CSF1R inhibitor JNJ-40346527 attenuates microglial proliferation and neurodegeneration in P301S mice

Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes in association with Alzheimer's disease, and experimental data have demonstrated microglial proliferation as a significant component of the neuropathology. In this study, we tested the efficacy of the selective CSF1R inhibitor JNJ-40346527 (JNJ-527) in the P301S mouse tauopathy model. We first demonstrated the anti-proliferative effects of JNJ-527 on microglia in the ME7 prion model, and its impact on the inflammatory profile, and provided potential CNS biomarkers for clinical investigation with the compound, including pharmacokinetic/pharmacodynamics and efficacy assessment by TSPO autoradiography and CSF proteomics. Then, we showed for the first time that blockade of microglial proliferation and modification of microglial phenotype leads to an attenuation of tau-induced neurodegeneration and results in functional improvement in P301S mice. Overall, this work strongly supports the potential for inhibition of CSF1R as a target for the treatment of Alzheimer's disease and other tau-mediated neurodegenerative diseases

Inflammatory biomarkers in Alzheimer's disease plasma

Introduction: Plasma biomarkers for Alzheimer's disease (AD) diagnosis/stratification are a \u201cHoly Grail\u201d of AD research and intensively sought; however, there are no well-established plasma markers. Methods: A hypothesis-led plasma biomarker search was conducted in the context of international multicenter studies. The discovery phase measured 53 inflammatory proteins in elderly control (CTL; 259), mild cognitive impairment (MCI; 199), and AD (262) subjects from AddNeuroMed. Results: Ten analytes showed significant intergroup differences. Logistic regression identified five (FB, FH, sCR1, MCP-1, eotaxin-1) that, age/APO\u3b54 adjusted, optimally differentiated AD and CTL (AUC: 0.79), and three (sCR1, MCP-1, eotaxin-1) that optimally differentiated AD and MCI (AUC: 0.74). These models replicated in an independent cohort (EMIF; AUC 0.81 and 0.67). Two analytes (FB, FH) plus age predicted MCI progression to AD (AUC: 0.71). Discussion: Plasma markers of inflammation and complement dysregulation support diagnosis and outcome prediction in AD and MCI. Further replication is needed before clinical translation

Neuroimaging-based classification of PTSD using data-driven computational approaches: a multisite big data study from the ENIGMA-PGC PTSD consortium

Background: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. Methods: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. Results: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for D-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. Conclusion: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.Stress-related psychiatric disorders across the life spa

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.New methods for child psychiatric diagnosis and treatment outcome evaluatio

The Immune Landscape of Cancer

We performed an extensive immunogenomic anal-ysis of more than 10,000 tumors comprising 33diverse cancer types by utilizing data compiled byTCGA. Across cancer types, we identified six im-mune subtypes\u2014wound healing, IFN-gdominant,inflammatory, lymphocyte depleted, immunologi-cally quiet, and TGF-bdominant\u2014characterized bydifferences in macrophage or lymphocyte signa-tures, Th1:Th2 cell ratio, extent of intratumoral het-erogeneity, aneuploidy, extent of neoantigen load,overall cell proliferation, expression of immunomod-ulatory genes, and prognosis. Specific drivermutations correlated with lower (CTNNB1,NRAS,orIDH1) or higher (BRAF,TP53,orCASP8) leukocytelevels across all cancers. Multiple control modalitiesof the intracellular and extracellular networks (tran-scription, microRNAs, copy number, and epigeneticprocesses) were involved in tumor-immune cell inter-actions, both across and within immune subtypes.Our immunogenomics pipeline to characterize theseheterogeneous tumors and the resulting data areintended to serve as a resource for future targetedstudies to further advance the field

Open data from the third observing run of LIGO, Virgo, KAGRA, and GEO

The global network of gravitational-wave observatories now includes five detectors, namely LIGO Hanford, LIGO Livingston, Virgo, KAGRA, and GEO 600. These detectors collected data during their third observing run, O3, composed of three phases: O3a starting in 2019 April and lasting six months, O3b starting in 2019 November and lasting five months, and O3GK starting in 2020 April and lasting two weeks. In this paper we describe these data and various other science products that can be freely accessed through the Gravitational Wave Open Science Center at https://gwosc.org. The main data set, consisting of the gravitational-wave strain time series that contains the astrophysical signals, is released together with supporting data useful for their analysis and documentation, tutorials, as well as analysis software packages

The roles of school psychologists working within a pediatric setting.

• With an increasing number of children presenting with health conditions, pediatric care has expanded from solely a medical definition to a more comprehensive service delivery approach that includes psychology and education (Perrin, 1999). • An interdisciplinary, inter-systemic approach is necessary to meet the needs of children across systems (Power, Shapiro, & DuPaul, 2003). • School psychologists are uniquely qualified to facilitate collaboration between settings and systems due to their expertise in consultation and intervention. • Roles in pediatric school psychology include: advocating for children’s educational and social needs; consulting with care providers, families, and educators; and facilitating collaboration among these individuals (Power & Parrish, 1995). • Conjoint behavioral consultation (CBC): o A structured, indirect model wherein a consultant works with a parent and teacher to promote collaborative, problem-solving partnerships across home and school (Sheridan, Kratochwill, & Bergan, 1996). o Effective in addressing a range of concerns across home and school (Sheridan, et al., 2001); high levels of parent and teacher acceptability and satisfaction reported (Freer & Watson, 1999; Sheridan & Steck, 1995). • Other roles: Individualized Education Plan (IEP) consultation, parent- or teacher-only consultation, observations, and provision of resources/referrals. • To date, no research has explored the conditions in which CBC is warranted in a pediatric medical setting and ones in which other services are appropriate

Aerosol decadal trends (II): In-situ aerosol particle number concentrations at GAW and ACTRIS stations

We have analysed the trends of total aerosol particle number concentrations (N) measured at long-term measurement stations involved either in the Global Atmosphere Watch (GAW) and/or EU infrastructure project ACTRIS. The sites are located in Europe, North America, Antarctica, and on Pacific Ocean islands. The majority of the sites showed clear decreasing trends both in the full-length time series, and in the intra-site comparison period of 2001–2010, especially during the winter months. Several potential driving processes for the observed trends were studied, and even though there are some similarities between N trends and air temperature changes, the most likely cause of many northern hemisphere trends was found to be decreases in the anthropogenic emissions of primary particles, SO2 or some coemitted species. We could not find a consistent agreement between the trends of N and particle optical properties in the few stations with long time series of all of these properties. The trends of N and the proxies for cloud condensation nuclei (CCN) were generally consistent in the few European stations where the measurements were available. This work provides a useful comparison analysis for modelling studies of trends in aerosol number concentrations