Purpose
Advances in functional imaging allowed us to visualize brain glucose metabolism in vivo and non-invasively with
18
Ffluoro-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.
Astrocytes can adopt multiple molecular phenotypes in the brain of Alzheimer's disease (AD) patients. Here, we studied the associations of cerebrospinal fluid (CSF) glial fibrillary acidic protein ...(GFAP) and chitinase-3-like protein 1 (YKL-40) levels with brain amyloid-β (Aβ) and tau pathologies. We assessed 121 individuals across the aging and AD clinical spectrum with positron emission tomography (PET) brain imaging for Aβ (
FAZD4694) and tau (
FMK-6240), as well as CSF GFAP and YKL-40 measures. We observed that higher CSF GFAP levels were associated with elevated Aβ-PET but not tau-PET load. By contrast, higher CSF YKL-40 levels were associated with elevated tau-PET but not Aβ-PET burden. Structural equation modeling revealed that CSF GFAP and YKL-40 mediate the effects of Aβ and tau, respectively, on hippocampal atrophy, which was further associated with cognitive impairment. Our results suggest the existence of distinct astrocyte biomarker signatures in response to brain Aβ and tau accumulation, which may contribute to our understanding of the complex link between reactive astrogliosis heterogeneity and AD progression.
•Behavior and synaptic proteins were modified by caffeine throughout life and during development.•Adult female rats receiving caffeine during development displayed impaired recognition ...memory.•Caffeine at highest dose throughout life attenuates anxiety-related behavior in both sexes.•Caffeine treatments modified locomotion in a different manner according to sexes.•Caffeine treatments change BDNF and related proteins in the hippocampus from both sexes.
Caffeine is the psychostimulant most consumed worldwide. In moderate doses, it affords a beneficial effect in adults and upon aging, but has a deleterious effect during brain development. We now tested if caffeine consumption by rats (0.1, 0.3, 1.0g/L in the drinking water, only during active cycle and weekdays) during adulthood could revert the potentially negative effects of caffeine during early life. Thus, we compared caffeine intake starting 15 days before mating and lasting either up to weaning (development) or up to adulthood, on behavior and synaptic proteins in male and female rats. Recognition memory was impaired only in female rats receiving caffeine (0.3 and 1.0g/L) during development, coincident with increased proBDNF and unchanged BDNF levels in the hippocampus. Caffeine in both treatment regimens caused hyperlocomotion only in male rats, whereas anxiety-related behavior was attenuated in both sexes by caffeine (1.0g/L) throughout life. Both caffeine treatment regimens decreased GFAP (as an astrocyte marker) and SNAP-25 (as a nerve terminals marker) in the hippocampus from male rats. TrkB receptor was decreased in the hippocampus from both sexes and treatment regimens. These findings revealed that caffeine intake during a specific time window of brain development promotes sex-dependent behavioral outcomes related to modification in BDNF signaling. Furthermore, caffeine throughout life can overcome the deleterious effects of caffeine on recognition memory during brain development in female rats.
Performance of saliva as a specimen to detect SARS-CoV-2 Fernandes, Paulo Alexandre da Costa; Ferreira, Fernando Alberto da Conceição; Morais, Orlando Miguel ...
Journal of clinical virology,
09/2021, Letnik:
142
Journal Article
Recenzirano
Odprti dostop
•Saliva affects viral gene detection sensitivity differently.•Between 9 and 26% (95% certainty) of COVID-19 patients will have false negative results in saliva.•RNA extraction from saliva will not ...offer better sensitivity than its use directly in RT-PCR.
Massive testing to detect SARS-CoV-2 is an imperious need in times of epidemic but also presents challenges in terms of its concretization. The use of saliva as an alternative to nasopharyngeal swabs (NPS) has advantages, being more friendly to the patient and not requiring trained health workers, so much needed in other functions.
This study used a total of 452 dual samples (saliva and NPS) of patients suspected of having COVID-19 to compare results obtained for the different specimens when using RT-PCR of RNA extracted from NPS and saliva, as well as saliva directly without RNA extraction.
SARS-CoV-2 was not detected in 13 saliva (direct) of the 80 positive NPS samples and in 16 saliva (RNA) of a total of 76 NPS positive samples. Sensitivity of detection of viral genes ORF1ab, E and N in saliva is affected differently and detection of these genes in saliva samples presents great variability when NPS samples present Ct-values above approximately 20, with sensitivities ranging from 76.3% to 86.3%. On average an increase in 7.3 Ct-values (average standard deviation of 4.78) is observed in saliva samples when compared to NPS.
The use of this specimen should be carefully considered due to the false negative rate and the system used for detection may be also very relevant since the different viral genes are affected differently in terms of detection sensitivity using saliva.
The hypothesis that Helicobactermight be a risk factor for human liver diseases has arisen after the detection of Helicobacter DNA in hepatic tissue of patients with hepatobiliary diseases. ...Nevertheless, no explanation that justifies the presence of the bacterium in the human liver has been proposed. We evaluated the presence of Helicobacterin the liver of patients with hepatic diseases of different aetiologies. We prospectively evaluated 147 patients (106 with primary hepatic diseases and 41 with hepatic metastatic tumours) and 20 liver donors as controls. Helicobacter species were investigated in the liver by culture and specific 16S rDNA nested-polymerase chain reaction followed by sequencing. Serum and hepatic levels of representative cytokines of T regulatory cell, T helper (Th)1 and Th17 cell lineages were determined using enzyme linked immunosorbent assay. The data were evaluated using logistic models. Detection of Helicobacter pylori DNA in the liver was independently associated with hepatitis B virus/hepatitis C virus, pancreatic carcinoma and a cytokine pattern characterised by high interleukin (IL)-10, low/absent interferon-γ and decreased IL-17A concentrations (p < 10(-3)). The bacterial DNA was never detected in the liver of patients with alcoholic cirrhosis and autoimmune hepatitis that are associated with Th1/Th17 polarisation. H. pylori may be observed in the liver of patients with certain hepatic and pancreatic diseases, but this might depend on the patient cytokine profile.
Most studies that have evaluated the stomachs of patients with Chagas disease were performed before the discovery of Helicobacter pylori and used no control groups. This study compared the gastric ...features of chagasic and non-chagasic patients and assessed whether gastritis could be associated with Chagas disease.
Gastric biopsy samples were taken from patients who underwent endoscopy for histological analysis according to the Updated Sydney System. H. pylori infection was assessed by histology, 16S ribosomal ribonucleic acid (rRNA) polymerase chain reaction (PCR), serology and the 13C-urea breath test. Patients were considered H. pylori-negative when all of these diagnostic tests were negative. Clinical and socio-demographic data were obtained by reviewing medical records and using a questionnaire.
The prevalence of H. pylori infection (70.3% versus 71.7%) and chronic gastritis (92.2% versus 85%) was similar in the chagasic and non-chagasic groups, respectively; such as peptic ulcer, atrophy and intestinal metaplasia. Gastritis was associated with H. pylori infection independent of Chagas disease in a log-binomial regression model. However, the chagasic H. pylori-negative patients showed a significantly higher grade of mononuclear (in the corpus) and polymorphonuclear (PMN) (in the antrum) cell infiltration. Additionally, the patients with the digestive form of Chagas disease showed a significantly lower prevalence of corpus atrophy than those with other clinical forms.
The prevalence of H. pylori infection and of gastric histological and endoscopic features was similar among the chagasic and non-chagasic patients. Additionally, this is the first controlled study to demonstrate that H. pylori is the major cause of gastritis in patients with Chagas disease.
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