Maureen Callaghan

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.

Diet Intervention and Cerebrospinal Fluid Biomarkers in Amnestic Mild Cognitive Impairment

OBJECTIVE To compare the effects of a 4-week high-saturated fat/high-glycemic index (HIGH) diet with a low-saturated fat/low-glycemic index (LOW) diet on insulin and lipid metabolism, cerebrospinal fluid (CSF) markers of Alzheimer disease, and cognition for healthy adults and adults with amnestic mild cognitive impairment (aMCI). DESIGN Randomized controlled trial. SETTING Veterans Affairs Medical Center clinical research unit. PARTICIPANTS Forty-nine older adults (20 healthy adults with a mean [SD] age of 69.3 [7.4] years and 29 adults with aMCI with a mean [SD] age of 67.6 [6.8] years). INTERVENTION Participants received the HIGH diet (fat, 45% [saturated fat, > 25%]; carbohydrates, 35%-40% [glycemic index, > 70]; and protein, 15%-20%) or the LOW diet (fat, 25%; [saturated fat, < 7%]; carbohydrates, 55%-60% [glycemic index, < 55]; and protein, 15%-20%) for 4 weeks. Cognitive tests, an oral glucose tolerance test, and lumbar puncture were conducted at baseline and during the fourth week of the diet. MAIN OUTCOME MEASURES The CSF concentrations of β-amyloid (Aβ42 and Aβ40), tau protein, insulin, F2-isoprostanes, and apolipoprotein E, plasma lipids and insulin, and measures of cognition. RESULTS For the aMCI group, the LOW diet increased CSF Aβ42 concentrations, contrary to the pathologic pattern of lowered CSF Aβ42 typically observed in Alzheimer disease. The LOW diet had the opposite effect for healthy adults, ie, decreasing CSF Aβ42, whereas the HIGH diet increased CSF Aβ42. The CSF apolipoprotein E concentration was increased by the LOW diet and decreased by the HIGH diet for both groups. For the aMCI group, the CSF insulin concentration increased with the LOW diet, but the HIGH diet lowered the CSF insulin concentration for healthy adults. The HIGH diet increased and the LOW diet decreased plasma lipids, insulin, and CSF F2-isoprostane concentrations. Delayed visual memory improved for both groups after completion of 4 weeks of the LOW diet. CONCLUSION Our results suggest that diet may be a powerful environmental factor that modulates Alzheimer disease risk through its effects on central nervous system concentrations of Aβ42, lipoproteins, oxidative stress, and insulin.

Effect of apolipoprotein e genotype and diet on apolipoprotein e lipidation and amyloid peptides randomized clinical trial

IMPORTANCE Sporadic Alzheimer disease (AD) is caused in part by decreased clearance of the β-amyloid (Aβ) peptide breakdown products. Lipid-depleted (LD) apolipoproteins are less effective at binding and clearing Aβ, and LD Aβ peptides are more toxic to neurons. However, not much is known about the lipid states of these proteins in human cerebrospinal fluid. OBJECTIVE To characterize the lipidation states of Aβ peptides and apolipoprotein E in the cerebrospinal fluid in adults with respect to cognitive diagnosis and APOE ε4 allele carrier status and after a dietary intervention. DESIGN Randomized clinical trial. SETTING Veterans Affairs Medical Center clinical research unit. PARTICIPANTS Twenty older adults with normal cognition (mean [SD] age, 69 [7] years) and 27 with amnestic mild cognitive impairment (67 [6] years). INTERVENTIONS Randomization to a diet high in saturated fat content and with a high glycemic index (High diet; 45% of energy from fat [>25% saturated fat], 35%-40% from carbohydrates with a mean glycemic index >70, and 15%-20% from protein) or a diet low in saturated fat content and with a low glycemic index (Low diet; 25% of energy from fat [<7% saturated fat], 55%-60% from carbohydrates with a mean glycemic index <55, and 15%-20% from protein). MAIN OUTCOMES AND MEASURES Lipid-depleted Aβ42 and Aβ40 and apolipoprotein E in cerebrospinal fluid. RESULTS Baseline levels of LD Aβ were greater for adults with mild cognitive impairment compared with adults with normal cognition (LD Aβ42, P = .05; LD Aβ40, P = .01). These findings were magnified in adults with mild cognitive impairment and the ε4 allele, who had higher LD apolipoprotein E levels irrespective of cognitive diagnosis (P < .001). The Low diet tended to decrease LD Aβ levels, whereas the High diet increased these fractions (LD Aβ42, P = .01; LD Aβ40, P = .15). Changes in LD Aβ levels with the Low diet negatively correlated with changes in cerebrospinal fluid levels of insulin (LD Aβ42 and insulin, r = -0.68 [P = .01]; LD Aβ40 and insulin, r = -0.78 [P = .002]). CONCLUSIONS AND RELEVANCE The lipidation states of apolipoproteins and Aβ peptides in the brain differ depending on APOE genotype and cognitive diagnosis. Concentrations can be modulated by diet. These findings may provide insight into the mechanisms through which apolipoprotein E4 and unhealthy diets impart risk for developing AD.

High-intensity physical activity modulates diet effects on cerebrospinal amyloid-β levels in normal aging and mild cognitive impairment.

We previously showed that amyloid-β 1-42 (Aβ(42)) levels in cerebrospinal fluid (CSF) were markedly altered in response to a 4-week dietary intervention in normal aging and mild cognitive impairment (MCI). Here, we re-examined the data to assess whether diet-induced effects on CSF Aβ(42) were modulated by high intensity physical activity (hi-PA). Normal older adults (n = 18, mean age = 68.6 ± 7.4 y) and adults with amnestic MCI (n = 23, mean age = 68.0 ± 6.5 y) received a low saturated fat/low glycemic index (LOW) diet or a high saturated fat/high glycemic index (HIGH) diet, and CSF levels of Aβ(42), tau, and IL-8 were measured at baseline and week 4. Pre-study activity levels were assessed using a 7-d questionnaire, and weekly duration of hi-PA was quantified. At baseline, increased hi-PA in normals predicted lower CSF levels of tau (r = -0.54, p = 0.020) and IL-8 (r = -0.70, p = 0.025). Diet-induced effects on CSF Aβ(42) during the intervention study were modulated by hi-PA, and the nature of this effect differed for normals and MCI (ANOVA, p = 0.039). That is, for normal adults, increased hi-PA attenuated the effects of the HIGH diet on CSF Aβ(42) whereas in MCI, increased hi-PA potentiated the effects of the LOW diet. Our results suggest that normal adults who engage in hi-PA are less vulnerable to the pathological effects of an unhealthy diet, while in MCI, the benefit of a healthy diet on Aβ modulation is greatest when paired with hi-PA. Exercise may thus interact with diet to alter pathological processes that ultimately modify risk of Alzheimers disease.

A randomized, placebo-controlled trial of intranasal insulin in amnestic MCI and early Alzheimer's

Background: Although not acknowledged by DSM-IV for example, attentional dysfunction is now recognised as a core cognitive symptom in Alzheimer’s disease (AD). The deficits are pronounced, directly related to disease severity, progress at a comparable rate to other deficits and respond well to treatment. In other dementias, such as Dementia with Lewy Bodies (DLB) and Parkinson’s Disease Dementia (PDD), recent consensus criteria recognize deficits to attention as central features of the conditions which should be evaluated in therapeutic trials. Methods: Much of the evidence for these deficits has been generated by the CDR System, an integrated set of automated tests of attention and memory. This paper will present the largest database of attentional deficits ever assembled from computerised testing in various dementia populations. Results: Data from over 3000 patients identifies differing profiles of attention deficits in AD, DLB, PDD, vascular dementia, Huntington’s disease and delirium. The rates of declines vary between the different groups as do the behavioural implications. The deficits to attention in AD, DLB and PDD respond to various treatments including donepezil, rivastigmine and galantamine. Conclusions: It will be concluded that attention is a major component of the cognitive dysfunction in all types of dementia, and that tests of attention should be part of the assessment profile in all therapeutic trials in the various conditions.

Aerobic exercise reduces phosphorylated tau protein in cerebrospinal fluid in older adults with mild cognitive impairment

3) clinical assessment by neurologist. The primary outcome for this study was the Alzheimer’s Disease Assessment Scale (ADAS-Cog). The AE classes were 60 minutes in duration and led by certified fitness instructors. Target heart rates were determined by the Karvonen formula. Participants of the UC group received an education seminar on nutrition once per month. Between-group differences in ADAS-Cog at trial completion was determined by analysis of covariance, with baseline ADASCog and baseline MoCA score included as covariates. Results: At trial completion, 62 of the 71 participants completed the trial. There were 2 drop outs from AE group and 7 from the UC group. Two additional individuals from the AE group were excluded from analyses due to medical reasons: 1 due to terminal and aggressive brain tumor and 1 due to rapid decline in overall function (likely due to mixed dementia). Compared with the UC group, participants in the AE group significant improved their cognitive function, as measured by the ADAS-Cog (p < 0.05). We also observed significant between-group differences in the Six-Minute Walk Test, providing evidence of treatment fidelity. Conclusions: AE may be an efficacious approach to improve cognitive function among individuals with mild SIVCI, and thereby, may prolong their functional independence and quality of life.

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.

EFFECTS OF AEROBIC EXERCISE ON COGNITION AND BIOMARKERS IN ADULTS WITH A DOUBLE-HIT RISK FOR DEMENTIA: MILD COGNITIVE IMPAIRMENT AND PREDIABETES

COGNITION AND BIOMARKERS IN ADULTS WITH A DOUBLE-HIT RISK FOR DEMENTIA: MILD COGNITIVE IMPAIRMENTAND PREDIABETES Laura D. Baker, Angela Hansen, Brenna Cholerton, Jeannine Skinner, Kaycee Sink, Maureen Callaghan, Suzanne Craft, Valerie Wilson, Wake Forest School of Medicine, Winston-Salem, North Carolina, United States; VA Puget Sound Health Care System, Seattle, Seattle, Washington, United States; 3 University of Washington Health Sciences, Seattle, Washington, United States; 4 Vanderbilt School of Medicine, Nashville, Tennessee, United States; Wake Forest School of Medicine, Winston-Salem, North Carolina, United States; VA Puget Sound Health Care System, Seattle, Tacoma, Washington, United States; 7 Wake Forest School of Medicine, Winston-Salem, North Carolina, United States. Contact e-mail: ldbaker@wakehealth.edu

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.

Influence of diet macronutrients on cognition and the interaction with ApoE ɛ4 genotype

beagles (98-115 months) were treated with a medical food cocktail containing (1) an extract of turmeric containing 95% curcuminoids; (2) an extract of green tea containing 50% epigallocatechin gallate; (3) N-acetyl cysteine; (4) R-alpha lipoic acid; (5) an extract of black pepper containing 95% piperine. Nine similarly aged dogs served as placebo-treated controls. We used a modified Wisconsin General Test apparatus for behavioral testing of the dogs for 10 or 12 trials/day, 5 days/week, with food rewards. Data acquisition was controlled using dedicated software (DOGMA). After a 1 month wash in, dogs were given a landmark discrimination task to measure spatial attention. Results: For the first 2 months of treatment, we observed a gradual but nonsignificant improvement in attention in treated animals as they progressively solved the problem using increasing landmark distances (0, 5, 18, 14 cm from the center of the correct object to be displaced). After 3 months of treatment, 13 dogs completed a 20-day variable distance version of the task. As compared to placebo-treated animals, dogs receiving the medical food cocktail had significantly lower error scores (t(11)1⁄4 4.3, P1⁄4 0.001) and were more accurate across all distances (F(1,9) 1⁄4 20.7, P 1⁄4 0.001). Blood biochemical measures from treated dogs had reduced aspartate transaminase (AST) (t(15) 1⁄4 3.5, P 1⁄4 0.003) and creatinine phosphokinase (CPK) (t(15) 1⁄4 2.93, P 1⁄4 0.01), indicating no liver or muscle toxicity with consumption of the medical food cocktail. Brain Ab remained unchanged in treated dogs and there appeared to be no change in gliosis. Conclusions: Our results indicate that this medical food cocktail may be beneficial for reducing or preventing symptoms associated with aging and AD.