CoV-2", "coronavirus", "RT-PCR", "real time PCR", and "diagnosis". RESULTS: The included studies were conducted in 31 different countries and reported on a total of 6831 patients. The median age of the participants was 49.95 years. The three most common symptoms were fever, cough, and dyspnea, which affected 4012 (58.68%), 3192 (46.69%), and 2009 patients (29.38%), respectively. Among the 90 included studies, 13 were prospective cohorts, 15 were retrospective cohorts, 36 were case reports, 20 were case series, and six were cross-sectional studies. The overall mean time between symptom onset and positive test result was 6.72 days. Fourteen articles were analyzed separately for the temporal profile of RT-PCR test results; the best performance was on days 22-24, when 98% of test results were positive. CONCLUSION: These findings corroborate the RT-PCR COVID-19 testing practices of some health units. In addition, the most frequently described symptoms of these patients can be considered the initial symptoms of infection and used in decision-making about RT-PCR testing.

Air Traffic Controllers and Executive Brain Function.

BACKGROUND: This study evaluated the executive functions of air traffic controllers (ATCs) in relation to demographic and occupational characteristics such as length of service, technical qualifications, and work shifts.METHODS: This was a cross-sectional study based on a convenience sample with sequential selection of 52 Brazilian ATCs using the Wisconsin Card Sorting Test (WCST), questionnaire applied to the ATCs, Student's t-test, and one-way analysis of variance with post hoc Tukey multiple comparisons of WCST with functional characteristics.RESULTS: ATCs with 0 to 5 yr of service presented scores significantly above the cohort average in the WCST [0-5 yr: 0.54 ± 0.01 vs. 6-15 yr: 0.31 ± 0.52 vs. 151 yr: -0.02 ± 0.80]. ATCs working a 3-shift pattern presented an efficient performance and fewer perseverative errors in the WCST (3-shift: -0.63 ± 0.38 vs. 4-shift: -0.45 ± 0.43), that did not rise to significance. In a comparison between executive brain functions and technical qualifications, the controllers who worked in the TWR (Aerodrome Control Tower) only, and those who worked in both the TWR and APP (Approach Control Service) showed no differences in the number of completed categories and in perseverative errors.DISCUSSION:The executive brain functioning of the ATCs, such as mental flexibility, strategic planning and inhibitory control, were identified as being above average when compared to the general population. While alterations in work shifts appear to have a negative (but nonsignificant) impact, newer ATCs showed stronger scores than more experienced ATCs on the WCST. Successful performance as an ATC has complex foundations, such as understanding the context of air navigation and having strong executive function capabilities.de Freitas AM, Portuguez MW, Russomano, T, da Costa JC. Air traffic controllers and executive brain function. Aerosp Med Hum Perform. 2022; 93(5):426-432.

Zika virus congenital microcephaly severity classification and the association of severity with neuropsychomotor development.

BACKGROUND: Zika virus infection during pregnancy is linked to birth defects, most notably microcephaly, which is associated with neurodevelopmental delays. OBJECTIVE: The goals of the study were to propose a method for severity classification of congenital microcephaly based on neuroradiologic findings of MRI scans, and to investigate the association of severity with neuropsychomotor developmental scores. We also propose a semi-automated method for MRI-based severity classification of microcephaly. MATERIALS AND METHODS: We conducted a cross-sectional investigation of 42 infants born with congenital Zika infection. Bayley Scales of Infant and Toddler Development III (Bayley-III) developmental evaluations and MRI scans were carried out at ages 13-39 months (mean: 24.8 months; standard deviation [SD]: 5.8 months). The severity score was generated based on neuroradiologist evaluations of brain malformations. Next, we established a distribution of Zika virus-microcephaly severity score including mild, moderate and severe and investigated the association of severity with neuropsychomotor developmental scores. Finally, we propose a simplified semi-automated procedure for estimating the severity score based only on volumetric measures. RESULTS: The results showed a correlation of r=0.89 (P<0.001) between the Zika virus-microcephaly severity score and the semi-automated method. The trimester of infection did not correlate with the semi-automated method. Neuropsychomotor development correlated with the severity classification based on the radiologic readings and semi-automated method; the more severe the imaging scores, the lower the neuropsychomotor developmental scores. CONCLUSION: These severity classification methods can be used to evaluate severity of microcephaly and possible association with developmental consequences. The semi-automated methods thus provide an alternative for predicting severity of microcephaly based on only one MRI sequence.

Clozapine induces astrocyte-dependent FDG-PET hypometabolism.

PURPOSE: Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with [18F]fluoro-2-deoxyglucose (FDG) positron emission tomography (PET) imaging. In the past decades, FDG-PET has been instrumental in the understanding of brain function in health and disease. The source of the FDG-PET signal has been attributed to neuronal uptake, with hypometabolism being considered as a direct index of neuronal dysfunction or death. However, other brain cells are also metabolically active, including astrocytes. Based on the astrocyte-neuron lactate shuttle hypothesis, the activation of the glutamate transporter 1 (GLT-1) acts as a trigger for glucose uptake by astrocytes. With this in mind, we investigated glucose utilization changes after pharmacologically downregulating GLT-1 with clozapine (CLO), an anti-psychotic drug. METHODS: Adult male Wistar rats (control, n = 14; CLO, n = 12) received CLO (25/35 mg kg-1) for 6 weeks. CLO effects were evaluated in vivo with FDG-PET and cortical tissue was used to evaluate glutamate uptake and GLT-1 and GLAST levels. CLO treatment effects were also assessed in cortical astrocyte cultures (glucose and glutamate uptake, GLT-1 and GLAST levels) and in cortical neuronal cultures (glucose uptake). RESULTS: CLO markedly reduced in vivo brain glucose metabolism in several brain areas, especially in the cortex. Ex vivo analyses demonstrated decreased cortical glutamate transport along with GLT-1 mRNA and protein downregulation. In astrocyte cultures, CLO decreased GLT-1 density as well as glutamate and glucose uptake. By contrast, in cortical neuronal cultures, CLO did not affect glucose uptake. CONCLUSION: This work provides in vivo demonstration that GLT-1 downregulation induces astrocyte-dependent cortical FDG-PET hypometabolism-mimicking the hypometabolic signature seen in people developing dementia-and adds further evidence that astrocytes are key contributors of the FDG-PET signal.

Airway inflammation induces anxiety-like behavior through neuroinflammatory, neurochemical, and neurometabolic changes in an allergic asthma model.

Allergic asthma is characterized by chronic airway inflammation and is constantly associated with anxiety disorder. Recent studies showed bidirectional interaction between the brain and the lung tissue. However, where and how the brain is affected in allergic asthma remains unclear. We aimed to investigate the neuroinflammatory, neurochemical, and neurometabolic alterations that lead to anxiety-like behavior in an experimental model of allergic asthma. Mice were submitted to an allergic asthma model induced by ovalbumin (OVA) and the control group received only Dulbecco's phosphate-buffered saline (DPBS). Our findings indicate that airway inflammation increases interleukin (IL) -9, IL-13, eotaxin, and IL-1ß release and changes acetylcholinesterase (AChE) and Na+,K+-ATPase activities in the brain of mice. Furthermore, we demonstrate that a higher reactive oxygen species (ROS) formation and antioxidant defense alteration that leads to protein damage and mitochondrial dysfunction. Therefore, airway inflammation promotes a pro-inflammatory environment with an increase of BDNF expression in the brain of allergic asthma mice. These pro-inflammatory environments lead to an increase in glucose uptake in the limbic regions and to anxiety-like behavior that was observed through the elevated plus maze (EPM) test and downregulation of glucocorticoid receptor (GR). In conclusion, the present study revealed for the first time that airway inflammation induces neuroinflammatory, neurochemical, and neurometabolic changes within the brain that leads to anxiety-like behavior. Knowledge about mechanisms that lead to anxiety phenotype in asthma is a beneficial tool that can be used for the complete management and treatment of the disease.

Bone marrow mononuclear cell transplant prevents rat depression and modulates inflammatory and neurogenic molecules.

INTRODUCTION: Major depressive disorder is associated with chronic inflammation and deficient production of brain-derived neurotrophic factor (BDNF). Bone marrow mononuclear cell (BMMC) transplantation has an anti-inflammatory effect and has been proven effective in restoring non-depressive behavior. This study investigated whether BMMC transplantation can prevent the development of depression or anxiety in chronic mild stress (CMS), as well as its effect on inflammatory and neurogenic molecules. METHOD: Three groups of animals were compared: BMMC-transplanted animals subjected to CMS for 45 days, CMS non-transplanted rats, and control animals. After the CMS period, the three groups underwent the following behavioral tests: sucrose preference test (SPT), eating-related depression test (ERDT), social avoidance test (SAT), social interaction test (SIT), and elevated plus maze test (EPMT). Transplanted cell tracking and measurement of the expression of high-mobility group box 1 (HMGB1), interleukin-1ß (IL-1ß), tumor necrosis factor (TNFα), and BDNF were performed on brain and spleen tissues. RESULTS: BMMC transplantation prevented the effects of CMS in the SPT, ERDT, SAT, and SIT, while prevention was less pronounced in the EPMT. It was found to prevent increased HMGB-1 expression induced by CMS in the hippocampus and spleen, increase BDNF expression in both tissues, and prevent increased IL-1ß expression in the hippocampus alone, while no effect of the transplant was observed in the TNFα expression. In addition, no transplanted cells were found in either the brain or spleen. CONCLUSIONS: BMMC transplantation prevents the development of depression and anxiety-like behavior triggered by CMS. It could prevent increased HMGB-1 and IL-1ß expression in the hippocampus and increased BDNF expression in the same tissue. Cell treatment represents a further perspective in the research and treatment of depression and possible mood disorders.

Amyloid-ß PET Classification on Cognitive Aging Stages Using the Centiloid Scale.

PROPOSE: This study aims to explore the use of the Centiloid (CL) method in amyloid-ß PET quantification to evaluate distinct cognitive aging stages, investigating subjects' mismatch classification using different cut-points for amyloid-ß positivity. PROCEDURES: The CL equation was applied in four groups of individuals: SuperAgers (SA), healthy age-matched controls (AC), healthy middle-aged controls (MC), and Alzheimer's disease (AD). The amyloid-ß burden was calculated and compared between groups and quantitative variables. Three different cut-points (Jack CR, Wiste HJ, Weigand SD, et al., Alzheimer's Dement 13:205-216, 2017; Salvadó G, Molinuevo JL, Brugulat-Serrat A, et al., Alzheimer's Res Ther 11:27, 2019; and Amadoru S, Doré V, McLean CA, et al., Alzheimer's Res Ther 12:22, 2020) were applied in CL values to differentiate the earliest abnormal pathophysiological accumulation of Aß and the established Aß pathology. RESULTS: The AD group exhibited a significantly increased Aß burden compared to the MC, but not AC groups. Both healthy control (MC and AC) groups were not significantly different. Visually, the SA group showed a diverse distribution of CL values compared with MC; however, the difference was not significant. The CL values have a moderate and significant relationship between Aß visual read, RAVLT DR and MMSE. Depending on the cut-point used, 10 CL, 19 CL, or 30 CL, 7.5% of our individuals had a different classification in the Aß positivity. For the AC group, we obtained about 40 to 60% of the individuals classified as positive. CONCLUSION: SuperAgers exhibited a similar Aß load to AC and MC, differing in cognitive performance. Independently of cut-point used (10 CL, 19 CL, or 30 CL), three SA individuals were classified as Aß positive, showing the duality between the individual's clinics and the biological definition of Alzheimer's. Different cut-points lead to Aß positivity classification mismatch in individuals, and an extra care is needed for individuals who have a CL value between 10 and 30 CL.

Evidence That Methylphenidate Treatment Evokes Anxiety-Like Behavior Through Glucose Hypometabolism and Disruption of the Orbitofrontal Cortex Metabolic Networks.

Methylphenidate (MPH) has been widely misused by children and adolescents who do not meet all diagnostic criteria for attention-deficit/hyperactivity disorder without a consensus about the consequences. Here, we evaluate the effect of MPH treatment on glucose metabolism and metabolic network in the rat brain, as well as on performance in behavioral tests. Wistar male rats received intraperitoneal injections of MPH (2.0 mg/kg) or an equivalent volume of 0.9% saline solution (controls), once a day, from the 15th to the 44th postnatal day. Fluorodeoxyglucose-18 was used to investigate cerebral metabolism, and a cross-correlation matrix was used to examine the brain metabolic network in MPH-treated rats using micro-positron emission tomography imaging. Performance in the light-dark transition box, eating-related depression, and sucrose preference tests was also evaluated. While MPH provoked glucose hypermetabolism in the auditory, parietal, retrosplenial, somatosensory, and visual cortices, hypometabolism was identified in the left orbitofrontal cortex. MPH-treated rats show a brain metabolic network more efficient and connected, but careful analyses reveal that the MPH interrupts the communication of the orbitofrontal cortex with other brain areas. Anxiety-like behavior was also observed in MPH-treated rats. This study shows that glucose metabolism evaluated by micro-positron emission tomography in the brain can be affected by MPH in different ways according to the region of the brain studied. It may be related, at least in part, to a rewiring in the brain the metabolic network and behavioral changes observed, representing an important step in exploring the mechanisms and consequences of MPH treatment.

Stem cell-based therapy for COVID-19 and ARDS: a systematic review.

Despite global efforts to establish effective interventions for coronavirus disease 2019 (COVID-19) and its major complications, such as acute respiratory distress syndrome (ARDS), the treatment remains mainly supportive. Hence, identifying an effective and safe therapy for severe COVID-19 is critical for saving lives. A significant number of cell-based therapies have been through clinical investigation. In this study, we performed a systematic review of clinical studies investigating different types of stem cells as treatments for COVID-19 and ARDS to evaluate the safety and potential efficacy of cell therapy. The literature search was performed using PubMed, Embase, and Scopus. Among the 29 studies, there were eight case reports, five Phase I clinical trials, four pilot studies, two Phase II clinical trials, one cohort, and one case series. Among the clinical studies, 21 studies used cell therapy to treat COVID-19, while eight studies investigated cell therapy as a treatment for ARDS. Most of these (75%) used mesenchymal stem cells (MSCs) to treat COVID-19 and ARDS. Findings from the analyzed articles indicate a positive impact of stem cell therapy on crucial immunological and inflammatory processes that lead to lung injury in COVID-19 and ARDS patients. Additionally, among the studies, there were no reported deaths causally linked to cell therapy. In addition to standard care treatments concerning COVID-19 management, there has been supportive evidence towards adjuvant therapies to reduce mortality rates and improve recovery of care treatment. Therefore, MSCs treatment could be considered a potential candidate for adjuvant therapy in moderate-to-severe COVID-19 cases and compassionate use.

Neuroprotective effects of the CTK 01512-2 toxin against neurotoxicity induced by 3-nitropropionic acid in rats.

The mitochondrial inhibitor 3-nitropropionic acid (3-NP) induces excitotoxicity. The authors hypothesized that CTK 01512-2, a recombinant peptide calcium channel N-type blocker, and the TRPA1 antagonist, could show neuroprotective effects. The male Wistar rats received 3-NP [25 mg/kg (i.p.) for 7 days], and a treatment of CTK 01512-2 was delivered intrathecally (i.t.), thrice a week. The neuroprotective effects were evaluated by [18F]FDG MicroPET analysis. The CTK 01512-2 toxin was able to reestablish similar glucose uptakes on the control animals. To detect the neurobehavioral effects from 3-NP, three protocols (6.25, 12.5, 18.75 mg/kg of 3-NP (i.p.), for 3, 4, and 6 days, respectively) were evaluated by performance tests (open field test, walk footprint, elevated plus-maze, Y-maze, and the object recognition test). Important disabilities in the gait of the rats were seen, as well as memory deficits, and anxious behavior in the animals that were treated with all 3-NP protocols. The dose of 18.75 mg/kg (for 3 days) showed the most pronounced behavioral effects and lethality, while the rats treated with 12.5 mg/kg (for 4 days) showed behavioral effects similar to the 6.25 mg/kg dose (for 6 days). The third protocol was then repeated and the rats were treated with the CTK 01512-2 toxin to be evaluated behaviorally again. The recombinant peptide prevented all of the gait-evaluated parameters that were induced by 3-NP at a 6.25 mg/kg dose, which displayed an improvement in the exploratory activities. Overall, these results have reinforced the positive effects of CTK 01512-2 against the behavioral changes that were induced by the mitochondrial inhibitor 3-NP.