Amy Claxton

Long-Acting Intranasal Insulin Detemir Improves Cognition for Adults with Mild Cognitive Impairment or Early-Stage Alzheimer's Disease Dementia

Previous trials have shown promising effects of intranasally administered insulin for adults with Alzheimers disease dementia (AD) or amnestic mild cognitive impairment (MCI). These trials used regular insulin, which has a shorter half-life compared to long-lasting insulin analogues such as insulin detemir. The current trial examined whether intranasal insulin detemir improves cognition or daily functioning for adults with MCI or AD. Sixty adults diagnosed with MCI or mild to moderate AD received placebo (n = 20), 20 IU of insulin detemir (n = 21), or 40 IU of insulin detemir (n = 19) for 21 days, administered with a nasal drug delivery device. Results revealed a treatment effect for the memory composite for the 40 IU group compared with placebo (p < 0.05). This effect was moderated by APOE status (p < 0.05), reflecting improvement for APOE-ε4 carriers (p < 0.02), and worsening for non-carriers (p < 0.02). Higher insulin resistance at baseline predicted greater improvement with the 40 IU dose (r = 0.54, p < 0.02). Significant treatment effects were also apparent for verbal working memory (p < 0.03) and visuospatial working memory (p < 0.04), reflecting improvement for subjects who received the high dose of intranasal insulin detemir. No significant differences were found for daily functioning or executive functioning. In conclusion, daily treatment with 40 IU insulin detemir modulated cognition for adults with AD or MCI, with APOE-related differences in treatment response for the primary memory composite. Future research is needed to examine the mechanistic basis of APOE-related treatment differences, and to further assess the efficacy and safety of intranasal insulin detemir.

Sex and ApoE Genotype Differences in Treatment Response to Two Doses of Intranasal Insulin in Adults with Mild Cognitive Impairment or Alzheimer’s Disease

A previous clinical trial demonstrated that four months of treatment with intranasal insulin improves cognition and function for patients with Alzheimers disease (AD) or mild cognitive impairment (MCI), but prior studies suggest that response to insulin treatment may differ by sex and ApoE ε4 carriage. Thus, responder analyses using repeated measures analysis of covariance were completed on the trials 104 participants with MCI or AD who received either placebo or 20 or 40 IU of insulin for 4 months, administered by a nasal delivery device. Results indicate that men and women with memory impairment responded differently to intranasal insulin treatment. On delayed story memory, men and women showed cognitive improvement when taking 20 IU of intranasal insulin, but only men showed cognitive improvement for the 40 IU dose. The sex difference was most apparent for ApoE ε4 negative individuals. For the 40 IU dose, ApoE ε4 negative men improved while ApoE ε4 negative women worsened. Their ApoE ε4 positive counterparts remained cognitively stable. This sex effect was not detected in functional measures. However, functional abilities were relatively preserved for women on either dose of intranasal insulin compared with men. Unlike previous studies with young adults, neither men nor women taking intranasal insulin exhibited a significant change in weight over 4 months of treatment.

Personality trait levels within older couples and between-spouse trait differences as predictors of marital satisfaction

In this study of 125 older couples married for an average of 34 years, multilevel models were computed to simultaneously examine intra-couple personality trait averages and between-spouse trait similarity as predictors of marital satisfaction. Our findings suggest that higher intra-couple levels of extraversion predict marital satisfaction, both husbands and wives. In addition, between-spouse similarity in openness to experience appears associated with higher levels of marital satisfaction as reported by husbands; concomitantly, between-spouse similarity in agreeableness predicts wives’ marital satisfaction. With respect to openness (husbands) and agreeableness (wives), it did not matter which spouse within couples reported higher or lower trait levels. The most notable finding to emerge from this study is that neuroticism is not associated with marital satisfaction, neither husbands nor wives. This result stands in contrast to previously reported findings – the vast majority of prior research conducted with dating and newlywed couples. Conflicting results may reflect the degree to which neuroticism determines divorce within the first years of married life, adaptation to the foibles of ones spouse over time, overreliance on younger samples in marriage and family research, or some combination of these alternate explanations.

Deconstructing Racial Differences: The Effects of Quality of Education and Cerebrovascular Risk Factors

OBJECTIVES To evaluate the effects of vascular conditions and education quality on cognition over time in White and African American (AA) older adults. METHOD We investigated cross-sectional and longitudinal racial differences in executive functioning (EF) and memory composites among Whites (n = 461) and AAs (n = 118) enrolled in a cohort study. We examined whether cerebrovascular risk factors and Shipley Vocabulary scores (a proxy for education quality) accounted for racial differences. RESULTS On average, AAs had lower quality of education and more cerebrovascular risk factors including hypertension, diabetes, and obesity. AAs had lower mean EF and memory at baseline, but there were no group differences in rates of decline. Cross-sectional racial differences in EF and memory persisted after controlling for vascular disease, but disappeared when controlling for Shipley Vocabulary. DISCUSSION Quality of education appears to be more important than cerebrovascular risk factors in explaining cross-sectional differences in memory and EF performance between White and AA older adults. Further investigation is needed regarding the relative contribution of education quality and cerebrovascular risk factors to cognitive decline among ethnically/racially diverse older adults.

Long-acting intranasal insulin detemir improves working memory for adults with mild cognitive impairment or early-stage Alzheimer's dementia

Background: The OPTIMA study (NCT00506415) demonstrated reduced deterioration with 13.3 (15cm 2) versus 9.5 mg/24h (10cm 2) rivastigmine patch in patients with Alzheimer’s disease (AD). Treatment response can vary according to patients’ individual characteristics. We conducted a responder analysis to identify the proportion of patients demonstrating a treatment response to each dose, and patient characteristics predictive of achieving a response. Methods: Details of OPTIMA are published (Cummings et al, 2012). Patients meeting prespecified decline criteria during treatment with 9.5 mg/24h patch, entered a 48-week, double-blind (DB) phase, and were randomized to 13.3 or 9.5 mg/24h. The AD Assessment Scale-cognitive subscale (ADAS-cog) and AD Cooperative Study-Instrumental Activities of Daily Living scale (ADCS-IADL) were co-primary endpoints. In this post-hoc analysis, the following criteria for achieving a treatment response were applied: 4 points’ improvement on ADAS-cog, and 4 points’ improvement on ADAS-cog combined with no decline on ADCS-IADL. The proportion of patients meeting these criteria in each treatment group was assessed at Weeks 24 and 48. Further analyses were conducted with additional response criteria, applied to reflect the unique study design with an active comparator (13.3 versus 9.5 mg/24h) in a declining population. These include 4 points’ decline in both ADAS-cog and ADCS-IADL. Analyses of possible predictors of response, using stepwise logistic regression, are underway and will be presented. Results: Demographics and baseline scores were comparable between patient groups (13.3 mg/24h, N1⁄4265; 9.5 mg/ 24h, N1⁄4271). For all responder criteria, a greater proportion of patients achieved a treatment response with 13.3 versus 9.5 mg/24h patch. At Week 24, 25 versus 14% (p1⁄40.001) of patients receiving 13.3 and 9.5 mg/24h patch, respectively, demonstrated 4 points’ improvement on ADAS-cog, and 17 versus 7% (p<0.001) demonstrated 4 points’ improvement on ADAS-cog and no decline on ADCS-IADL. Of patients receiving 13.3 and 9.5 mg/24h patch, respectively, at Week 48, 16% and 10% (p1⁄40.020) displayed 4 points’ improvement on ADAS-cog, and 8% versus 4% (p1⁄40.023) demonstrated 4 points’ improvement on ADAS-cog and no decline on ADCS-IADL. Conclusions: Titration of patients with mild-to-moderate AD to the high-dose (13.3 mg/24h) rivastigmine patch (15cm 2) increases the likelihood of achieving a clinically meaningful treatment response.

Intranasal insulin treatment response in Alzheimer's disease influenced by glucose-stimulated insulin secretion

properties. Molecular modeling studies have indicated the central fused acridine ring undergoes favourable interactions within the catalytic site of AChE enzyme. Preliminary data on their ability to inhibit both AChE and BuChEs, their ability to chelate metals and antioxidant properties along with detailed enzyme-ligand binding investigations will be discussed. Conclusions: It is anticipated that our research should lead to the development of novel class of disease-modifying agents to treat AD by developing novel (i) heterocyclic small molecules possessing dual ChE (AChE/BuChE) inhibition; (ii) identify metal chelating and antioxidant pharmacophores in the design of small molecule therapeutics to treat AD.