Age moderates associations between dementia worry and subjective cognition.

The present study assessed whether dementia worry is associated with adults' subjective cognitive difficulties, and whether any associations are moderated by age. Participants were 477 adults aged 18-90 years. They completed standard, subjective measures of dementia worry and everyday cognitive difficulties (i.e. attention, language, verbal and visual-spatial memory, and visual-perceptual ability). Moderated regression analyses included dementia worry as a predictor of specific cognitive difficulties, and age as a moderator. Covariates included gender, trait cognitive and somatic anxiety, general aging-related anxiety, depression, stress, mental health treatment status, and health status. Greater overall dementia worry, and specifically more frequent dementia worry, were both associated with greater attentional difficulty in middle-aged and older adults, but not in young adults. Cognitions about developing dementia in reaction to memory lapses were also associated with greater cognitive difficulties across the adult lifespan for multiple cognitive domains. Results highlight a robust relationship between dementia worry and subjective attentional difficulties, especially in middle-aged and older adults. Worry frequency is also more influential with adult aging. A cognitive or meta-cognitive mechanism may underlie subjective cognitive concerns across the adult lifespan.

Adult Aging Moderates the Relationship Between Trait Cognitive Anxiety and Subjective Everyday Cognitive Difficulties.

The present aim was to determine, across the adult lifespan, the extent to which different dimensions of trait anxiety might affect subjective cognitive difficulties in everyday life. Following Attentional Control Theory (ACT; Eysenck et al., 2007), we predicted that trait anxiety would have a greater effect on attention and verbal abilities than on visual abilities. We also expected trait cognitive anxiety to exhibit more robust relationships with cognition than trait somatic anxiety. Importantly, we predicted that effects of anxiety would be greater in older adults, in line with the Strength and Vulnerability Integration model (SAVI; Charles, 2010). The sample comprised 286 United Kingdom-based adults aged 18-93 years. Participants completed self-report measures of trait cognitive and somatic anxiety (the State-Trait Inventory for Cognitive and Somatic Anxiety; STICSA, Ree et al., 2008) and everyday cognitive difficulties (the Multiple Abilities Self-Report Questionnaire; MASQ, Seidenberg et al., 1994). Moderated regression models were constructed, including trait cognitive or somatic anxiety as a predictor of cognitive difficulties, and age as the moderator variable. Covariates included depression, stress (the Depression Anxiety Stress Scales-short form; DASS-21, Lovibond and Lovibond, 1995), gender, current mental health treatment status, and physical health status. When cognitive anxiety was the predictor variable, somatic anxiety was also included as a covariate, and vice-versa. Trait cognitive anxiety and age interacted to predict all MASQ subscales other than visual-perceptual ability. Difficulties with attention, verbal memory, and language abilities were significantly greater at higher levels of anxiety for all age groups, with the effect greatest in older adults. Difficulties with visual-spatial memory were significantly greater at higher levels of anxiety in middle-aged and older adults only. Higher trait somatic anxiety predicted difficulties with verbal memory and language ability independently of age, and interacted with age to predict language difficulties. Interestingly, age also significantly predicted less subjective difficulty with attention, independently of anxiety level. The results show that trait cognitive and somatic anxiety are both related to subjective, everyday cognitive difficulties. However, effects of trait cognitive anxiety are more robust across cognitive domains and tend to increase, or first appear, over the course of the adult lifespan.

A systematic review of the impacts of intergenerational engagement on older adults' cognitive, social, and health outcomes.

BACKGROUND: Intergenerational engagement could benefit health and wellbeing within an ageing population. This systematic review evaluated the impacts of intergenerational engagement on cognitive, social, and health outcomes in healthy older adults and older adults with mild cognitive impairment. RESEARCH DESIGN AND METHODS: Comprehensive literature searches were undertaken, with records filtered according to pre-registered criteria. Study quality was formally assessed, and a narrative synthesis of the findings produced. RESULTS: Forty-four studies were reviewed. Regarding quantitative evidence, 4 out of 8 studies found significant intergenerational engagement effects on cognitive outcomes, 15 of 24 on social outcomes, and 21 of 31 on health-related outcomes. Qualitative evidence was also important for understanding perceived impacts and experiences of intergenerational programmes. Only 11 studies fully met criteria for high quality research, of which the majority focused on social outcomes. DISCUSSION AND IMPLICATIONS: There are a range of potential benefits of intergenerational engagement, most notably regarding anxiety, generativity, cross-age attitudes, and physical activity. However, heterogeneity in programme context, sample design, dosage, and duration indicate that more research is required to enable wider implementation and generalisability. Scientific rigour in both quantitative and qualitative research should also be employed as far as possible, to provide the highest quality evidence.

Impacts of trait anxiety on visual working memory, as a function of task demand and situational stress.

Higher trait anxiety can impair cognitive functioning via attention, but relatively little is known about the impacts on visual working memory. These were investigated using previously validated visual feature binding tasks. In Study 1, participants' memory for visual features (shapes) and feature bindings (coloured shapes) was assessed. Stimulus presentation was simultaneous or sequential, varying attentional demand, and participants were grouped according to trait cognitive anxiety (low, moderate, high). No reliable effect of trait anxiety, either cognitive or somatic, was found on memory accuracy, but moderate trait cognitive anxiety was associated with faster correct response times (i.e. increased efficiency) when stimuli were sequentially presented. In Study 2, the role of situational stress was explored during a simultaneously presented task. Higher trait cognitive and somatic anxiety were both associated with poorer efficiency during both shape and binding memory tasks. Trait somatic anxiety also predicted poorer binding effectiveness (i.e. accuracy), in those reporting higher state cognitive anxiety. Situational stress predicted binding effectiveness, but never interacted with trait anxiety, and was therefore not necessary to observe these trait anxiety-visual working memory relationships. Trait cognitive and somatic anxiety, and situational stress, therefore each influence visual working memory performance.

Discovery of {4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetic acid (GSK726701A), a novel EP4 receptor partial agonist for the treatment of pain.

A novel series of EP4 agonists and antagonists have been identified, and then used to validate their potential in the treatment of inflammatory pain. This paper describes these novel ligands and their activity within a number of pre-clinical models of pain, ultimately leading to the identification of the EP4 partial agonist GSK726701A.

Inhibition of fucosylation reshapes inflammatory macrophages and suppresses type II collagen-induced arthritis.

OBJECTIVE: Fucosylation catalyzed by fucosyltransferases (FUTs) is an important posttranslational modification involved in a variety of biologic processes. This study was undertaken to determine the roles of fucosylation in rheumatoid arthritis (RA) and to assess the efficacy of reestablishing immune homeostasis with the use of 2-deoxy-d-galactose (2-d-gal), a fucosylation inhibitor. METHODS: Quantitative polymerase chain reaction was performed to determine the expression of FUT genes in synovial tissue from RA and osteoarthritis (OA) patients and in fluorescence-activated cell-sorted cells from RA synovial fluid. The in vivo inhibitory effect of 2-d-gal was evaluated in a murine collagen-induced arthritis (CIA) model. The in vitro effects of 2-d-gal on differentiation of inflammatory macrophages, production of cytokines, and antigen uptake, processing, and presentation functions were analyzed. RESULTS: FUTs that are involved in terminal or subterminal fucosylation, but not those involved in core fucosylation or O-fucosylation, were up-regulated in RA compared to OA synovial tissue. The expression of terminal FUTs was highly positively correlated with the expression of TNF (encoding for tumor necrosis factor α). Terminal FUTs were predominantly expressed in M1 macrophages. In vivo, 2-d-gal treatment of mice precluded the development of CIA by reducing inflammatory macrophages and Th17 cells in the draining lymph nodes and decreasing the levels of TNFα, interleukin-6 (IL-6), and antibodies to type II collagen in the serum. In vitro, treatment with 2-d-gal skewed the differentiation of M1 macrophages to IL-10-producing M2 macrophages. Furthermore, 2-d-gal significantly inhibited the antigen-presenting function of M1 macrophages. CONCLUSION: Terminal fucosylation is a novel hallmark of inflammatory macrophages. Inhibition of terminal FUTs reshapes the differentiation and functions of M1 macrophages, leading to resolution of inflammation in arthritis.

Death receptor 5-targeted depletion of interleukin-23-producing macrophages, Th17, and Th1/17 associated with defective tyrosine phosphatase in mice and patients with rheumatoid arthritis.

OBJECTIVE: Bidirectional interactions between granulocyte-macrophage colony-stimulating factor-positive (GM-CSF+) T cells and interferon regulatory factor 5-positive (IRF-5+) macrophages play a major role in autoimmunity. In the absence of SH2 domain-containing phosphatase 1 (SHP-1), GM-CSF-stimulated cells are resistant to death receptor (DR)-mediated apoptosis. The objective of this study was to determine whether TRA-8, an anti-DR5 agonistic antibody, can eliminate inflammatory macrophages and CD4 T cells in the SHP-1-deficient condition. METHODS: Ubiquitous Cre (Ubc.Cre) human/mouse-chimeric DR5-transgenic mice were crossed with viable SHP-1-defective motheaten (mev/mev) mice. TRA-8 was administered weekly for up to 4 weeks. The clinical scores, histopathologic severity, and macrophage and CD4 T cell phenotypes were evaluated. The role of TRA-8 in depleting inflammatory macrophages and CD4 T cells was also evaluated, using synovial fluid obtained from patients with rheumatoid arthritis (RA). RESULTS: The levels of inflammatory macrophages (interleukin-23-positive [IL-23+] IRF-5+) and CD4 T cells (IL-17+ GM-CSF+) were elevated in mev/mev mice. In DR5-transgenic mev/mev mice, DR5 expression was up-regulated in these 2 cell populations. TRA-8 treatment depleted these cell populations and resulted in a significant reduction in inflammation and in the titers of autoantibodies. In synovial cells from patients with RA, the expression of IRF5 and DR5 was negatively correlated with the expression of PTPN6. TRA-8, but not TRAIL, suppressed RA inflammatory macrophages and Th17 cells under conditions in which the expression of SHP-1 is low. CONCLUSION: In contrast to TRAIL, which lacks the capability to counteract the survival signal in the absence of SHP-1, TRA-8 eliminated both IRF-5+ IL-23+ M1 macrophages and pathogenic GM-CSF+ IL-17+ CD4 T cells in a SHP-1-independent manner. The results of the current study suggest that TRA-8 can deplete inflammatory cell populations that result from a hyperactive GM-CSF/IRF-5 axis.

Impact of chronic inflammation on the pharmacokinetic-pharmacodynamic relationship of naproxen.

OBJECTIVES: The use of biomarkers for predicting the clinical doses of analgesic drugs relies on the understanding of the relationship between drug exposure and response under disease conditions. In this study, we demonstrate the relevance of such a relationship for COX-inhibitors by modelling the effect of naproxen on prostaglandin E2 (PGE(2)) and thromboxane B2 (TXB(2)) in a chronic inflammation model in rats. METHODS: Rats were treated with Freund's complete adjuvant (FCA) by intraplantar injection. On post-inoculation days (PID) 7-21, animals received single or chronic (qd until day 21) doses of naproxen (10mg/kg). Blood samples were collected at various intervals after dosing to characterise naproxen pharmacokinetics and its effects on PGE(2) and TXB(2) production. PK-PD modelling was performed using nonlinear mixed effects in NONMEM. RESULTS: The inhibition of PGE(2) and TXB(2) could be described by a sigmoid E(max) model. A decrease in the potency estimates of both biomarkers was observed under chronic inflammation, as compared to healthy animals. IC(50) values for PGE(2) inhibition showed a shift from 2840+/-510 to 4000+/-677ng/ml(mean+/-SD), whilst IC(50) values for TXB(2) inhibition increased from 1180+/-323 to 3360+/-453ng/ml in healthy and FCA-inoculated animals, respectively. CONCLUSIONS: Our results show that chronic inflammation causes a significant change in the potency estimates for COX-inhibition. These findings illustrate the implications of pathophysiological processes on pharmacodynamics and consequently on the required exposure levels for achieving response during chronic treatment.

Orally active C-6 heteroaryl- and heterocyclyl-substituted imidazo[1,2-a]pyridine acid pump antagonists (APAs).

Acid pump antagonists (APAs) such as the imidazo[1,2-a]pyridine AZD-0865 2 have proven efficacious at low oral doses in acid related gastric disorders. Herein we describe some of the broader SAR in this class of molecule and detail the discovery of an imidazo[1,2-a]pyridine 15 which has excellent efficacy in animal models of gastric acid secretion following oral administration, as well as a good overall developability profile. The discovery strategy focuses on use of heteroaryl and heterocyclic substituents at the C-6 position and optimization of developability characteristics through modulation of global physico-chemical properties.

Differences in the sensitivity of behavioural measures of pain to the selectivity of cyclo-oxygenase inhibitors.

OBJECTIVES: Freund's complete adjuvant (FCA) is an animal model of inflammatory pain commonly used in the screening of COX-inhibitors. However, there is little understanding of how behavioural measures of the anti-inflammatory effect in the FCA model correlate to differences in mechanism of action and whether such endpoints equally reflect drug activity in humans. In the current investigation we evaluate the time course of the analgesic effect for different endpoints after treatment with drugs with varying degrees of selectivity for COX-1 and COX-2. We also assess prostaglandin (PGE(2)) and thromboxane (TXB(2)) inhibition to establish the correlation between behavioural measures and the degree of selectivity for COX-1 and COX-2. METHODS: Sprague-Dawley rats were treated with FCA by intra-plantar injection. On post-inoculation day (PID) 7, rats received a single oral dose of naproxen, diclofenac, ketorolac or rofecoxib. Drug treatment continued until PID 21. A control group received placebo only. Behavioural endpoints for inflammatory pain and blood samples for biomarkers were obtained at various time points before and after dosing to characterise the time course of drug effect and disease progression. RESULTS: COX-inhibitors showed no effect on the dynamic plantar test. In contrast, full analgesia was observed after drug administration for weight bearing capacity (WBC) and paw pressure (PP), with varying duration of the effect for each of the endpoints. No tolerance to drug effect was observed up to 14 days of chronic treatment. Rofecoxib showed an increase in baseline pain threshold values after chronic treatment, which may be related to its pharmacokinetic characteristics. CONCLUSIONS: Changes in paw pressure threshold seem to best reflect the anti-hyperalgesic properties of COX-inhibitors with enough sensitivity to enable estimation of the dose-exposure-response curve.

1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists: Structure-activity relationships of 4- and 5-substituted benzoic acid derivatives.

This paper details the SAR of 1,5-biaryl pyrrole derivatives with substituents in the 2-, 4-, and 5-positions of the benzoic acid group as EP1 receptor antagonists. Substitution at the 2-position was poorly tolerated, whereas only fluorine was tolerated at the 4-position. In contrast, a range of substituents at the 5-position were discovered which enhanced the in vitro affinity and led to compounds with promising oral exposure. Three derivatives showed efficacy in a preclinical model of inflammatory pain when dosed orally to rats.

The discovery of 6-[2-(5-chloro-2-{[(2,4-difluorophenyl)methyl]oxy}phenyl)-1-cyclopenten-1-yl]-2-pyridinecarboxylic acid, GW848687X, a potent and selective prostaglandin EP1 receptor antagonist for the treatment of inflammatory pain.

The discovery of a series of selective EP1 receptor antagonists based on a 1,2-diarylcyclopentene template is described. After defining the structural requirements for EP1 potency and selectivity, heterocyclic rings were incorporated to reduce logD and improve in vitro pharmacokinetic properties. The 2,6-substituted pyridines and pyridazines gave an appropriate balance of potency, in vivo pharmacokinetic properties and a low potential for inhibiting a range of CYP450 enzymes. From this series, GW848687X was shown to have an excellent profile in models of inflammatory pain and was selected as a development candidate.

1,5-Biaryl pyrrole derivatives as EP1 receptor antagonists. Structure-activity relationships of 6-substituted and 5,6-disubstituted benzoic acid derivatives.

Herein we describe the SAR of 1,5-biaryl pyrrole derivatives, with substituents in the 6-position of the benzoic acid moiety, as EP(1) receptor antagonists. Substitution at this position was well tolerated and led to the identification of several analogues with high affinity for the EP(1) receptor that displayed good efficacy in the established FCA model of inflammatory pain. Furthermore, several analogues were prepared which combined substitution at the 5- and 6-positions as well as derivatives with an aromatic ring fused to the 5- and 6-positions.

Pyridone derivatives as potent, orally bioavailable VLA-4 integrin antagonists.

A series of pyridone-N-benzyl-propanoic acids have been optimised to afford potent orally bioavailable VLA-4 antagonists.

Structure-activity relationships of 1,5-biaryl pyrroles as EP1 receptor antagonists.

The preliminary SAR of a series of novel 1,5-biaryl pyrrole EP1 receptor antagonists derived from compound 1 is described. Replacement of the benzyl group of 1 with isosteric groups was investigated. The most effective replacement was found to be the isobutyl group. The cyclopentylmethyl and cyclohexylmethyl groups were also effective benzyl replacements. The cyclohexylmethyl derivative 19 demonstrated the lowest metabolic clearance within this series. In addition, several high affinity substituted benzyl analogues were also identified. Compound 39 was found to have good bioavailability in rats and demonstrated efficacy in the established FCA preclinical model of inflammatory pain with a calculated ED50 of 9.2mg/kg.

Correlation between in vitro and in vivo concentration-effect relationships of naproxen in rats and healthy volunteers.

Understanding the mechanisms underlying the analgesic effect of new cyclooxygenase inhibitors is essential to identify dosing requirements in early stages of drug development. Accurate extrapolation to humans of in vitro and in vivo findings in preclinical species is needed to optimise dosing regimen in inflammatory conditions. The current investigation characterises the inhibition of prostaglandin E2 (PGE(2)) and thromboxane B2 (TXB(2)) by naproxen in vitro and in vivo in rat and human blood. The inhibition of PGE(2) in the absence or presence of increasing concentrations of naproxen (10(-8)-10(-1) M) was measured by ex vivo whole blood stimulation with LPS, whereas inhibition of TXB(2) was measured in serum following blood clotting. In further experiments, inhibition of PGE(2) and TXB(2) levels was also assessed ex vivo in animals treated with naproxen (2.5, 10, 25 mg kg(-1)). Subsequently, pharmacokinetic (PK)/pharmacodynamics (PD) modelling of in vitro and in vivo data was performed using nonlinear mixed effects in NONMEM (V). Inhibition of PGE(2) and TXB(2) was characterised by a sigmoid E(max) model. The exposure-response relationships in vitro and in vivo were of the same order of magnitude in both species. IC(80) estimates obtained in vitro were similar for PGE(2) inhibition (130.8 +/- 11 and 131.9 +/- 19 10(-6) M, mean +/- s.d. for humans and rats, respectively), but slightly different for TXB(2) inhibition (103.9+/-15 and 151.4 +/- 40 10(-6) M, mean +/- s.d. for humans and rats, respectively, P < 0.05). These differences, however, may not be biologically relevant. The results confirm the value of exposure-effect relationships determined in vitro as a means to predict the pharmacological activity in vivo. This analysis also highlights the need to parameterise concentration-effect relationships in early drug development, as indicated by the estimates of IC(80) for PGE(2) and TXB(2) inhibition.

Discovery of novel biaryl heterocyclic EP1 receptor antagonists.

We describe the generation of novel EP(1) receptor antagonists by investigation of thiophene isosteres. In addition, we disclose preliminary in vitro and in vivo DMPK for selected compounds.

Improving the in vitro prediction of in vivo central nervous system penetration: integrating permeability, P-glycoprotein efflux, and free fractions in blood and brain.

This work examines the inter-relationship between the unbound drug fractions in blood and brain homogenate, passive membrane permeability, P-glycoprotein (Pgp) efflux ratio, and log octanol/water partition coefficients (cLogP) in determining the extent of central nervous system (CNS) penetration observed in vivo. The present results demonstrate that compounds often considered to be Pgp substrates in rodents (efflux ratio greater than 5 in multidrug resistant Madin-Darby canine kidney cells) with poor passive permeability may still exhibit reasonable CNS penetration in vivo; i.e., where the unbound fractions and nonspecific tissue binding act as a compensating force. In these instances, the efflux ratio and in vitro blood-brain partition ratio may be used to predict the in vivo blood-brain ratio. This relationship may be extended to account for the differences in CNS penetration observed in vivo between mdr1a/b wild type and knockout mice. In some instances, cross-species differences that might initially seem to be related to differing transporter expression can be rationalized from knowledge of unbound fractions alone. The results presented in this article suggest that the information exists to provide a coherent picture of the nature of CNS penetration in the drug discovery setting, allowing the focus to be shifted away from understanding CNS penetration toward the more important aspect of understanding CNS efficacy.