Matthew Arbuckle

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.

Beneficial effect of a weight-stable, low-fat/low-saturated fat/low-glycaemic index diet to reduce liver fat in older subjects

Non-alcoholic fatty liver disease is associated with insulin resistance and dyslipidaemia and can progress to steatohepatitis and cirrhosis. We sought to determine whether dietary fat and saturated fat content alter liver fat in the absence of weight change in an older population. Liver fat was quantified by magnetic resonance spectroscopy before and after 4 weeks on an isoenergetic low-fat/low-saturated fat/low-glycaemic index (LGI) (LSAT: 23 % fat/7 % saturated fat/GI < 55) or a high-fat/high-saturated fat/high-GI (HSAT: 43 % fat/24 % saturated fat/GI>70) diet in older subjects. In the present study, twenty subjects (seven males/thirteen females; age 69.3 (SEM 1.6) years, BMI 26.9 (SEM 0.8) kg/m2) were randomised to the LSAT diet and fifteen subjects (six males/nine females; age 68.6 (SEM 1.8) years, BMI 28.1 (SEM 0.9) kg/m2) to the HSAT diet. Weight remained stable. Liver fat decreased significantly on the LSAT diet (median 2.2 (interquartile range (IQR) 3.1) to 1.7 (IQR 1.8) %, P= 0.002) but did not change on the HSAT diet (median 1.2 (IQR 4.1) to 1.6 (IQR 3.9) %). The LSAT diet lowered fasting glucose and total cholesterol, HDL-cholesterol and LDL-cholesterol and raised TAG (P< 0.05), while the HSAT diet had no effect on glucose or HDL-cholesterol but increased total cholesterol and LDL-cholesterol (P< 0.05). Fasting insulin and homeostasis model of insulin resistance did not change significantly on either diet, but the Matsuda index of insulin sensitivity improved on the LSAT diet (P< 0.05). Assignment to the LSAT v. HSAT diet was a predictor of changes in lipid parameters but not liver fat. We conclude that diet composition may be an important factor in the accumulation of liver fat, with a low-fat/low-saturated fat/LGI diet being beneficial.

Insulin and sex interactions in older adults with mild cognitive impairment

Alzheimers disease (AD) and other dementias are likely preceded by a protracted preclinical state. Thus, identification of biomarkers that signal potential points of intervention during this prodromal phase (during which patients are largely able to compensate for their cognitive deficits) is of paramount importance. Insulin is a pancreatic hormone with potent central nervous system effects, and insulin dysregulation has been implicated in the pathogenesis of both AD and vascular dementia. The aim of the current study was to determine whether circulating insulin differs as a function of mild cognitive impairment (MCI) diagnosis, and whether this relationship is mediated by sex and apolipoprotein E (APOE) genotype. A sample of 549 nondemented participants aged 65 and over from the Adult Changes in Thought community-based cohort underwent cognitive testing and blood draw to determine fasting levels of plasma insulin. Subjects were categorized as having normal cognitive functioning, amnestic MCI, or nonamnestic MCI. Results showed that the relationship between insulin and diagnostic category is moderated by sex, such that men with nonamnestic or amnestic MCI have higher fasting plasma insulin than cognitively normal men, while women with amnestic MCI have lower fasting plasma insulin than cognitively normal women. Exploratory analyses suggest that APOE ε4 genotype may further influence the relationship between sex and insulin. Future research will help determine whether insulin dysregulation results in differential effects on vascular function and AD pathology as a function of sex and/or APOE genotype.

Associations between Markers of Glucose and Insulin Function and Cognitive Function in Healthy African American Elders

BACKGROUND Glucose and insulin are important moderators of cognitive function. African Americans have poorer glycemic control across the glycemic spectrum and are at increased risk for type 2 diabetes and poor cognitive health. It is unclear which glucoregulatory markers predict cognitive function in this at-risk population. The purpose of this study was to examine the association between cognitive function and common markers of glucoregulation in non-diabetic African Americans elders. METHODS Thirty-four, community-dwelling African Americans, aged 50-75 years completed cognitive testing and blood collection as part of a health screening assessment. Cognitive outcomes were composite scores derived from neuropsychological tests of executive function and verbal memory. Linear regression was used to examine relationships between cognitive composite scores and fasting blood levels of glucose, insulin, and hemoglobin A1C, with adjustments for age, education, body mass index, and antihypertensive medication use. RESULTS Fasting plasma glucose was negatively associated with executive function (β=-0.41, p=0.03). There was a trend of an association between fasting plasma glucose and verbal memory (β=-0.34, p=0.06). Fasting insulin and hemoglobin A1c were not associated with cognitive function. CONCLUSION High non-diabetic fasting glucose levels were associated with poorer executive function and verbal memory. These results provide preliminary support for proactive glucose control in older African Americans even before glycemic criteria for type 2 diabetes are met. Our findings suggests that high-normal FPG levels may represent an early red-flag to signify increased risk of cognitive impairment or decline.

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.

Mild cognitive impairment: Classification methods and two-year dementia conversion rates

disorder characterized by amajor degeneration of the brain cortex with presence of extracellular amyloid plaques, intra-neuronal fibrillary tangles and neuronal cell loss in specific cortical and subcortical areas. Ab is the major component of amyloid plaques and is considered to play a crucial role in the progression of AD. Several lines of evidence suggest that these Ab peptides induce neuronal apoptosis, resulting in neurodegeneration and cognitive dysfunction. N-trans feruloyltyramine (NTF), purified from a traditional medicine tree, Polyalthia suberosa, has been suggested to be a potent anti-oxidant. In the present study, we examined the protective effect of NTF against Ab 1-42 -induced cytotoxicity, Bax, caspase 3 and reactive oxygen species (ROS) in cultured rat cortical neurons.Methods: Primary cultured neurons were treated with 0, 25, 50 and 100 mMNTF for 1 hour before the addition of 10 mM oligomeric Ab1-42 at sublethal dose, followed by incubation for a further 24 hour prior to cell viability (MTTassay) determination, Western blotting and ROS formation assay. Conclusions: Exposure of cultured cortical neurons to 10 mM A b 1-42 for 24 hours caused apoptotic cell death, as evidence by morphological changes and presence of activated caspase-3 and pro-apoptotic Bax protein, which could be attenuated by pretreatment with NTF (25-250 mM for 1 hour). Apoptotic cell death was accompanied by elevated levels of ROS. These findings suggest that the protective effect of NTF against Ab1-42-induced neuronal death might be due to its antioxidative property.