The glutamatergic system in Alzheimer's disease: a systematic review with meta-analysis.

Glutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer's disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta-analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain. We searched PubMed and Web of Science (database origin-October 2023) reports evaluating glutamate, glutamine, glutaminase, glutamine synthetase, glutamate reuptake, aspartate, excitatory amino acid transporters, vesicular glutamate transporters, glycine, D-serine, metabotropic and ionotropic glutamate receptors in the AD human brain (PROSPERO #CDRD42022299518). The studies were synthesized by outcome and brain region. We included cortical regions, the whole brain (cortical and subcortical regions combined), the entorhinal cortex and the hippocampus. Pooled effect sizes were determined with standardized mean differences (SMD), random effects adjusted by false discovery rate, and heterogeneity was examined by I2 statistics. The search retrieved 6 936 articles, 63 meeting the inclusion criteria (N = 709CN/786AD; mean age 75/79). We showed that the brain of AD individuals presents decreased glutamate (SMD = -0.82; I2 = 74.54%; P < 0.001) and aspartate levels (SMD = -0.64; I2 = 89.71%; P = 0.006), and reuptake (SMD = -0.75; I2 = 83.04%; P < 0.001. We also found reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPAR)-GluA2/3 levels (SMD = -0.63; I2 = 95.55%; P = 0.046), hypofunctional N-methyl-D-aspartate receptor (NMDAR) (SMD = -0.60; I2 = 91.47%; P < 0.001) and selective reduction of NMDAR-GluN2B subunit levels (SMD = -1.07; I2 = 41.81%; P < 0.001). Regional differences include lower glutamate levels in cortical areas and aspartate levels in cortical areas and in the hippocampus, reduced glutamate reuptake, reduced AMPAR-GluA2/3 in the entorhinal cortex, hypofunction of NMDAR in cortical areas, and a decrease in NMDAR-GluN2B subunit levels in the entorhinal cortex and hippocampus. Other parameters studied were not altered. Our findings show depletion of the glutamatergic system and emphasize the importance of understanding glutamate-mediated neurotoxicity in AD. This study has implications for the development of therapies and biomarkers in AD.

The GABAergic system in Alzheimer's disease: a systematic review with meta-analysis.

The γ-aminobutyric acid (GABA)ergic system is the primary inhibitory neurotransmission system in the mammalian brain. Its dysregulation has been shown in multiple brain conditions, but in Alzheimer's disease (AD) studies have provided contradictory results. Here, we conducted a systematic review with meta-analysis to investigate whether the GABAergic system is altered in AD patients compared to healthy controls (HC), following the PRISMA 2020 Statement. We searched PubMed and Web of Science from database inception to March 18th, 2023 for studies reporting GABA, glutamate decarboxylase (GAD) 65/67, GABAA, GABAB, and GABAC receptors, GABA transporters (GAT) 1-3 and vesicular GAT in the brain, and GABA levels in the cerebrospinal fluid (CSF) and blood. Heterogeneity was estimated using the I2 index, and the risk of bias was assessed with an adapted questionnaire from the Joanna Briggs Institute Critical Appraisal Tools. The search identified 3631 articles, and 48 met the final inclusion criteria (518 HC, mean age 72.2, and 603 AD patients, mean age 75.6). Random-effects meta-analysis [standardized mean difference (SMD)] revealed that AD patients presented lower GABA levels in the brain (SMD = -0.48 [95% CI = -0.7, -0.27], adjusted p value (adj. p) < 0.001) and in the CSF (-0.41 [-0.72, -0.09], adj. p = 0.042), but not in the blood (-0.63 [-1.35, 0.1], adj. p = 0.176). In addition, GAD65/67 (-0.67 [-1.15, -0.2], adj. p = 0.006), GABAA receptor (-0.51 [-0.7, -0.33], adj. p < 0.001), and GABA transporters (-0.51 [-0.92, -0.09], adj. p = 0.016) were lower in the AD brain. Here, we showed a global reduction of GABAergic system components in the brain and lower GABA levels in the CSF of AD patients. Our findings suggest the GABAergic system is vulnerable to AD pathology and should be considered a potential target for developing pharmacological strategies and novel AD biomarkers.

Ultrasonography of the Superficial Temporal and Axillary Arteries in Giant Cell Arteritis diagnosis.

OBJECTIVES: Giant cell arteritis (GCA) is the main systemic vasculitis in individuals aged ≥ 50 years. Color Doppler ultrasound (CDS) has an established role in GCA diagnosis and management. This study aims to assess the clinical characteristics associated with a positive CDS evaluation and the impact of additional axillary artery examination on diagnostic sensitivity. MATERIAL AND METHODS: We conducted a retrospective analysis of patients undergoing CDS of the superficial temporal arteries, with or without axillary artery assessment, at our hospital, between 2009 and 2023. Patients meeting the new 2022 diagnostic criteria for GCA were included and their characteristics were analyzed according to the presence of the halo sign on CDS. RESULTS: Of the 135 included patients (54% female, mean age 75±8 years), the halo sign was observed in 57%, correlating with higher systemic symptom prevalence (61% vs 42%, p=0.035), lower hemoglobin (p<0.001), and higher erythrocyte sedimentation rate (p=0.028). The halo sign inversely related to prior corticosteroid therapy (p=0.033). Patients with axillary halo sign had fewer external carotid symptoms and a higher vertebral halo sign prevalence. Vertebral halo sign was associated with posterior circulation ischemic stroke (65%, p < 0.001). Axillary artery studies improved diagnostic sensitivity by 9%. CONCLUSION: In our study, the halo sign correlated with higher systemic symptoms and analytical abnormalities. Axillary artery examination enhanced CDS sensitivity, linked to severe outcomes like stroke. Prior corticosteroid therapy reduced CDS sensitivity. The correlation of clinical, laboratory, and ultrasound findings provides a more comprehensive understanding of GCA pathogenesis and evolution.

Acute clinical outcomes predict both generic and specific health-related quality of life six and 12 months after stroke: A one-year prospective study developed in a middle-income country.

OBJECTIVE: To identify acute predictors of generic and specific health-related quality of life (HRQoL) six and 12 months after stroke in individuals from a middle-income country. MATERIAL AND METHODS: This was a prospective study. The dependent outcomes assessed during six and 12 months after stroke included both generic and specific HRQoL (Short Form Health Survey-36 [SF-36] and stroke-specific quality of life [SSQOL]). The predictors were age, sex, education level, length of hospital stay, current living arrangement, stroke severity, functional independence, and motor impairment. RESULTS: 122 (59.9±14 years) and 103 (59.8±14.71 years) individuals were evaluated six and 12 months after stroke, respectively. Functional independence and sex were significant acute predictors of both generic and specific HRQoL. Functional independence was the strongest predictor (0.149≤R2≤0.262; 20.01≤F≤43.96, p<0.001), except for generic HRQoL at 12 months, where sex was the strongest predictor (R2=0.14; F=17.97, p<0.001). CONCLUSION: Generic and specific HRQoL in chronic individuals six and 12 months after stroke, from a middle-income country, can be predicted based on functional independence, the strongest predictor, assessed in the acute phase, except for generic HRQoL at 12 months. Functional independence can be modified by rehabilitation strategies and thus should be considered for HRQoL prognoses at chronic phase.

Access to rehabilitation professionals by individuals with stroke one month after hospital discharge from a stroke unit in Brazil is insufficient regardless of the pandemic.

OBJECTIVE: To compare access to rehabilitation professionals by individuals with stroke one month after hospital discharge from a stroke unit in Brazil, before and during the COVID-19 pandemic. MATERIALS AND METHODS: This longitudinal and prospective study included individuals aged 20 years or older without previous disabilities admitted into a stroke unit due to a first stroke. Individuals were divided into two groups: before (G1) and during (G2) the COVID-19 pandemic. Groups were matched for age, sex, education level, socioeconomic status, and stroke severity. One month after hospital discharge, individuals were contacted via telephone to collect data regarding their access to rehabilitation services based on the number of referred rehabilitation professionals. Then, between-group comparisons were conducted (α = 5%). RESULTS: The access to rehabilitation professionals was similar between groups. Rehabilitation professionals accessed included medical doctors, occupational therapists, physical therapists, and speech therapists. The first consultation after hospital discharge was mainly provided by public services. Despite the pandemic, telehealth was not frequent in any period evaluated. In both groups, the number of accessed professionals (G1 = 110 and G2 = 90) was significantly lower than the number of referrals (G1 = 212 and G2 = 194; p < 0.001). CONCLUSIONS: Access to rehabilitation professionals was similar between groups. However, the number of accessed rehabilitation professionals was lower than that of referred ones during both periods. This finding indicates a compromised comprehensiveness of care for individuals with stroke, regardless of the pandemic.

Reduction in the cerebrospinal fluid protein level after bevacizumab treatment in patients with optic pathway low-grade gliomas.

Optic pathway gliomas (OPG) can cause elevated cerebrospinal fluid (CSF) protein concentrations. We report on two patients with suprasellar low-grade gliomas and high CSF protein levels (590 and 551 mg/dl) that precluded shunt implantation. After two and three doses of bevacizumab, respectively, the levels dropped dramatically to 191 and 178 mg/dl, respectively. Bevacizumab treatment was associated with a decrease in CSF protein level, allowing successful shunt placement. Our results are consistent with the pharmacological mechanism of bevacizumab, which decreases protein leakage from blood vessels to the ventricles.

The Flavonol Quercitrin Hinders GSK3 Activity and Potentiates the Wnt/ß-Catenin Signaling Pathway.

The Wnt/ß-catenin signaling pathway dictates cell proliferation and differentiation during embryonic development and tissue homeostasis. Its deregulation is associated with many pathological conditions, including neurodegenerative disease, frequently downregulated. The lack of efficient treatment for these diseases, including Alzheimer's disease (AD), makes Wnt signaling an attractive target for therapies. Interestingly, novel Wnt signaling activating compounds are less frequently described than inhibitors, turning the quest for novel positive modulators even more appealing. In that sense, natural compounds are an outstanding source of potential drug leads. Here, we combine different experimental models, cell-based approaches, neuronal culture assays, and rodent behavior tests with Xenopus laevis phenotypic analysis to characterize quercitrin, a natural compound, as a novel Wnt signaling potentiator. We find that quercitrin potentiates the signaling in a concentration-dependent manner and increases the occurrence of the Xenopus secondary axis phenotype mediated by Xwnt8 injection. Using a GSK3 biosensor, we describe that quercitrin impairs GSK3 activity and increases phosphorylated GSK3ß S9 levels. Treatment with XAV939, an inhibitor downstream of GSK3, impairs the quercitrin-mediated effect. Next, we show that quercitrin potentiates the Wnt3a-synaptogenic effect in hippocampal neurons in culture, which is blocked by XAV939. Quercitrin treatment also rescues the hippocampal synapse loss induced by intracerebroventricular injection of amyloid-ß oligomers (AßO) in mice. Finally, quercitrin rescues AßO-mediated memory impairment, which is prevented by XAV939. Thus, our study uncovers a novel function for quercitrin as a Wnt/ß-catenin signaling potentiator, describes its mechanism of action, and opens new avenues for AD treatments.

Innate immune memory mediates increased susceptibility to Alzheimer's disease-like pathology in sepsis surviving mice.

Sepsis survivors show long-term impairments, including alterations in memory and executive function. Evidence suggests that systemic inflammation contributes to the progression of Alzheimers disease (AD), but the mechanisms involved in this process are still unclear. Boosted (trained) and diminished (tolerant) innate immune memory has been described in peripheral immune cells after sepsis. However, the occurrence of long-term innate immune memory in the post-septic brain is fully unexplored. Here, we demonstrate that sepsis causes long-lasting trained innate immune memory in the mouse brain, leading to an increased susceptibility to Aß oligomers (AßO), central neurotoxins found in AD. Hippocampal microglia from sepsis-surviving mice shift to an amoeboid/phagocytic morphological profile when exposed to low amounts of AßO, and this event was accompanied by the upregulation of several pro-inflammatory proteins (IL-1ß, IL-6, INF-γ and P2X7 receptor) in the mouse hippocampus, suggesting that a trained innate immune memory occurs in the brain after sepsis. Brain exposure to low amounts of AßO increased microglial phagocytic ability against hippocampal synapses. Pharmacological blockage of brain phagocytic cells or microglial depletion, using minocycline and colony stimulating factor 1 receptor inhibitor (PLX3397), respectively, prevents cognitive dysfunction induced by AßO in sepsis-surviving mice. Altogether, our findings suggest that sepsis induces a long-lasting trained innate immune memory in the mouse brain, leading to an increased susceptibility to AßO-induced neurotoxicity and cognitive impairment.

Clinical, Laboratory and Ultrasonographic Interrelations in Giant Cell Arteritis.

OBJECTIVES: The diagnosis of giant cell arteritis (GCA) is based on the presence of clinical and laboratory features. Color-duplex sonography (CDS) may supplant the limited sensitivity of temporal artery biopsy. The aim of our work was to characterize clinical and laboratory findings in patients with positive CDS for GCA. MATERIALS AND METHODS: Retrospective study of all consecutive patients of our center fulfilling American College of Rheumatology criteria for GCA who performed CDS study between 2009-2019. Data on clinical and laboratory features were compared in two groups: with and without halo sign. RESULTS: Ninety-one patients were included. Temporal halo sign was identified in 46% of patients. Halo sign was more often present in older patients (77 ± 8 vs 73 ± 8 years, p = 0.022), associated with systemic features (58% vs 42%, p = 0.011), higher erythrocyte sedimentation rate (84 ± 26 vs 74 ± 34 mm/hour, p = 0.020), and lower hemoglobin values (10.9 ± 1.5 vs 12.1 ± 1.6 g/dL, p < 0.001). The number of patients under corticosteroids before CDS was higher in the group without halo (62% vs 33%, p = 0.005). Ischemic stroke occurred in 17 patients (19%), 76% in the vertebrobasilar territory, and stroke was associated with vertebral halo sign (p < 0.001). CONCLUSIONS: Halo sign was present in half of our patients. Previous corticosteroids treatment decreased positive CDS findings. Systemic symptoms and laboratory findings are more notorious in halo sign subgroup of patients. Stroke cases in GCA patients disproportionally affected the posterior circulation. Ultrasonography provides information about a more pronounced systemic involvement and a higher risk of major complications.

Acute phase treatment in central retinal artery occlusion: thrombolysis, hyperbaric oxygen therapy or both?

Central retinal artery occlusion (CRAO) is a neuro-ophthalmological emergency. There is a finite time window for acute interventions such as revascularization (e.g. intravenous thrombolysis-IVT) and retinal oxygenation (e.g. hyperbaric oxygen therapy-HBOT) therapies. Case 1: A 35-year-old female presented with CRAO in the right eye (OD) confirmed by fluorescein angiography (FA) and optical coherence tomography (OCT). She underwent 4 sessions of HBOT (100% O2 at 2.4 atmosphere absolute for 90 min). Afterwards, visual defect on the nasal field was kept but visual acuity (VA) improved from counting fingers to 1.0. Case 2: A 65-year-old male presented with CRAO in his left eye (OS) with 1.5 h of evolution. Orbital sonography and OCT confirmed the presence of an embolus and he underwent IVT with rTPA (0.9 mg/kg). VA improved from light perception to 0.1. Case 3: A 21-year-old male presented acute visual loss in his OD with 2.5 h of evolution. OCT and retinography identified CRAO. He was submitted to IVT (rTPA-0.9 mg/kg) followed by 12 sessions of HBOT. VA improved from hand motion to 1.0. Our case series depicts the approaches and possible outcomes in acute management of an infrequent, but highly morbid, cerebroretinovascular disorder. Future clinical trials are warranted to tackle current difficulties in CRAO treatment.

Endolymphatic hydrops evaluation on MRI: Practical considerations.

Four-hour delayed three-dimensional fluid-attenuated inversion recovery (3D-FLAIR) sequence after intravenous gadolinium-based contrast agent administration is an optimal magnetic resonance imaging technique to evaluate endolymphatic hydrops in patients with known or suspected Ménière's disease. Nonenhanced endolymphatic space surrounded by enhanced perilymphatic space is evaluated in the cochlea and vestibule separately. In cochlear hydrops, the scala media is enlarged, potentially obliterating the scala vestibuli. In vestibular hydrops, the size of the saccule becomes equal to or larger than that of the utricle; as hydrops progresses, the saccule and utricle become larger and confluent until complete obliteration of the vestibule's perilymphatic space. In patients with a unilateral clinical presentation of Ménière's disease, it is possible to depict the asymmetries of perilymph enhancement, which may be increased on the affected side and reflect a permeability alteration of the blood-perilymph barrier. In addition, endolymphatic hydrops can be observed in the asymptomatic ear of these patients with a unilateral clinical presentation, showing that Ménière's disease tends to undergo bilateral evolution over time.

Balance between S-nitrosylation and denitrosylation modulates myoblast proliferation independently of soluble guanylyl cyclase activation.

Nitric oxide (NO) contributes to myogenesis by regulating the transition between myoblast proliferation and fusion through cGMP signaling. NO can form S-nitrosothiols (RSNO), which control signaling pathways in many different cell types. However, neither the role of RSNO content nor its regulation by the denitrosylase activity of S-nitrosoglutathione reductase (GSNOR) during myogenesis is understood. Here, we used primary cultures of chick embryonic skeletal muscle cells to investigate whether changes in intracellular RSNO alter proliferation and fusion of myoblasts in the presence and absence of cGMP. Cultures were grown to fuse most of the myoblasts into myotubes, with and without S-nitrosocysteine (CysNO), 8-Br-cGMP, DETA-NO, or inhibitors for NO synthase (NOS), GSNOR, soluble guanylyl cyclase (sGC), or a combination of these, followed by analysis of GSNOR activity, protein expression, RSNO, cGMP, and cell morphology. Although the activity of GSNOR increased progressively over 72 h, inhibiting GSNOR (by GSNOR inhibitor - GSNORi - or by knocking down GSNOR with siRNA) produced an increase in RSNO and in the number of myoblasts and fibroblasts, accompanied by a decrease in myoblast fusion index. This was also detected with CysNO supplementation. Enhanced myoblast number was proportional to GSNOR inhibition. Effects of the GSNORi and GSNOR knockdown were blunted by NOS inhibition, suggesting their dependence on NO synthesis. Interestingly, GSNORi and GSNOR knockdown reversed the attenuated proliferation obtained with sGC inhibition in myoblasts, but not in fibroblasts. Hence myoblast proliferation is enhanced by increasing RSNO, and regulated by GSNOR activity, independently of cGMP production and signaling.

Immediate results of photodynamic therapy for the treatment of halitosis in adolescents: a randomized, controlled, clinical trial.

UNLABELLED: Light with or without chemical agents has been used to induce therapeutic and antimicrobial effects. With photodynamic therapy, the antimicrobial effect is confined to areas covered by a photosensitive dye and irradiated with light. The aim of the present study was to evaluate the effect of photodynamic therapy for the treatment of halitosis in adolescents through the analysis of volatile sulfur compounds, especially sulfide. A controlled, clinical trial was conducted with 45 adolescents randomly allocated to three groups: group 1, photodynamic therapy administered to the dorsum of the tongue; group 2, treatment with a tongue scraper; and group 3, treatment with a tongue scraper combined with photodynamic therapy. The diagnosis of halitosis was performed using gas chromatography before and after treatment. Comparisons were made using the Kruskal-Wallis test followed by the Student-Newman-Keuls test, with the level of significance set at 5 % (p < 0.05). After treatment, a statistically significant reduction in halitosis was found in all groups (p < 0.001). The greatest reduction in total sulfides (median = 0) occurred with the combination of tongue scraper and photodynamic therapy. The present study describes a novel option for the treatment of halitosis in adolescents with an immediate effect that does not involve the mechanical aggression of the lingual papillae that occurs with conventional treatment. TRIAL REGISTRATION: Photodynamic Therapy in Adolescents Halitosis ( https://clinicaltrials.gov/ct2/show/NCT02007993?term=NCT02007993&rank=1 )Number: NCT02007993FUNDING:FAPESPNumber: 2013/13032-8.

DBScope as a versatile computational toolbox for the visualization and analysis of sensing data from deep brain stimulation.

Different neurostimulators for deep brain stimulation (DBS) come already with the ability to chronically sense local field potentials during stimulation. This invaluable new data has the potential to increase our understanding of disease-related brain activity patterns, their temporal evolution, and their modulation in response to therapies. It also gives the opportunity to unveil new electrophysiological biomarkers and ultimately bring adaptive stimulation therapies closer to clinical practice. Unfortunately, there are still very limited options on how to visualize, analyze, and exploit the full potential of the sensing data from these new DBS neurostimulators. To answer this need, we developed a free open-source toolbox, named DBScope, that imports data from neurostimulation devices and can be operated in two ways: via user interface and programmatically, as a library of functions. In this way, it can be used by both clinicians during clinical sessions (for instance, to visually inspect data from the current or previous in-clinic visits), and by researchers in their research pipelines (e.g., for pre-processing, feature extraction and biomarker search). All in all, the DBScope toolbox is set to facilitate the clinical decision-making process and the identification of clinically relevant biomarkers. The toolbox is already being used in clinical and research environments, and it is freely available to download at GitHub (where it is also fully documented).