Mark A. Fishel

Effects of Aerobic Exercise on Mild Cognitive Impairment: A Controlled Trial

OBJECTIVESnTo examine the effects of aerobic exercise on cognition and other biomarkers associated with Alzheimer disease pathology for older adults with mild cognitive impairment, and assess the role of sex as a predictor of response.nnnDESIGNnSix-month, randomized, controlled, clinical trial.nnnSETTINGnVeterans Affairs Puget Sound Health Care System clinical research unit.nnnPARTICIPANTSnThirty-three adults (17 women) with amnestic mild cognitive impairment ranging in age from 55 to 85 years (mean age, 70 years). Intervention Participants were randomized either to a high-intensity aerobic exercise or stretching control group. The aerobic group exercised under the supervision of a fitness trainer at 75% to 85% of heart rate reserve for 45 to 60 min/d, 4 d/wk for 6 months. The control group carried out supervised stretching activities according to the same schedule but maintained their heart rate at or below 50% of their heart rate reserve. Before and after the study, glucometabolic and treadmill tests were performed and fat distribution was assessed using dual-energy x-ray absorptiometry. At baseline, month 3, and month 6, blood was collected for assay and cognitive tests were administered.nnnMAIN OUTCOME MEASURESnPerformance measures on Symbol-Digit Modalities, Verbal Fluency, Stroop, Trails B, Task Switching, Story Recall, and List Learning. Fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulinlike growth factor-I, and beta-amyloids 40 and 42.nnnRESULTSnSix months of high-intensity aerobic exercise had sex-specific effects on cognition, glucose metabolism, and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction. For women, aerobic exercise improved performance on multiple tests of executive function, increased glucose disposal during the metabolic clamp, and reduced fasting plasma levels of insulin, cortisol, and brain-derived neurotrophic factor. For men, aerobic exercise increased plasma levels of insulinlike growth factor I and had a favorable effect only on Trails B performance.nnnCONCLUSIONSnThis study provides support, using rigorous controlled methodology, for a potent nonpharmacologic intervention that improves executive control processes for older women at high risk of cognitive decline. Moreover, our results suggest that a sex bias in cognitive response may relate to sex-based differences in glucometabolic and hypothalamic-pituitary-adrenal axis responses to aerobic exercise.

Preserved Cognition in Patients With Early Alzheimer Disease and Amnestic Mild Cognitive Impairment During Treatment With Rosiglitazone A Preliminary Study

OBJECTIVEnInsulin resistance (impaired insulin action) has been associated with Alzheimer disease (AD) and memory impairment, independent of AD. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists improve insulin sensitivity and regulate in-vitro processing of the amyloid precursor protein (APP). Authors evaluated the effects of the PPAR-gamma agonist rosiglitazone on cognition and plasma levels of the APP derivative beta-amyloid (Abeta) in humans.nnnMETHODSnIn a placebo-controlled, double-blind, parallel-group pilot study, 30 subjects with mild AD or amnestic mild cognitive impairment were randomized to a 6-month course of rosiglitazone (4 mg daily; N = 20) or placebo (N = 10). Primary endpoints were cognitive performance and plasma Abeta levels.nnnRESULTSnRelative to the placebo group, subjects receiving rosiglitazone exhibited better delayed recall (at Months 4 and 6) and selective attention (Month 6). At Month 6, plasma Abeta levels were unchanged from baseline for subjects receiving rosiglitazone but declined for subjects receiving placebo, consistent with recent reports that plasma Abeta42 decreases with progression of AD.nnnCONCLUSIONSnFindings provide preliminary support that rosiglitazone may offer a novel strategy for the treatment of cognitive decline associated with AD. Future confirmation in a larger study is needed to fully demonstrate rosiglitazones therapeutic potential.

Effects of intranasal insulin on cognition in memory-impaired older adults: modulation by APOE genotype.

Raising insulin acutely in the periphery and in brain improves verbal memory. Intranasal insulin administration, which raises insulin acutely in the CNS without raising plasma insulin levels, provides an opportunity to determine whether these effects are mediated by central insulin or peripheral processes. Based on prior research with intravenous insulin, we predicted that the treatment response would differ between subjects with (epsilon4+) and without (epsilon4-) the APOE-epsilon4 allele. On separate mornings, 26 memory-impaired subjects (13 with early Alzheimers disease and 13 with amnestic mild cognitive impairment) and 35 normal controls each underwent three intranasal treatment conditions consisting of saline (placebo) or insulin (20 or 40 IU). Cognition was tested 15 min post-treatment, and blood was acquired at baseline and 45 min after treatment. Intranasal insulin treatment did not change plasma insulin or glucose levels. Insulin treatment facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults. These effects were stronger for memory-impaired epsilon4- subjects than for memory-impaired epsilon4+ subjects and normal adults. Unexpectedly, memory-impaired epsilon4+ subjects showed poorer recall following insulin administration on one test of memory. These findings suggest that intranasal insulin administration may have therapeutic benefit without the risk of peripheral hypoglycemia and provide further evidence for apolipoprotein E (APOE) related differences in insulin metabolism.

Intranasal Insulin Administration Dose-Dependently Modulates Verbal Memory and Plasma Amyloid-β in Memory-Impaired Older Adults

Intranasal insulin administration raises central nervous system (CNS) insulin levels in humans and acutely facilitates verbal memory in patients with Alzheimers disease (AD), an effect that may differ by APOE genotype. The purpose of this study was to examine the cognitive dose response curves for intranasal insulin administration, and determine whether the effects of insulin differ between participants with (epsilon4+) and without (epsilon4-) the APOE- epsilon4 allele. On separate mornings, 33 memory-impaired adults with AD or amnestic mild cognitive impairment and 59 normal adults each underwent five intranasal treatment conditions consisting of insulin (10, 20, 40, or 60 IU) or placebo. Cognition was tested 15-minutes post-treatment, and blood was acquired at baseline and 45-minutes post-treatment. Plasma insulin and glucose levels were unaffected by treatment. Insulin administration facilitated recall on two measures of verbal memory in memory-impaired epsilon4- adults, with performance generally peaking at 20 IU. In contrast, memory-impaired epsilon4+ subjects demonstrated a relative decline in verbal memory. Insulin also differentially modulated plasma amyloid-beta for memory-impaired subjects and normal controls, effects that again differed by APOE genotype. These findings suggest that groups with different genetic risks for AD may show differential dose-response curves following intranasal insulin administration.

Aerobic exercise improves cognition for older adults with glucose intolerance, a risk factor for Alzheimer's disease.

Impaired glucose regulation is a defining characteristic of type 2 diabetes mellitus (T2DM) pathology and has been linked to increased risk of cognitive impairment and dementia. Although the benefits of aerobic exercise for physical health are well-documented, exercise effects on cognition have not been examined for older adults with poor glucose regulation associated with prediabetes and early T2DM. Using a randomized controlled design, twenty-eight adults (57-83 y old) meeting 2-h tolerance test criteria for glucose intolerance completed 6 months of aerobic exercise or stretching, which served as the control. The primary cognitive outcomes included measures of executive function (Trails B, Task Switching, Stroop, Self-ordered Pointing Test, and Verbal Fluency). Other outcomes included memory performance (Story Recall, List Learning), measures of cardiorespiratory fitness obtained via maximal-graded exercise treadmill test, glucose disposal during hyperinsulinemic-euglycemic clamp, body fat, and fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulin-like growth factor-1, amyloid-β (Aβ40 and Aβ42). Six months of aerobic exercise improved executive function (MANCOVA, p=0.04), cardiorespiratory fitness (MANOVA, p=0.03), and insulin sensitivity (p=0.05). Across all subjects, 6-month changes in cardiorespiratory fitness and insulin sensitivity were positively correlated (p=0.01). For Aβ42, plasma levels tended to decrease for the aerobic group relative to controls (p=0.07). The results of our study using rigorous controlled methodology suggest a cognition-enhancing effect of aerobic exercise for older glucose intolerant adults. Although replication in a larger sample is needed, our findings potentially have important therapeutic implications for a growing number of adults at increased risk of cognitive decline.

Cognitive response to estradiol in postmenopausal women is modified by high cortisol

Estradiol has potent favorable effects on brain function and behavior in animals while in human trials, the results are inconsistent. A number of potential mediating variables influencing response to estradiol have been proposed to account for this variability, 1 of which includes stress. We conducted a placebo-controlled study to examine joint and independent effects of estradiol and elevated levels of the stress hormone cortisol on cognition and biomarkers of aging and neurodegenerative disease. Thirty-nine healthy postmenopausal women (56-84 years) received 0.10 mg/dL of transdermal 17β-estradiol (E2) or placebo for 8 weeks. During the last 4 days of the trial, subjects also received 90 mg/day (30 mg 3×/day) of oral hydrocortisone (CORT) to induce stress-level elevations in cortisol, or a matched placebo. The 4 groups thus included placebo (placebo patch/placebo pill), CORT-alone (placebo patch/hydrocortisone), E2-alone (estradiol patch/placebo pill), and E2+CORT (estradiol patch/hydrocortisone). Eight weeks of E2 increased plasma estradiol by 167%, and 4 days of CORT increased plasma cortisol by 119%. Overall, E2 had favorable effects on verbal memory (p = 0.03), working memory (p = 0.02), and selective attention (p = 0.04), and the magnitude of these effects was attenuated for E2+CORT. E2-alone and E2+CORT had opposing effects on plasma levels of the amyloid-β (Aβ) biomarker (Aβ40/42 ratio, p < 0.05), with the more favorable response observed for E2-alone. CORT-induced increases in insulin-like growth factor-1 were blunted by E2 coadministration. Our findings indicate that cognitive and physiological responses to estradiol are adversely affected by elevated stress hormone levels of cortisol in healthy postmenopausal women.

O3-05-05

human antibody product that contains natural antibodies against the amyloid beta peptide (A ). Eight patients with mild to moderate stage Alzheimer’s disease (AD) were treated with IVIg in an open label dose-finding Phase Ia clinical study. Subjects treated for 6 months with doses of IVIg between 0.4g/kg/2 weeks and 2g/kg/month remained stable or improved an average of 2.75 points on the Folstein MMSE (mean 26, range 20-29). All subjects had significantly lower cerebrospinal fluid A levels after six months of treatment relative to baseline. Subsequent washout of IVIg for 3 months led to a return to the pre-treatment cognitive state. Objective(s): To determine whether resumption of IVIg treatment after washout exerts beneficial effects on cognition in AD patients. Methods: All eight patients (1M, 7F) who completed the Phase Ia IVIg treatment trial gave informed consent for resumption of IVIg infusions for an additional nine months. In Phase Ib, subjects with a mean age of 75 (range 67-86) were treated with IVIg (Gammagard S/D) at a dose of 1g/kg/2 weeks for 3 months followed by 0.4g/kg/2 weeks for 6 months. Subjects were maintained on stable doses of cholinesterase inhibitors and memantine during this extension study. Mental status was assessed using MMSE immediately post-washout and every three months following subsequent commencement of IVIg treatment. Results: In contrast to the rapid decline subjects experienced during washout, cognitive status remained stable throughout the first three months of follow-up treatment and trended upward in the majority of cases during the remaining 6 months. MMSE scores in all our patients who have completed Phase Ib to date are stable or have increased relative to their baseline MMSE scores at entry into Phase Ia. Only minor treatment-related side effects occurred during this nine-month extension study. Conclusions: Resumption of IVIg treatment after a washout period led to extension of cognitive benefits for a period encompassing 18 months from the time of initial treatment. This study suggests that IVIg can exert long-term benefits for the treatment of cognitive decline in Alzheimer’s disease. Support: WMC GCRC M01 RR00047, Grant from Baxter BioScience.

Therapeutic effects of intranasal insulin in patients with AD and amnestic MCI

ments for age, sex, and APOE. Vitamin E users who had a history of stroke (HR 3.18, 95% CI 1.32-7.68), coronary artery bypass graft (HR 5.00, 95% CI 3.21-7.78), or myocardial infarction (HR 1.97, 95% CI 1.26-3.07) had increased mortality risks. Similarly, participants taking vitamin E and nitrates were at significantly increased risk of death (HR 5.96, 95% CI 3.04-11.69) after adjustments. When we adjusted for nitrates, the risk associated with cardiovascular events was no greater in vitamin E users than non-users. An interaction was found between vitamin E, coumadin, and nitrates used in combination. A portion of this interaction was independent of coumadin use. Conclusions: Regular use of vitamin E ( 400IU) does not increase the risk of mortality in healthy individuals aged 65 . Vitamin E supplementation does, however, increase the risk of mortality in those with severe CVD, possibly due to medication interactions. We identified interactions between vitamin E, nitrates, and coumadin. It appears the increased risk of mortality associated with vitamin E use in persons with severe CVD can be accounted for by these interactions although disease by vitamin E interaction cannot be ruled out.