Prazosin during threat discrimination boosts memory of the safe stimulus

The α-1 adrenoreceptor antagonist prazosin has shown promise in the treatment of post-traumatic stress disorder (PTSD) symptoms, but its mechanisms are not well understood. Here we administered prazosin or placebo prior to threat conditioning (day 1) and tested subsequent extinction (day 2) and reextinction (day 3) in healthy human participants. Prazosin did not affect threat conditioning but augmented stimulus discrimination during extinction and reextinction, via lower responding to the safe stimulus. These results suggest that prazosin during threat acquisition may have influenced encoding or consolidation of safety processing in particular, subsequently leading to enhanced discrimination between the safe and threatening stimuli

Depressive Symptoms Are Associated with Cognitive Function in the Elderly with Type 2 Diabetes

Background: Type 2 diabetes (T2D) is a metabolic condition associated with poor clinical and cognitive outcomes including vascular disease, depressive symptoms, cognitive impairment, and dementia. In the general elderly population, depression has been consistently identified as a risk factor for cognitive impairment/decline. However, the association between depression and cognitive function in T2D has been understudied. Objective: We investigated the association between depression and cognitive function in a large sample of cognitively normal elderly with T2D. Methods: In this cross-sectional study, we examined 738 participants, aged 65–88 years old, enrolled in the Israel Diabetes and Cognitive Decline study. For each cognitive domain (Episodic Memory, Executive Function, Attention/Working Mem- ory, Language/Semantic Categorization) and Overall Cognition, multiple linear regressions assessed its association with depression (score greater than 5 on the 15-item version of the Geriatric Depression Scale [GDS]), adjusting for age, sex, and education. Results: Depression (n = 66, 8.9%) was associated with worse performance on tasks of Executive Function (p = 0.004), Language/Semantic Categorization (p \u3c 0.001), and Overall Cognition (p \u3c 0.002), but not Episodic Memory (p = 0.643) or Attention/Working Memory (p = 0.488). Secondary analyses using GDS as a continuous variable did not sub- stantially change the results. Adjusting also for a history of antidepressant medication use slightly weakened the findings. Conclusion: Significant associations of depression with several cognitive domains and Overall Cognition even in cognitively normal elderly with T2D, suggest that depression may have a role in impaired cognitive function in T2D, which may be attenuated by antidepressants

Association of the Haptoglobin Gene Polymorphism With Cognitive Function and Decline in Elderly African American Adults With Type 2 Diabetes: Findings From the Action to Control Cardiovascular Risk in Diabetes–Memory in Diabetes (ACCORD-MIND) Study

IMPORTANCE African American individuals have higher dementia risk than individuals of white race/ethnicity. They also have higher rates of type 2 diabetes, which may contribute to this elevated risk. This study examined the association of the following 2 classes of alleles at the haptoglobin (Hp) locus that are associated with poor cognition, cardiovascular disease, and mortality: Hp 1-1 (associated with poor cognition and cerebrovascular disease) and Hp 2-1 and Hp 2-2 (associated with greater risk ofmyocardial infarction and mortality). An additional polymorphism in the promoter region of the Hp 2 allele, restricted to individuals of African descent, yields a fourth genotype, Hp 2-1m. African American adults have a higher prevalence of Hp 1-1 (approximately 30%) compared with individuals of white race/ethnicity (approximately 14%), but the potential role of the Hp genotype in cognition among elderly African American individuals with type 2 diabetes is unknown. OBJECTIVE To assess the association of the Hp genotypes with cognitive function and decline in elderly African American adults with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS This cohort study used publicly available data and specimens from the Action to Control Cardiovascular Risk in Diabetes–Memory in Diabetes (ACCORD-MIND) study to investigate the association of the Hp genotypes with cognitive function and decline in 466 elderly African American participants with type 2 diabetes. The hypothesis was that the Hp 1-1 genotype compared with the other genotypes would be associated with more cognitive impairment and faster cognitive decline in elderly African American adults with type 2 diabetes. The initial ACCORD trialwas performed from October 28, 1999, to September 15, 2014. This was a multicenter clinical study performed in an academic setting. EXPOSURES The Hp genotypes were determined from serum samples by polyacrylamide gel electrophoresis and by enzyme-linked immunosorbent assay. MAIN OUTCOMES AND MEASURES The Mini-Mental State Examination (MMSE) was used to measure cognitive function and change after 40 months. The MMSE score ranges from 0 to 30 points; higher scores represent better cognition. Associations were examined with analysis of covariance and linear regression, adjusting for age, sex, education, baseline glycated hemoglobin level, systolic blood pressure, diastolic blood pressure, cholesterol level, creatinine level, and treatment arm (intensive vs standard). The cognitive change model adjusted also for the baseline MMSE score. RESULTS Among 466 African American study participants (mean [SD] age, 62.3 [5.7] years), 64.8% were women, and the genotype prevalences were 29.4%(n = 137) for Hp 1-1, 36.1%(n = 168) for Hp 2-1, 10.9%(n = 51) for Hp 2-1m, and 23.6%(n = 110) for Hp 2-2. The groups differed in their baseline MMSE scores (P = .006): Hp 1-1 had the lowest MMSE score (mean [SE], 25.68 [0.23]), and Hp 2-1m had the highest MMSE score (mean [SE], 27.15 [0.36]). Using the least squares method, the 40-month decline was significant for Hp 1-1 (mean [SE], −0.41 [0.19]; P = .04) and for Hp 2-2 (mean [SE], −0.68 [0.21]; P = .001). However, the overall comparison across the 4 groups did not reach statistical significance for the fully adjusted model. The interaction of age with the Hp 1-1 genotype on MMSE score decline estimate per year change was significant (mean [SE], −0.87 [0.37]; P = .005), whereas itwas not significant for Hp 2-1 (mean [SE], 0.06 [0.37]; P = .85), Hp 2-1m (mean [SE], −0.06 [0.51]; P = .89), and Hp 2-2 (mean [SE], −0.44 [0.41]; P = .29), indicating that cognitive decline in Hp 1-1 carrierswas accentuated in older ages, whereas it was not significant for the other Hp genotypes. CONCLUSIONS AND RELEVANCE In this study, the Hp 1-1 genotype, which is 2-fold (approximately 30%) more prevalent among African American individuals than among individuals of white race/ ethnicity, was associated with poorer cognitive function and greater cognitive decline than the other Hp genotypes. The Hp gene polymorphism may explain the elevated dementia risk in African American adults. The neuropathological substrates and mechanisms for these associations merit further investigation

The Association of Depressive Symptoms With Brain Volume Is Stronger Among Diabetic Elderly Carriers of the Haptoglobin 1-1 Genotype Compared to Non-carriers

Aim: Depression is highly prevalent in type 2 diabetes and is associated with lower adherence to medical treatments, worse glycemic control, and increased risk for diabetes-related complications. The mechanisms underlying depression in type 2 diabetes are unclear. The haptoglobin (Hp) genotype is associated with type 2 diabetes related complications including increased risk for cerebrovascular pathology and worse cognitive performance. Its relationship with depression is unknown. We investigated the role of Hp genotype on the association of depression with brain and white matter hyperintensities (WMH) volumes.Methods: Depressive symptoms (measured with the 15-item Geriatric Depression Scale), brain MRI, and Hp genotypes, were examined in elderly subjects with type 2 diabetes [29 (13.8%) Hp 1–1 carriers and 181 (86.2%) non-carriers]. The interaction of Hp genotype with number of depressive symptoms on regional brain measures was assessed using regression analyses.Results: The significant interactions were such that in Hp 1–1 carriers but not in non-carriers, number of depressive symptoms was associated with overall frontal cortex (p = 0.01) and WMH (p = 0.04) volumes but not with middle temporal gyrus volume (p = 0.43).Conclusions: These results suggest that subjects with type 2 diabetes carrying the Hp 1–1 genotype may have higher susceptibility to depression in the context of white matter damage and frontal lobe atrophy. The mechanisms underlying depression in diabetes may differ by Hp genotype