Protein arginine methyltransferase 2 controls inflammatory signaling in acute myeloid leukemia.

Arginine methylation is catalyzed by protein arginine methyltransferases (PRMTs) and is involved in various cellular processes, including cancer development. PRMT2 expression is increased in several cancer types although its role in acute myeloid leukemia (AML) remains unknown. Here, we investigate the role of PRMT2 in a cohort of patients with AML, PRMT2 knockout AML cell lines as well as a Prmt2 knockout mouse model. In patients, low PRMT2 expressors are enriched for inflammatory signatures, including the NF-κB pathway, and show inferior survival. In keeping with a role for PRMT2 in control of inflammatory signaling, bone marrow-derived macrophages from Prmt2 KO mice display increased pro-inflammatory cytokine signaling upon LPS treatment. In PRMT2-depleted AML cell lines, aberrant inflammatory signaling has been linked to overproduction of IL6, resulting from a deregulation of the NF-κB signaling pathway, therefore leading to hyperactivation of STAT3. Together, these findings identify PRMT2 as a key regulator of inflammation in AML.

DAT1 and BDNF polymorphisms interact to predict Aß and tau pathology.

Previous work has associated polymorphisms in the dopamine transporter gene (rs6347 in DAT1/SLC6A3) and brain derived neurotrophic factor gene (Val66Met in BDNF) with atrophy and memory decline. However, it is unclear whether these polymorphisms relate to atrophy and cognition through associations with Alzheimer's disease pathology. We tested for effects of DAT1 and BDNF polymorphisms on cross-sectional and longitudinal ß-amyloid (Aß) and tau pathology (measured with positron emission tomography (PET)), hippocampal volume, and cognition. We analyzed a sample of cognitively normal older adults (cross-sectional n = 321) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). DAT1 and BDNF interacted to predict Aß-PET, tau-PET, and hippocampal atrophy. Carriers of both "non-boptimal" DAT1 C and BDNF Met alleles demonstrated greater pathology and atrophy. Our findings provide novel links between dopamine and neurotrophic factor genes and AD pathology, consistent with previous research implicating these variants in greater risk for developing AD.

Functional network reconfiguration supporting memory-guided attention.

Studies have identified several brain regions whose activations facilitate attentional deployment via long-term memories. We analyzed task-based functional connectivity at the network and node-specific level to characterize large-scale communication between brain regions underlying long-term memory guided attention. We predicted default mode, cognitive control, and dorsal attention subnetworks would contribute differentially to long-term memory guided attention, such that network-level connectivity would shift based on attentional demands, requiring contribution of memory-specific nodes within default mode and cognitive control subnetworks. We expected that these nodes would increase connectivity with one another and with dorsal attention subnetworks during long-term memory guided attention. Additionally, we hypothesized connectivity between cognitive control and dorsal attention subnetworks facilitating external attentional demands. Our results identified both network-based and node-specific interactions that facilitate different components of LTM-guided attention, suggesting a crucial role across the posterior precuneus and restrosplenial cortex, acting independently from the divisions of default mode and cognitive control subnetworks. We found a gradient of precuneus connectivity, with dorsal precuneus connecting to cognitive control and dorsal attention regions, and ventral precuneus connecting across all subnetworks. Additionally, retrosplenial cortex showed increased connectivity across subnetworks. We suggest that connectivity from dorsal posterior midline regions is critical for the integration of external information with internal memory that facilitates long-term memory guided attention.

Functional reconfiguration of task-active frontoparietal control network facilitates abstract reasoning.

While the brain's functional network architecture is largely conserved between resting and task states, small but significant changes in functional connectivity support complex cognition. In this study, we used a modified Raven's Progressive Matrices Task to examine symbolic and perceptual reasoning in human participants undergoing fMRI scanning. Previously, studies have focused predominantly on discrete symbolic versions of matrix reasoning, even though the first few trials of the Raven's Advanced Progressive Matrices task consist of continuous perceptual stimuli. Our analysis examined the activation patterns and functional reconfiguration of brain networks associated with resting state and both symbolic and perceptual reasoning. We found that frontoparietal networks, including the cognitive control and dorsal attention networks, were significantly activated during abstract reasoning. We determined that these same task-active regions exhibited flexibly-reconfigured functional connectivity when transitioning from resting state to the abstract reasoning task. Conversely, we showed that a stable network core of regions in default and somatomotor networks was maintained across both resting and task states. We propose that these regionally-specific changes in the functional connectivity of frontoparietal networks puts the brain in a "task-ready" state, facilitating efficient task-based activation.

Reference Percentiles for Bioelectrical Phase Angle in Athletes.

The present study aimed to develop reference values for bioelectrical phase angle in male and female athletes from different sports. Overall, 2224 subjects participated in this study [1658 males (age 26.2 ± 8.9 y) and 566 females (age 26.9 ± 6.6 y)]. Participants were categorized by their sport discipline and sorted into three different sport modalities: endurance, velocity/power, and team sports. Phase angle was directly measured using a foot-to-hand bioimpedance technology at a 50 kHz frequency during the in-season period. Reference percentiles (5th, 15th, 50th, 85th, and 95th) were calculated and stratified by sex, sport discipline and modality using an empirical Bayesian analysis. This method allows for the sharing of information between different groups, creating reference percentiles, even for sports disciplines with few observations. Phase angle differed (men: p < 0.001; women: p = 0.003) among the three sport modalities, where endurance athletes showed a lower value than the other groups (men: vs. velocity/power: p = 0.010, 95% CI = -0.43 to -0.04; vs. team sports: p < 0.001, 95% CI = -0.48 to -0.02; women: vs. velocity/power: p = 0.002, 95% CI = -0.59 to -0.10; vs. team sports: p = 0.015, 95% CI = -0.52 to -0.04). Male athletes showed a higher phase angle than female athletes within each sport modality (endurance: p < 0.01, 95% CI = 0.63 to 1.14; velocity/power: p < 0.01, 95% CI = 0.68 to 1.07; team sports: p < 0.01, 95% CI = 0.98 to 1.23). We derived phase angle reference percentiles for endurance, velocity/power, and team sports athletes. Additionally, we calculated sex-specific references for a total of 22 and 19 sport disciplines for male and female athletes, respectively. This study provides sex- and sport-specific percentiles for phase angle that can track body composition and performance-related parameters in athletes.

Dynamic Network Analysis Demonstrates the Formation of Stable Functional Networks During Rule Learning.

Variations in the functional connectivity of large-scale cortical brain networks may explain individual differences in learning ability. We used a dynamic network analysis of fMRI data to identify changes in functional brain networks that are associated with context-dependent rule learning. During fMRI scanning, naïve subjects performed a cognitive task designed to test their ability to learn context-dependent rules. Notably, subjects were given minimal instructions about the task prior to scanning. We identified several key network characteristics associated with fast and accurate rule learning. First, consistent with the formation of stable functional networks, a dynamic community detection analysis revealed regionally specific reductions in flexible switching between different functional communities in successful learners. Second, successful rule learners showed decreased centrality of ventral attention regions and increased assortative mixing of cognitive control regions as the rules were learned. Finally, successful subjects showed greater decoupling of default and attention communities throughout the entire task, whereas ventral attention and cognitive control regions became more connected during learning. Overall, the results support a framework by which a stable ventral attention community and more flexible cognitive control community support sustained attention and the formation of rule representations in successful learners.

PET neuroimaging reveals histone deacetylase dysregulation in schizophrenia.

BACKGROUND: Patients with schizophrenia (SCZ) experience chronic cognitive deficits. Histone deacetylases (HDACs) are enzymes that regulate cognitive circuitry; however, the role of HDACs in cognitive disorders, including SCZ, remains unknown in humans. We previously determined that HDAC2 mRNA levels were lower in dorsolateral prefrontal cortex (DLPFC) tissue from donors with SCZ compared with controls. Here we investigated the relationship between in vivo HDAC expression and cognitive impairment in patients with SCZ and matched healthy controls using [11C]Martinostat positron emission tomography (PET). METHODS: In a case-control study, relative [11C]Martinostat uptake was compared between 14 patients with SCZ or schizoaffective disorder (SCZ/SAD) and 17 controls using hypothesis-driven region-of-interest analysis and unbiased whole brain voxel-wise approaches. Clinical measures, including the MATRICS consensus cognitive battery, were administered. RESULTS: Relative HDAC expression was lower in the DLPFC of patients with SCZ/SAD compared with controls, and HDAC expression positively correlated with cognitive performance scores across groups. Patients with SCZ/SAD also showed lower relative HDAC expression in the dorsomedial prefrontal cortex and orbitofrontal gyrus, and higher relative HDAC expression in the cerebral white matter, pons, and cerebellum compared with controls. CONCLUSIONS: These findings provide in vivo evidence of HDAC dysregulation in patients with SCZ and suggest that altered HDAC expression may impact cognitive function in humans. FUNDING: National Institute of Mental Health (NIMH), Brain and Behavior Foundation, Massachusetts General Hospital (MGH), Athinoula A. Martinos Center for Biomedical Imaging, National Institute of Biomedical Imaging and Bioengineering (NIBIB), NIH Shared Instrumentation Grant Program.

HDAC6 Brain Mapping with [18F]Bavarostat Enabled by a Ru-Mediated Deoxyfluorination.

Histone deacetylase 6 (HDAC6) function and dysregulation have been implicated in the etiology of certain cancers and more recently in central nervous system (CNS) disorders including Rett syndrome, Alzheimer's and Parkinson's diseases, and major depressive disorder. HDAC6-selective inhibitors have therapeutic potential, but in the CNS drug space the development of highly brain penetrant HDAC inhibitors has been a persistent challenge. Moreover, no tool exists to directly characterize HDAC6 and its related biology in the living human brain. Here, we report a highly brain penetrant HDAC6 inhibitor, Bavarostat, that exhibits excellent HDAC6 selectivity (>80-fold over all other Zn-containing HDAC paralogues), modulates tubulin acetylation selectively over histone acetylation, and has excellent brain penetrance. We further demonstrate that Bavarostat can be radiolabeled with 18F by deoxyfluorination through in situ formation of a ruthenium π-complex of the corresponding phenol precursor: the only method currently suitable for synthesis of [18F]Bavarostat. Finally, by using [18F]Bavarostat in a series of rodent and nonhuman primate imaging experiments, we demonstrate its utility for mapping HDAC6 in the living brain, which sets the stage for first-in-human neurochemical imaging of this important target.

PET Neurochemical Imaging Modes.

PET has deep roots in neuroscience stemming from its first application in brain tumor and brain metabolism imaging. PET emerged over the past few decades and continues to play a prominent role in the study of neurochemistry in the living human brain. Over time, neurochemical imaging with PET has been expanded to address a host of research questions related to, among many others, protein density, drug occupancy, and endogenous neurochemical release. Each of these imaging modes has distinct design and analysis considerations that are critical for enabling quantitative measurements. The number of considerations required for a neurochemical PET study can make it unapproachable. This article aims to orient those interested in neurochemical PET imaging to three of the common imaging modes and to provide some perspective on needs that exist for expansion of neurochemical PET imaging.

[Evaluation of adherence to recommendations within 3 months after comprehensive geriatric assessment by an inpatient geriatric consultation team]. / Évaluation du suivi des recommandations à 3 mois après prise en charge par une équipe mobile gériatrique hospitalière.

BACKGROUND: Frail elderly patients during their hospitalization can benefit of a comprehensive geriatric assessment (CGA) by an inpatient geriatric consultation team (IGCT). This assessment yields recommendations aiming to improve medical and social management during the patient's hospital stay and after discharge. OBJECTIVES: This study examines the socio-demographic profile of patients assessed by the IGCT and describes the type of recommendations, their adherence rate at 3 months and their impact in terms of mortality, rehospitalization, and institutionalization. METHODS: Retrospective, single center study including all patients assessed by the IGCT during the 4 first months of 2009. These 151 patients fulfilled criteria of either medical and/or social frailty or had been submitted to an inappropriate in-hospital trajectory. Hospital records and telephone follow-up (with informal and/or professional caregivers as well as primary care physicians) were used to monitor the implementation of recommendations up to three months after hospital discharge. RESULTS: Mean age of the 151 patients was 85.6 years, 63% were women. 94% of patients lived at home, 70% had a non-supportive environment, 85% were frail and 11% had dementia. On admission, 64% of them had an acute functional loss. 93% of patients were admitted via the emergency room where 67% benefited from CGA. The median hospital duration stay was 14 days. At discharge, 76% of patients went back home, 12% were institutionalized and 12% had died. Three months after discharge, 18% of the 134 patients surviving hospitalization had been readmitted, 26% institutionalized and 12% had died. The CGA yielded an average of 7 recommendations (median value). The mean adherence rate was 78%. The majority of medical recommendations concerned ancillary care and standard medical management, showing high adherence rates (95%). Recommendations concerning the management of cognitive problems were less frequent and overall poorly adhered to (62%). CONCLUSION: Mean adherence rate was maximal (97%) when the number of recommendations was limited to 4 and it dropped under 80% with more than 5 recommendations. The recommendations concerning management at home were generally followed (60-77%). Regarding to social outcomes, the main recommendation was to mobilize home assistance and its financial support. There was no significant difference between adherence rate in the hospital and in the community. The extent of adherence rate did not correlate with mortality or readmission at 3 months.