Cognitive reserve in granulin-related frontotemporal dementia: from preclinical to clinical stages

OBJECTIVE Consistent with the cognitive reserve hypothesis, higher education and occupation attainments may help persons with neurodegenerative dementias to better withstand neuropathology before developing cognitive impairment. We tested here the cognitive reserve hypothesis in patients with frontotemporal dementia (FTD), with or without pathogenetic granulin mutations (GRN+ and GRN-), and in presymptomatic GRN mutation carriers (aGRN+). METHODS Education and occupation attainments were assessed and combined to define Reserve Index (RI) in 32 FTD patients, i.e. 12 GRN+ and 20 GRN-, and in 17 aGRN+. Changes in functional connectivity were estimated by resting state fMRI, focusing on the salience network (SN), executive network (EN) and bilateral frontoparietal networks (FPNs). Cognitive status was measured by FTD-modified Clinical Dementia Rating Scale. RESULTS In FTD patients higher level of premorbid cognitive reserve was associated with reduced connectivity within the SN and the EN. EN was more involved in FTD patients without GRN mutations, while SN was more affected in GRN pathology. In aGRN+, cognitive reserve was associated with reduced SN. CONCLUSIONS This study suggests that cognitive reserve modulates functional connectivity in patients with FTD, even in monogenic disease. In GRN inherited FTD, cognitive reserve mechanisms operate even in presymptomatic to clinical stages

Normal-state magnetic susceptibility in a bilayer cuprate

The magnetic susceptibility of high-T_c superconductors is investigated in the normal state using a coupled bilayer model. While this model describes in a natural way the normal-state pseudogaps seen in c-axis optical conductivity on underdoped samples, it predicts a weakly increasing susceptibility with decreasing temperature and cannot explain the magnetic pseudogaps exhibited in NMR measurements. Our result, together with some experimental evidence suggest that the mechanism governing the c-axis optical pseudogap is different from that for the $a-b$ plane magnetic pseudogap.Comment: 5 pages, 2 figure

Infants’ behavioral and physiological profile and mother–infant interaction

This study aims to (a) identify and profile groups of infants according to their behavioral and physiological characteristics, considering their neurobehavioral organization, social withdrawal behavior, and endocrine reactivity to stress, and to (b) analyze group differences in the quality of mother–infant interaction. Ninety seven 8-week-old infants were examined using the Neonatal Behavioral Assessment Scale and the Alarm Distress Baby Scale. Cortisol levels were measured both before and after routine inoculation between 8 and 12 weeks. At 12 to 16 weeks mother–infant interaction was assessed using the Global Rating Scales of Mother–Infant Interaction. Three groups of infants were identified: (a) ‘‘withdrawn’’; (b) ‘‘extroverted’’; (c) ‘‘underaroused.’’ Differences between them were found regarding both infant and mother behaviors in the interaction and the overall quality of mother–infant interaction. The identification of behavioral and physiological profiles in infants is an important step in the study of developmental pathways

Autoantibodies to Osteoprotegerin are Associated with Low Hip Bone Mineral Density and History of Fractures in Axial Spondyloarthritis: A Cross-Sectional Observational Study

Osteoporosis is a recognised complication of axial spondyloarthritis (axSpA) and is thought to be due to functional impairment and the osteoclast-activating effects of proinflammatory cytokines. The development of autoantibodies to OPG (OPG-Ab) has been associated with severe osteoporosis and increased bone resorption in rheumatoid arthritis. In this study, we screened for the presence of OPG-Ab in axSpA and reviewed their clinical significance. We studied 134 patients, recruited from two centres in the United Kingdom. Their mean age was 47.5 years and 75% were male. Concentrations of OPG-Ab were related to bone mineral density (BMD) and fracture history using linear and logistic regression models adjusting for age, gender, disease duration and activity, body mass index and bisphosphonate use. We detected OPG-Ab in 11/134 patients (8.2%). Femoral neck and total hip BMD were significantly reduced in OPG-Ab positive patients (0.827 vs. 0.967 g/cm2, p = 0.008 and 0.868 vs. 1.028 g/cm2, p = 0.002, respectively). Regression analysis showed that the presence of OPG-Ab was independently associated with total hip osteopenia (ORadj 24.2; 95% CI 2.57, 228) and history of fractures (ORadj 10.5; 95% CI 2.07, 53.3). OPG-Ab concentration was associated with total hip BMD in g/cm2 (ß = −1.15; 95% CI −0.25, −0.04). There were no associations between OPG-Ab concentration and bone turnover markers, but free sRANKL concentrations were lower in OPG-Ab-positive patients (median 0.04 vs. 0.11 pmol/L, p = 0.050). We conclude that OPG-Ab are associated with hip BMD and fractures in axSpA suggesting that they may contribute to the pathogenesis of bone loss in some patients with this condition

False Heart Rate Feedback and the Perception of Heart Symptoms in Patients with Congenital Heart Disease and Anxiety

Background Little is known about the mechanisms explaining an increased perception of heart symptoms in congenital heart disease (ConHD). In the present study, it was suggested that a combination of high trait anxiety and disease history increases the perception of heart symptoms. Purpose It was tested whether false heart cues will result in an increased perception of heart symptoms in patients with ConHD and anxiety. Method Thirty-six patients with ConHD and 44 healthy controls performed two exercise tasks. During one of the exercise tasks, participants were exposed to a false heart cue consisting of false heart rate feedback (regular or irregular). Perceived heart symptoms were assessed and heart rate, arterial partial pressure of CO2, and respirator rate were monitored continuously. Results In line with the predictions, false heart rate feedback resulted in an increased perception of heart symptoms in high trait anxious patients with ConHD that could not be explained by acute heart dysfunction. However, unexpectedly, this effect was not observed immediately after the false heart rate feedback task but after a second exercise task without false feedback. Conclusion The results suggest that not the sole presence of ConHD but ConHD in combination with high trait anxiety results in a vulnerability to overperceive heart symptom

AKT1 polymorphisms are associated with risk for metabolic syndrome

Converging lines of evidence suggest that AKT1 is a major mediator of the responses to insulin, insulin-like growth factor 1 (IGF1), and glucose. AKT1 also plays a key role in the regulation of both muscle cell hypertrophy and atrophy. We hypothesized that AKT1 variants may play a role in the endophenotypes that make up metabolic syndrome. We studied a 12-kb region including the first exon of the AKT1 gene for association with metabolic syndrome-related phenotypes in four study populations [FAMUSS cohort (n = 574; age 23.7 ± 5.7 years), Strong Heart Study (SHS) (n = 2,134; age 55.5 ± 7.9 years), Dynamics of Health, Aging and Body Composition (Health ABC) (n = 3,075; age 73.6 ± 2.9 years), and Studies of a Targeted Risk Reduction Intervention through Defined Exercise (STRRIDE) (n = 175; age 40–65 years)]. We identified a three SNP haplotype that we call H1, which represents the ancestral alleles at the three loci and H2, which represents the derived alleles at the three loci. In young adult European Americans (FAMUSS), H1 was associated with higher fasting glucose levels in females. In middle age Native Americans (SHS), H1 carriers showed higher fasting insulin and HOMA in males, and higher BMI in females. In older African-American and European American subjects (Health ABC) H1 carriers showed a higher incidence of metabolic syndrome. Homozygotes for the H1 haplotype showed about twice the risk of metabolic syndrome in both males and females (p < 0.001). In middle-aged European Americans with insulin resistance (STRRIDE) studied by intravenous glucose tolerance test (IVGTT), H1 carriers showed increased insulin resistance due to the Sg component (p = 0.021). The 12-kb haplotype is a risk factor for metabolic syndrome and insulin resistance that needs to be explored in further populations

3 years of liraglutide versus placebo for type 2 diabetes risk reduction and weight management in individuals with prediabetes: a randomised, double-blind trial

Background: Liraglutide 3·0 mg was shown to reduce bodyweight and improve glucose metabolism after the 56-week period of this trial, one of four trials in the SCALE programme. In the 3-year assessment of the SCALE Obesity and Prediabetes trial we aimed to evaluate the proportion of individuals with prediabetes who were diagnosed with type 2 diabetes. Methods: In this randomised, double-blind, placebo-controlled trial, adults with prediabetes and a body-mass index of at least 30 kg/m2, or at least 27 kg/m2 with comorbidities, were randomised 2:1, using a telephone or web-based system, to once-daily subcutaneous liraglutide 3·0 mg or matched placebo, as an adjunct to a reduced-calorie diet and increased physical activity. Time to diabetes onset by 160 weeks was the primary outcome, evaluated in all randomised treated individuals with at least one post-baseline assessment. The trial was conducted at 191 clinical research sites in 27 countries and is registered with ClinicalTrials.gov, number NCT01272219. Findings: The study ran between June 1, 2011, and March 2, 2015. We randomly assigned 2254 patients to receive liraglutide (n=1505) or placebo (n=749). 1128 (50%) participants completed the study up to week 160, after withdrawal of 714 (47%) participants in the liraglutide group and 412 (55%) participants in the placebo group. By week 160, 26 (2%) of 1472 individuals in the liraglutide group versus 46 (6%) of 738 in the placebo group were diagnosed with diabetes while on treatment. The mean time from randomisation to diagnosis was 99 (SD 47) weeks for the 26 individuals in the liraglutide group versus 87 (47) weeks for the 46 individuals in the placebo group. Taking the different diagnosis frequencies between the treatment groups into account, the time to onset of diabetes over 160 weeks among all randomised individuals was 2·7 times longer with liraglutide than with placebo (95% CI 1·9 to 3·9, p&lt;0·0001), corresponding with a hazard ratio of 0·21 (95% CI 0·13–0·34). Liraglutide induced greater weight loss than placebo at week 160 (–6·1 [SD 7·3] vs −1·9% [6·3]; estimated treatment difference −4·3%, 95% CI −4·9 to −3·7, p&lt;0·0001). Serious adverse events were reported by 227 (15%) of 1501 randomised treated individuals in the liraglutide group versus 96 (13%) of 747 individuals in the placebo group. Interpretation: In this trial, we provide results for 3 years of treatment, with the limitation that withdrawn individuals were not followed up after discontinuation. Liraglutide 3·0 mg might provide health benefits in terms of reduced risk of diabetes in individuals with obesity and prediabetes. Funding: Novo Nordisk, Denmark