PPAR Gamma and Viral Infections of the Brain Layrolle, Pierre; Payoux, Pierre; Chavanas, Stéphane
International journal of molecular sciences,
08/2021, Letnik:
22, Številka:
16
Journal Article
Recenzirano
Odprti dostop
Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a master regulator of metabolism, adipogenesis, inflammation and cell cycle, and it has been extensively studied in the brain in relation ...to inflammation or neurodegeneration. Little is known however about its role in viral infections of the brain parenchyma, although they represent the most frequent cause of encephalitis and are a major threat for the developing brain. Specific to viral infections is the ability to subvert signaling pathways of the host cell to ensure virus replication and spreading, as deleterious as the consequences may be for the host. In this respect, the pleiotropic role of PPARγ makes it a critical target of infection. This review aims to provide an update on the role of PPARγ in viral infections of the brain. Recent studies have highlighted the involvement of PPARγ in brain or neural cells infected by immunodeficiency virus 1, Zika virus, or human cytomegalovirus. They have provided a better understanding on PPARγ functions in the infected brain, and revealed that it can be a double-edged sword with respect to inflammation, viral replication, or neuronogenesis. They unraveled new roles of PPARγ in health and disease and could possibly help designing new therapeutic strategies.
Abstract
Non-Pharmacological Interventions (NPIs) are increasingly being introduced into healthcare, but their mechanisms are unclear. In this study, 30 healthy participants received foot reflexology ...(FR) and sham massage, and went through a resting-state functional magnetic resonance imaging (rs-fMRI) to evaluate NPIs effect on brain. Rs-fMRI revealed an effect of both NPIs on functional connectivity with changes occurring in the default-mode network, the sensorimotor network and a Neural Network Correlates of Pain (NNCP—a newly discovered network showing great robustness). Even if no differences were found between FR and SM, this study allowed to report brain biomarkers of well-being as well as the safety of NPIs. In further research, it could be relevant to study it in patients to look for a true reflexology induced-effect dependent of patient reported outcomes. Overall, these findings enrich the understanding of the neural correlates of well-being experienced with NPIs and provided insight into the basis of the mechanisms of NPIs.
Brain organoids are invaluable tools for pathophysiological studies or drug screening, but there are still challenges to overcome in making them more reproducible and relevant. Recent advances in ...three-dimensional (3D) bioprinting of human neural organoids is an emerging approach that may overcome the limitations of self-organized organoids. It requires the development of optimal hydrogels, and a wealth of research has improved our knowledge about biomaterials both in terms of their intrinsic properties and their relevance on 3D culture of brain cells and tissue. Although biomaterials are rarely biologically neutral, few articles have reviewed their roles on neural cells. We here review the current knowledge on unmodified biomaterials amenable to support 3D bioprinting of neural organoids with a particular interest in their impact on cell homeostasis. Alginate is a particularly suitable bioink base for cell encapsulation. Gelatine is a valuable helper agent for 3D bioprinting due to its viscosity. Collagen, fibrin, hyaluronic acid and laminin provide biological support to adhesion, motility, differentiation or synaptogenesis and optimize the 3D culture of neural cells. Optimization of specialized hydrogels to direct differentiation of stem cells together with an increased resolution in phenotype analysis will further extend the spectrum of possible bioprinted brain disease models.
BACKGROUND/OBJECTIVES
Cognitive decline associated with impaired kidney function might involve neurodegeneration. Our objectives were to evaluate the longitudinal association between kidney function ...and cognitive decline in older adults and to assess the involvement of cortical beta‐amyloid and hippocampal atrophy (features of Alzheimer's disease (AD)) in this association.
DESIGN
Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial (MAPT).
SETTINGS
Thirteen memory centers (France and Monaco, 2008–2016).
PARTICIPANTS
A total of 1,334 community‐dwellers >70 years old without dementia at baseline.
MEASUREMENTS
We estimated glomerular filtration rate (eGFR) from serum creatinine using CKD‐Epi equation. Cognition was assessed at baseline, 6, 12, 24, 36, 48, and 60 months using a composite Z‐score designed for MAPT. The Clinical Dementia Rating (CDR) score was used to assess cognition and functional independence. We examined the association between eGFR and (1) evolution of the composite cognitive Z‐score using mixed‐effect models and (2) progression on CDR using Cox models and mixed‐effect models. Adjustments were made for age, sex, education, ApoE genotype, cardiovascular risk factors and disease, hippocampal volume (measured with magnetic resonance), and cortical beta‐amyloid (measured with positron emission tomography).
RESULTS
Median (IQR) eGFR was 73(60–84) mL/min/1.73 m2. Two hundred sixty‐nine participants experienced progression on CDR score during follow‐up. eGFR<60 was significantly associated with progression on CDR score (adjusted hazard ratio (aHR) = 1.35, 95% CI 1.01–1.80) and with both the cognitive and functional independence components of CDR, but not with the evolution of the composite cognitive Z‐score (adjusted β‐coefficient −0.004, 95% CI −0.014; 0.006). Associations were not modified after further adjustment for beta‐amyloid (subsample: n = 252) and hippocampal volume (subsample: n = 270).
CONCLUSIONS
We did not find a mild to moderate renal insufficiency to be associated with brain imaging features of AD, and our results do not support the involvement of AD mechanisms in the incidence of cognitive impairment and functional decline associated with chronic kidney disease.
Childhood RMS is a rare malignant disease in which evaluation of tumour spread at diagnosis is essential for therapeutic management. F-18 FDG-PET imaging is currently used for initial RMS disease ...staging.
This multicentre retrospective study in six French university hospitals was designed to analyse the prognostic accuracy of MTV at diagnosis for patients with RMS between 1 January 2007 and 31 October 2017, for overall (OS) and progression-free survival (PFS). MTV was defined as the sum of the primitive tumour and the largest metastasis, where relevant, with a 40% threshold of the primary tumour SUVmax. Additional aims were to define the prognostic value of SUVmax, SUVpeak, and bone lysis at diagnosis.
Participants were 101 patients with a median age of 7.4 years (IQR 4.0-12.5, 62 boys), with localized disease (35 cases), regional nodal spread (43 cases), or distant metastases (23). 44 patients had alveolar subtypes. In a univariate analysis, a MTV greater than 200 cm3 was associated with OS (HR = 3.47 1.79;6.74, p<0.001) and PFS (HR = 3.03 1.51;6.07, p = 0.002). SUVmax, SUVpeak, and bone lysis also influenced OS (respectively p = 0.005, p = 0.004 and p = 0.007) and PFS (p = 0.029, p = 0.019 and p = 0.015). In a multivariate analysis, a MTV greater than 200 cm3 was associated with OS (HR = 2.642 1.272;5.486, p = 0.009) and PFS (HR = 2.707 1.322;5.547, p = 0.006) after adjustment for confounding factors, including SUVmax, SUVpeak, and bone lysis.
A metabolic tumor volume greater than 200 cm3, SUVmax, SUVpeak, and bone lysis in the pre-treatment assessment were unfavourable for outcome.
Large-scale longitudinal multi-site MRI brain morphometry studies are becoming increasingly crucial to characterize both normal and clinical population groups using fully automated segmentation ...tools. The test–retest reproducibility of morphometry data acquired across multiple scanning sessions, and for different MR vendors, is an important reliability indicator since it defines the sensitivity of a protocol to detect longitudinal effects in a consortium. There is very limited knowledge about how across-session reliability of morphometry estimates might be affected by different 3T MRI systems. Moreover, there is a need for optimal acquisition and analysis protocols in order to reduce sample sizes. A recent study has shown that the longitudinal FreeSurfer segmentation offers improved within session test–retest reproducibility relative to the cross-sectional segmentation at one 3T site using a nonstandard multi-echo MPRAGE sequence. In this study we implement a multi-site 3T MRI morphometry protocol based on vendor provided T1 structural sequences from different vendors (3D MPRAGE on Siemens and Philips, 3D IR-SPGR on GE) implemented in 8 sites located in 4 European countries. The protocols used mild acceleration factors (1.5–2) when possible. We acquired across-session test–retest structural data of a group of healthy elderly subjects (5 subjects per site) and compared the across-session reproducibility of two full-brain automated segmentation methods based on either longitudinal or cross-sectional FreeSurfer processing. The segmentations include cortical thickness, intracranial, ventricle and subcortical volumes. Reproducibility is evaluated as absolute changes relative to the mean (%), Dice coefficient for volume overlap and intraclass correlation coefficients across two sessions. We found that this acquisition and analysis protocol gives comparable reproducibility results to previous studies that used longer acquisitions without acceleration. We also show that the longitudinal processing is systematically more reliable across sites regardless of MRI system differences. The reproducibility errors of the longitudinal segmentations are on average approximately half of those obtained with the cross sectional analysis for all volume segmentations and for entorhinal cortical thickness. No significant differences in reliability are found between the segmentation methods for the other cortical thickness estimates. The average of two MPRAGE volumes acquired within each test–retest session did not systematically improve the across-session reproducibility of morphometry estimates. Our results extend those from previous studies that showed improved reliability of the longitudinal analysis at single sites and/or with non-standard acquisition methods. The multi-site acquisition and analysis protocol presented here is promising for clinical applications since it allows for smaller sample sizes per MRI site or shorter trials in studies evaluating the role of potential biomarkers to predict disease progression or treatment effects.
•We implemented a multi-site 3T MRI protocol for brain morphometry on 8EU sites.•We acquired across-session test-retest data on 40 healthy elderly subjects.•We calculated the reproducibility of cortical and volumetric FreeSurfer estimates.•Longitudinal segmentation was more reliable than cross-sectional on all sites.
Dynamic Functional Connectivity (dFC) in the resting state (rs) is considered as a correlate of cognitive processing. Describing dFC as a flow across morphing connectivity configurations, our notion ...of dFC speed quantifies the rate at which FC networks evolve in time. Here we probe the hypothesis that variations of rs dFC speed and cognitive performance are selectively interrelated within specific functional subnetworks.
In particular, we focus on Sleep Deprivation (SD) as a reversible model of cognitive dysfunction. We found that whole-brain level (global) dFC speed significantly slows down after 24h of SD. However, the reduction in global dFC speed does not correlate with variations of cognitive performance in individual tasks, which are subtle and highly heterogeneous. On the contrary, we found strong correlations between performance variations in individual tasks –including Rapid Visual Processing (RVP, assessing sustained visual attention)– and dFC speed quantified at the level of functional sub-networks of interest. Providing a compromise between classic static FC (no time) and global dFC (no space), modular dFC speed analyses allow quantifying a different speed of dFC reconfiguration independently for sub-networks overseeing different tasks. Importantly, we found that RVP performance robustly correlates with the modular dFC speed of a characteristic frontoparietal module.
•Sleep Deprivation (SD) slows down the random walk in FC space implemented by Dynamic Functional Connectivity (dFC) at rest.•Whole-brain level slowing of dFC speed does not selectively correlate with fine and task-specific changes in performance.•We quantify dFC speed separately for different link-based modules coordinated by distinct regional “meta-hubs”.•Modular dFC speed variations capture subtle and task-specific variations of cognitive performance induced by SD.
Purpose
NMDA receptors (NMDARs) dysfunction plays a central role in the physiopathology of psychiatric and neurodegenerative disorders whose mechanisms are still poorly understood. The development ...of a PET (positron emission tomography) tracer able to selectively bind to the NMDARs intra-channel PCP site may make it possible to visualize NMDARs in an open and active state. We describe the
in vitro
pharmacological characterization of
18
F-fluoroethylnormemantine (
18
F-FNM) and evaluate its ability to localize activated NMDA receptors in a rat preclinical model of excitotoxicity.
Procedures
The affinity of the non-radioactive analog for the intra-channel PCP site was determined in a radioligand competition assay using
3
HTCP (
3
HN-(1-thienylcyclohexyl)piperidine) on rat brain homogenates. Selectivity was also investigated by the displacement of specific radioligands targeting various cerebral receptors.
In vivo
brain lesions were performed using stereotaxic quinolinic acid (QA) injections in the left motor area (M1) of seven Sprague Dawley rats. Each rat was imaged with a microPET/CT camera, 40 min after receiving a dose of 30 MBq + / − 20 of
18
F-FNM, 24 and 72 h after injury. Nine non-injured rats were also imaged using the same protocol.
Results
FNM displayed IC
50
value of 13.0 ± 8.9 µM in rat forebrain homogenates but also showed significant bindings on opioid receptors. In the frontal and left somatosensory areas,
18
FFNM PET detected a mean of 37% and 41% increase in
18
FFNM uptake (
p
< 0,0001) 24 and 72 h after QA stereotaxic injection, respectively, compared to the control group.
Conclusions
In spite of FNM’s poor affinity for NMDAR PCP site, this study supports the ability of this tracer to track massive activation of NMDARs in neurological diseases.
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