Metabolic hormones mediate cognition.

Recent biochemical and behavioural evidence indicates that metabolic hormones not only regulate energy intake and nutrient content, but also modulate plasticity and cognition in the central nervous system. Disruptions in metabolic hormone signalling may provide a link between metabolic syndromes like obesity and diabetes, and cognitive impairment. For example, altered metabolic homeostasis in obesity is a strong determinant of the severity of age-related cognitive decline and neurodegenerative disease. Here we review the evidence that eating behaviours and metabolic hormones-particularly ghrelin, leptin, and insulin-are key players in the delicate regulation of neural plasticity and cognition. Caloric restriction and antidiabetic therapies, both of which affect metabolic hormone levels can restore metabolic homeostasis and enhance cognitive function. Thus, metabolic hormone pathways provide a promising target for the treatment of cognitive decline.

The spontaneous location recognition task for assessing spatial pattern separation and memory across a delay in rats and mice.

Keeping similar memories distinct from one another is a critical cognitive process without which we would have difficulty functioning in everyday life. Memories are thought to be kept distinct through the computational mechanism of pattern separation, which reduces overlap between similar input patterns to amplify differences among stored representations. At the behavioral level, impaired pattern separation has been shown to contribute to memory deficits seen in neuropsychiatric and neurodegenerative diseases, including Alzheimer's disease, and in normal aging. This protocol describes the use of the spontaneous location recognition (SLR) task in mice and rats to behaviorally assess spatial pattern separation ability. This two-phase spontaneous memory task assesses the extent to which animals can discriminate and remember object locations presented during the encoding phase. Using three configurations of the task, the similarity of the to-be-remembered locations can be parametrically manipulated by altering the spatial positions of objects-dissimilar, similar or extra similar-to vary the load on pattern separation. Unlike other pattern separation tasks, SLR varies the load on pattern separation during encoding, when pattern separation is thought to occur. Furthermore, SLR can be used in standard rodent behavioral facilities with basic expertise in rodent handling. The entire protocol takes ~20 d from habituation to testing of the animals on all three task configurations. By incorporating breaks between testing, and varying the objects used as landmarks, animals can be tested repeatedly, increasing experimental power by allowing for within-subjects manipulations.

Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: an updated systematic review and meta-analysis of randomised cardiovascular outcome trials.

BACKGROUND: In our 2015 systematic review and meta-analysis of cardiovascular outcome trials for glucose-lowering drugs or strategies in people with or at risk of type 2 diabetes, we reported a modest reduction in atherosclerotic cardiovascular events and an increased risk of heart failure, but with heterogeneous effects by drug or intervention type. In view of the completion of many large cardiovascular outcome trials since our previous analysis, including trials of novel drugs that have shown beneficial effects on cardiovascular outcomes, we aimed to update our analysis to incorporate these findings. METHODS: We did an updated systematic review and meta-analysis of large cardiovascular outcome trials of glucose-lowering drugs or strategies in people with or at risk of type 2 diabetes. We searched Ovid MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials databases for reports of trials published from Nov 15, 2013 to Nov 20, 2019. We included randomised controlled trials with a minimum of 1000 adults (aged ≥19 years) with or at risk of type 2 diabetes, with major adverse cardiovascular events (MACE) as an outcome, and with follow-up of at least 12 months. We excluded trials with patients enrolled with an acute cardiovascular event. The main outcomes of interest were MACE (generally defined as a composite of cardiovascular death, myocardial infarction, or stroke) and heart failure. We calculated pooled risk ratios (RRs) and 95% CIs with inverse-variance random-effects models, did meta-regression to analyse treatment effects per difference in bodyweight achieved, and explored results stratified by baseline subgroups. FINDINGS: Our updated search yielded 30 eligible trials (n=225 305). The mean age of participants was 63·0 years (SD 8·4) and mean duration of diabetes was 9·4 years (6·6). After a mean follow-up of 3·8 years (1·8), 23 016 (10·2%) participants had MACE and 8169 (3·6%) had a heart failure event. Glucose-lowering drugs or strategies lowered the risk of MACE compared with standard care or placebo (RR 0·92, 95% CI 0·89-0·95, p<0·0001), with no overall effect on the risk of heart failure (0·98, 0·90-1·08, p=0·71). However, across drug classes or strategies, the magnitude and directionality of RR for heart failure varied (pinteraction<0·0001), with meta-regression showing that a decrease in bodyweight of 1 kg was associated with a 5·9% (3·9-8·0) relative decrease in the risk of heart failure (p<0·0001). Among trials that assessed drug classes or strategies associated with weight loss (intensive lifestyle changes, GLP-1 receptor agonists, or SGLT2 inhibitors), the risk reduction for MACE was consistent among participants with (0·87, 0·83-0·92) and without (0·92, 0·83-1·02) established cardiovascular disease at baseline (pinteraction=0·33). For heart failure, the RR for drug classes or strategies associated with weight loss was consistent among participants with (0·80, 0·73-0·89) and without (0·84, 0·74-0·95) cardiovascular disease at baseline (pinteraction=0·63). INTERPRETATION: Glucose-lowering drugs or strategies overall reduced the risk of fatal and non-fatal atherosclerotic events. The effect on heart failure was neutral overall but varied substantially by intervention type, with interventions associated with weight loss showing a beneficial effect. The cardiovascular and heart failure benefits of interventions associated with weight loss might extend to patients without established cardiovascular disease. FUNDING: None.

Awareness and perceived risk of cardiovascular disease among individuals living with rheumatoid arthritis is low: results of a systematic literature review.

BACKGROUND: Individuals with rheumatoid arthritis (RA) are at risk of developing cardiovascular disease (CVD), but patient perceptions of CVD are not routinely assessed. We performed a systematic literature review to evaluate awareness of the association between RA and CVD, and perceived risk of CVD among individuals with RA. METHODS: Three electronic databases (MEDLINE, EMBASE, and PubMed) were searched for English language articles between the years of 1990-2018. Search terms pertained to RA, CVD, knowledge, awareness, or perceptions of CVD risk. Abstracts were screened for inclusion/exclusion by two independent reviewers. RESULTS: A total of 33 abstracts were screened and 6 underwent full review. The overall sample size was 478 subjects and included patients with established RA who were predominantly female with a mean age range of 53 to 64 years. RA disease characteristics relevant to CVD were not uniformly reported, including the use of DMARDs, corticosteroids, or NSAIDs. A high proportion of subjects (range 73 to 97%) were unaware of an increased risk of developing CVD in relation to their RA, and this frequently occurred in those with a greater number of traditional CVD risk factors. Misperceptions about CVD were common, and the majority of subjects misestimated their actual CVD risk. CONCLUSION: Individuals with RA at highest risk for CVD report low awareness and perceived risk of this comorbidity. This represents a knowledge gap in need of intervention but must be tailored to patients' needs. An understanding of the system- and individual-level barriers preventing CVD awareness is needed. Only then will approaches to improve CVD screening and management in RA be successful.

Marital status and outcomes after myocardial infarction: Observations from the Canadian Observational Antiplatelet Study (COAPT).

While divorced or living alone, patients with stable cardiovascular disease are at increased risk for adverse cardiovascular events. The importance of marital status following a myocardial infarction (MI) is less clear. We hypothesized that marital status may affect cardiovascular outcomes following MI. We analyzed outcomes among patients with MI who underwent percutaneous coronary intervention from the Canadian Observational Antiplatelet Study (COAPT). Marital status was categorized into 3 groups: married/common-law patients living together; never married; and divorced, separated, or widowed patients. Patients were followed for 15 months and our primary outcome was the occurrence of a major adverse cardiovascular event (MACE), defined as a composite of mortality, repeat acute MI, stroke, or urgent coronary revascularization. Multivariable logistic regression models were performed, with married/common-law patients living together considered the reference group. Among 2100 patients included in analyses, 1519 (72.3%) were married/common-law patients living together, 358 (17.1%) were separated/divorced/widowed, and 223 (10.6%) patients were never married. Dual antiplatelet therapy use after 15 months was similar across groups (75.4%, 77.8%, and 73.6%, respectively). The risk of MACE after 15 months was similar among married patients living together (12.7%; referent) compared with patients who were never married (13.9%; adjusted odds ratio: 1.09, 95% confidence interval: 0.58-2.07, P = 0.79) and patients separated/divorced/widowed (14.3%; adjusted odds ratio: 0.71, 95% confidence interval: 0.40-1.25, P = 0.23). Similarly, the risk of individual endpoints, including mortality, was similar across the 3 groups. Among patients stabilized following an MI, we found no association between marital status and 15-month outcomes.