-
[show abstract]
[hide abstract]
ABSTRACT: This manuscript describes the study design and rationale for the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS Cognitive and Affective ancillary study (KEEPS Cog). KEEPS is a multicenter, randomized, double-blinded, placebo-controlled trial, designed to test the hypothesis that low-dose hormone therapy (HT) initiated in recently postmenopausal women will reduce the progression of subclinical atherosclerosis as measured by carotid artery intima-media thickness (CIMT) and coronary artery calcification (CAC) over four years. The KEEPS Cog ancillary study was designed to assess potential estrogenic treatment effects on cognition and mood. We present the KEEPS trial in the context of issues raised by the Women's Health Initiative (WHI) and the Women's Health Initiative Memory Study (WHIMS). Here we also describe the most recent results and ongoing HT-related research studies designed to address similar issues.
Brain research 04/2013; · 2.46 Impact Factor
-
Ozioma C Okonkwo,
Guofan Xu,
Jennifer M Oh,
N Maritza Dowling,
Cynthia M Carlsson,
Catherine L Gallagher,
Alex C Birdsill,
Matthew Palotti,
Whitney Wharton,
Bruce P Hermann,
Asenath Larue,
Barbara B Bendlin,
Howard A Rowley, Sanjay Asthana,
Mark A Sager,
Sterling C Johnson
[show abstract]
[hide abstract]
ABSTRACT: Cerebral blood flow (CBF) provides an indication of the metabolic status of the cortex and may have utility in elucidating preclinical brain changes in persons at risk for Alzheimer's disease (AD) and related diseases. In this study, we investigated CBF in 327 well-characterized adults including patients with AD (n = 28), patients with amnestic mild cognitive impairment (aMCI, n = 23), older cognitively normal (OCN, n = 24) adults, and asymptomatic middle-aged adults (n = 252) with and without a family history (FH) of AD. Compared with the asymptomatic cohort, AD patients displayed significant hypoperfusion in the precuneus, posterior cingulate, lateral parietal cortex, and the hippocampal region. Patients with aMCI exhibited a similar but less marked pattern of hypoperfusion. Perfusion deficits within the OCN adults were primarily localized to the inferior parietal lobules. Asymptomatic participants with a maternal FH of AD showed hypoperfusion in hippocampal and parietofrontal regions compared with those without a FH of AD or those with only a paternal FH of AD. These observations persisted when gray matter volume was included as a voxel-wise covariate. Our findings suggest that having a mother with AD might confer a particular risk for AD-related cerebral hypoperfusion in midlife. In addition, they provide further support for the potential utility of arterial spin labeling for the measurement of AD-related neurometabolic dysfunction, particularly in situations where [18F]fluorodeoxyglucose imaging is infeasible or clinically contraindicated.
Cerebral Cortex 12/2012; · 6.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: OBJECTIVE
Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer disease. Insulin resistance may play a role in Alzheimer disease etiopathogenesis. This longitudinal study examined whether insulin resistance among late middle-aged, cognitively healthy individuals was associated with 1) less gray matter in Alzheimer disease-sensitive brain regions and 2) worse cognitive performance.RESEARCH DESIGN AND METHODS
Homeostasis model assessment of insulin resistance, gray matter volume, and the Rey Auditory Verbal Learning Test (RAVLT) were acquired in 372 participants at baseline and a consecutive subset of 121 individuals ~4 years later. Voxel-based morphometry and tensor-based morphometry were used, respectively, to test the association of insulin resistance with baseline brain volume and progressive gray matter atrophy.RESULTSHigher insulin resistance predicted less gray matter at baseline and 4 years later in medial temporal lobe, prefrontal cortices, precuneus, and other parietal gyri. A region-of-interest analysis, independent of the voxel-wise analyses, confirmed that higher insulin resistance was related to medial temporal lobe atrophy. Atrophy itself corresponded to cognitive deficits in the RAVLT. Temporal lobe atrophy that was predicted by higher insulin resistance significantly mediated worse RAVLT encoding performance.CONCLUSIONS
These results suggest that insulin resistance in an asymptomatic, late middle-aged cohort is associated with progressive atrophy in regions affected by early Alzheimer disease. Insulin resistance may also affect the ability to encode episodic information by negatively influencing gray matter volume in medial temporal lobe.
Diabetes care 10/2012; · 8.09 Impact Factor
-
Whitney Wharton,
James H Stein,
Claudia Korcarz,
Jane Sachs,
Sandra R Olson,
Henrik Zetterberg,
Maritza Dowling,
Shuyun Ye,
Carey E Gleason,
Gail Underbakke,
Laura E Jacobson,
Sterling C Johnson,
Mark A Sager, Sanjay Asthana,
Cynthia M Carlsson
[show abstract]
[hide abstract]
ABSTRACT: Research shows that certain antihypertensives taken during midlife confer Alzheimer's disease (AD) related benefits in later life. We conducted a clinical trial to evaluate the extent to which the angiotensin converting enzyme inhibitor (ACE-I), ramipril, affects AD biomarkers including cerebrospinal fluid (CSF) amyloid-β (Aβ) levels and ACE activity, arterial function, and cognition in participants with a parental history of AD. This four month randomized, double-blind, placebo-controlled, pilot clinical trial evaluated the effects of ramipril, a blood-brain-barrier crossing ACE-I, in cognitively healthy individuals with mild, or Stage I hypertension. Fourteen participants were stratified by gender and apolipoprotein E ε4 (APOE ε4) status and randomized to receive 5 mg of ramipril or matching placebo daily. Participants were assessed at baseline and month 4 on measures of CSF Aβ1-42 and ACE activity, arterial function, and cognition. Participants were middle-aged (mean 54 y) and highly educated (mean 15.4 y), and included 50% men and 50% APOE ε4 carriers. While results did not show a treatment effect on CSF Aβ1-42 (p = 0.836), data revealed that ramipril can inhibit CSF ACE activity (p = 0.009) and improve blood pressure, however, there were no differences between groups in arterial function or cognition. In this study, ramipril therapy inhibited CSF ACE activity and improved blood pressure, but did not influence CSF Aβ1-42. While larger trials are needed to confirm our CSF Aβ results, it is possible that prior research reporting benefits of ACE-I during midlife may be attributed to alternative mechanisms including improvements in cerebral blood flow or the prevention of angiotensin II-mediated inhibition of acetylcholine.
Journal of Alzheimer's disease: JAD 07/2012; 32(1):147-56. · 3.74 Impact Factor
-
Trygve E Bakken,
J Cooper Roddey,
Srdjan Djurovic,
Natacha Akshoomoff,
David G Amaral,
Cinnamon S Bloss,
B J Casey,
Linda Chang,
Thomas M Ernst,
Jeffrey R Gruen, [......],
Bruce Rosen,
Nitzah Gebhard,
Holly Manigan,
Jean Frazier,
David Kennedy,
Lauren Yakutis,
Michael Hill,
Jeffrey Gruen,
Joan Bosson-Heenan,
Heatherly Carlson
[show abstract]
[hide abstract]
ABSTRACT: Visual cortical surface area varies two- to threefold between human individuals, is highly heritable, and has been correlated with visual acuity and visual perception. However, it is still largely unknown what specific genetic and environmental factors contribute to normal variation in the area of visual cortex. To identify SNPs associated with the proportional surface area of visual cortex, we performed a genome-wide association study followed by replication in two independent cohorts. We identified one SNP (rs6116869) that replicated in both cohorts and had genome-wide significant association (P(combined) = 3.2 × 10(-8)). Furthermore, a metaanalysis of imputed SNPs in this genomic region identified a more significantly associated SNP (rs238295; P = 6.5 × 10(-9)) that was in strong linkage disequilibrium with rs6116869. These SNPs are located within 4 kb of the 5' UTR of GPCPD1, glycerophosphocholine phosphodiesterase GDE1 homolog (Saccharomyces cerevisiae), which in humans, is more highly expressed in occipital cortex compared with the remainder of cortex than 99.9% of genes genome-wide. Based on these findings, we conclude that this common genetic variation contributes to the proportional area of human visual cortex. We suggest that identifying genes that contribute to normal cortical architecture provides a first step to understanding genetic mechanisms that underlie visual perception.
Proceedings of the National Academy of Sciences 03/2012; 109(10):3985-90. · 9.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: It is tentatively estimated that 25% of people with early Alzheimer's disease (AD) show impaired awareness of disease-related changes in their own cognition. Research examining both normative self-awareness and altered awareness resulting from brain disease or injury points to the central role of the medial prefrontal cortex (MPFC) in generating accurate self-appraisals. The current project builds on this work - examining changes in MPFC functional connectivity that correspond to impaired self-appraisal accuracy early in the AD time course. Our behavioral focus was self-appraisal accuracy for everyday memory function, and this was measured using the Memory Function Scale of the Memory Awareness Rating Scale - an instrument psychometrically validated for this purpose. Using regression analysis of data from people with healthy memory (n=12) and people with impaired memory due to amnestic mild cognitive impairment or early AD (n=12), we tested the hypothesis that altered MPFC functional connectivity - particularly with other cortical midline structures and dorsolateral prefrontal cortex - explains variation in memory self-appraisal accuracy. We spatially constrained (i.e., explicitly masked) our regression analyses to those regions that work in conjunction with the MPFC to evoke self-appraisals in a normative group. This empirically derived explicit mask was generated from the result of a psychophysiological interaction analysis of fMRI self-appraisal task data in a separate, large group of cognitively healthy individuals. Results of our primary analysis (i.e., the regression of memory self-appraisal accuracy on MPFC functional connectivity) were generally consistent with our hypothesis: people who were less accurate in making memory self-appraisals showed attenuated functional connectivity between the MPFC seed region and proximal areas within the MPFC (including subgenual anterior cingulate cortex), bilateral dorsolateral prefrontal cortex, bilateral caudate, and left posterior hippocampus. Contrary to our expectations, MPFC functional connectivity with the posterior cingulate was not significantly related to accuracy of memory self-appraisals. Results reported here corroborate findings of variable memory self-appraisal accuracy during the earliest emergence of AD symptoms and reveal alterations in MPFC functional connectivity that correspond to impaired memory self-appraisal.
Neuropsychologia 01/2012; 50(5):603-11. · 3.64 Impact Factor
-
Barbara B Bendlin,
Cynthia M Carlsson,
Sterling C Johnson,
Henrik Zetterberg,
Kaj Blennow,
Auriel A Willette,
Ozioma C Okonkwo,
Aparna Sodhi,
Michele L Ries,
Alex C Birdsill,
Andrew L Alexander,
Howard A Rowley,
Luigi Puglielli, Sanjay Asthana,
Mark A Sager
[show abstract]
[hide abstract]
ABSTRACT: Cerebrospinal fluid (CSF) biomarkers T-Tau and Aβ(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. Voxel-wise image analysis methods were used to test whether baseline CSF Aβ(42), total tau (T-Tau), phosphorylated tau (P-Tau) and neurofilament light protein predicted brain microstructure as indexed by DTI and gray matter volume indexed by T1-weighted imaging. T-Tau and T-Tau/Aβ(42) were widely correlated with indices of brain microstructure (mean, axial, and radial diffusivity), notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Aβ(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter.
PLoS ONE 01/2012; 7(6):e37720. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This study investigated the phenomenon known as the healthy user bias by equating hormone therapy (HT) use (past or current) with healthy user status.
Data from the Survey of Midlife in the United States were used to identify the predictors of HT use. The unique Survey of Midlife in the United States data include psychological, demographic, health-related, and behavioral variables as well as history of HT use. Predictors of HT use were combined to derive propensity scores, describing the likelihood that a woman was an HT user, based on her psychological, demographic, physical, and behavioral profile (ie, likelihood of being a healthy user) as opposed to her actual use of HT. Finally, cognitive performance on an executive function test was examined in women stratified by propensity score.
Using a multiple logistic regression model, nine variables emerged as predictors of HT use. The nine variables were used to estimate the propensity or conditional probability of using HT for each subject; resultant propensity scores were ranked and divided into tertiles. Women in the highest tertile demonstrated shorter median response latencies on a test of executive function than did women who did not use HT.
From an array of psychological, medical, and behavioral variables, nine emerged as predictors of HT use. If validated, these features may serve as a means of estimating the phenomenon known as healthy user bias. Moreover, these data suggest that the degree to which a woman fits a model of a healthy user may influence cognitive response to HT.
Menopause (New York, N.Y.) 12/2011; 19(5):524-33. · 3.08 Impact Factor
-
Laura D Baker, Sanjay Asthana,
Brenna A Cholerton,
Charles W Wilkinson,
Stephen R Plymate,
Pattie S Green,
George R Merriam,
Mark A Fishel,
G Stennis Watson,
Monique M Cherrier,
Monica L Kletke,
Pankaj D Mehta,
Suzanne Craft
[show abstract]
[hide abstract]
ABSTRACT: 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.
Neurobiology of aging 08/2011; 33(4):829.e9-20. · 5.94 Impact Factor
-
Sterling C Johnson,
Asenath La Rue,
Bruce P Hermann,
Guofan Xu,
Rebecca L Koscik,
Erin M Jonaitis,
Barbara B Bendlin,
Kirk J Hogan,
Allen D Roses,
Ann M Saunders,
Michael W Lutz, Sanjay Asthana,
Robert C Green,
Mark A Sager
[show abstract]
[hide abstract]
ABSTRACT: Apolipoprotein E (APOE) genotypes are associated with variable risk of developing late-onset Alzheimer's disease (LOAD), with APOE epsilon 4 (APOE ε4) having higher risk. A variable poly-T length polymorphism at rs10524523, within intron 6 of the translocase of the outer mitochondrial membrane (TOMM40) gene, has been shown to influence age of onset in LOAD, with very long (VL) poly-T length associated with earlier disease onset, and short poly-T length associated with later onset. In this study, we tested the hypothesis that brain and cognitive changes suggestive of presymptomatic LOAD may be associated with this TOMM40 polymorphism.
Among healthy APOE ε3 homozygous adults (N = 117; mean age, 55 years), we compared those who were homozygous for VL/VL (n = 35) TOMM40 poly-T lengths (who were presumably at higher risk) with those homozygous for short (S/S; n = 38) poly-T lengths, as well as those with heterozygous (S/VL; n = 44) poly-T length polymorphisms, on measures of learning and memory and on structural brain imaging.
The VL/VL group showed lower performance than the S/S TOMM40 group on primacy retrieval from a verbal list learning task, a finding which is also seen in early Alzheimer's disease. A dose-dependent increase in the VL TOMM40 polymorphism (from no VL alleles, to S/VL heterozygous, to VL/VL homozygous) was associated with decreasing gray matter volume in the ventral posterior cingulate and medial ventral precuneus, a region of the brain affected early in LOAD.
These findings among APOE ε3/ε3 late middle-aged adults suggest that a subgroup with VL TOMM40 poly-T lengths may be experiencing incipient LOAD-related cognitive and brain changes.
Alzheimer's & dementia: the journal of the Alzheimer's Association 07/2011; 7(4):456-65. · 5.90 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: We aimed to conduct a placebo-controlled, double-blind, parallel-group design intervention study to evaluate the therapeutic efficacy of hormone therapy (HT) in postmenopausal women with mild to moderate Alzheimer's disease (AD). The trial was designed to evaluate the dose-dependent effects of transdermal 17-β estradiol, unopposed and opposed with medroxyprogesterone (MPA, Provera©), for 12 months in 43 postmenopausal women with AD. Participants were assessed using cognitive measures at baseline, months 1, 3, 6, and 12 of treatment and eight weeks post treatment (month 15). The dropout rate was 49% across 12 months. As a result of the Women's Health Initiative (WHI) and anticipated increased attrition, the protocol was modified to examine data only at time points where attrition was less than 30%. The results of sensitivity analyses indicated robust and reliable data collected in the first three months of the trial. Data collected in the first three months of the trial for forty-three participants were analyzed. HT had favorable cognitive effects across multiple cognitive domains, including visual memory (p-values < 0.030) and semantic memory (p-values < 0.037) in postmenopausal women with AD. Moreover, treatment-related changes in plasma estradiol were positively correlated with improvements in visual memory. Short-term HT that includes the use of estradiol has favorable effects on cognition in women with AD.
Journal of Alzheimer's disease: JAD 06/2011; 26(3):495-505. · 3.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Brain alterations in structure and function have been identified in people with risk factors for sporadic type Alzheimer's disease (AD), suggesting that alterations can be detected decades before AD diagnosis. Although the effect of apolipoprotein E (APOE) varepsilon4 on the brain is well-studied, less is known about the effect of family history of AD. We examined the main effects of family history and APOE varepsilon4 on brain integrity, in addition to assessing possible additive effects of these two risk factors.
Diffusion tensor imaging was performed in 136 middle-aged asymptomatic participants stratified on family history and APOE varepsilon4. Mean diffusivity and fractional anisotropy (FA) were entered in factorial analyses to test the effect of AD risk on microstructural brain integrity. We performed a post hoc analysis of the three principal diffusivities (lambda1, lambda2, lambda3) to provide potential additional insight on underlying tissue differences.
Parental family history of AD was associated with lower FA in regions of the brain known to be affected by AD, including cingulum, corpus callosum, tapetum, uncinate fasciculus, hippocampus, and adjacent white matter. Contrary to previous reports, there was no main effect of APOE varepsilon4; however, there was an additive effect of family history and APOE varepsilon4 in which family history-positive participants who were also APOE varepsilon4 carriers had the lowest FA compared with the other groups.
The data indicate that unknown risk factors contained in family history are associated with changes in microstructural brain integrity in areas of the brain known to be affected by AD. Importantly, the results provide further evidence that AD pathology might be detected before cognitive changes, perhaps decades before disease onset.
Alzheimer's & dementia: the journal of the Alzheimer's Association 09/2010; 6(5):394-403. · 5.90 Impact Factor
-
Michael A Ward,
Barbara B Bendlin,
Donald G McLaren,
Timothy M Hess,
Catherine L Gallagher,
Erik K Kastman,
Howard A Rowley, Sanjay Asthana,
Cynthia M Carlsson,
Mark A Sager,
Sterling C Johnson
[show abstract]
[hide abstract]
ABSTRACT: Dyslipidemia is common in adults and contributes to high rates of cardiovascular disease and may be linked to subsequent neurodegenerative and neurovascular diseases. This study examined whether lower brain volumes and cognition associated with dyslipidemia could be observed in cognitively healthy adults, and whether apolipoprotein E (APOE) genotype or family history of Alzheimer's disease (FHAD) alters this effect. T1-weighted magnetic resonance imaging was used to examine regional brain gray matter (GM) and white matter (WM) in 183 individuals (58.4 +/- 8.0 years) using voxel-based morphometry. A non-parametric multiple linear regression model was used to assess the effect of high-density lipoprotein (HDL) and non-HDL cholesterol, APOE, and FHAD on regional GM and WM volume. A post hoc analysis was used to assess whether any significant correlations found within the volumetric analysis had an effect on cognition. HDL was positively correlated with GM volume in the bilateral temporal poles, middle temporal gyri, temporo-occipital gyri, and left superior temporal gyrus and parahippocampal region. This effect was independent of APOE and FHAD. A significant association between HDL and the Brief Visuospatial Memory Test was found. Additionally, GM volume within the right middle temporal gyrus, the region most affected by HDL, was significantly associated with the Controlled Oral Word Association Test and the Center for Epidemiological Studies Depression Scale. These findings suggest that adults with decreased levels of HDL cholesterol may be experiencing cognitive changes and GM reductions in regions associated with neurodegenerative disease and therefore, may be at greater risk for future cognitive decline.
Frontiers in aging neuroscience. 01/2010; 2.
-
[show abstract]
[hide abstract]
ABSTRACT: To examine awareness of memory abilities by groups (healthy control, suspected dementia/mild cognitive impairment, MCI, and diagnosed dementia/MCI), and to describe group differences in the relationship between awareness and cognitive performance in a community sample.
In a cross-sectional design, 183 subjects were evaluated in a community setting and categorized into 3 groups based on their cognitive performance and reported medical history. Awareness of memory abilities was quantified using a published anosognosia ratio (AR) comparing the estimated to the objective memory performance by subjects. Each group was further categorized into 'overestimators', 'accurate estimators', and 'underestimators' based on their AR scores.
The suspected and diagnosed dementia/MCI groups had significantly higher AR scores than the controls. The suspected group also had a significantly larger proportion (96.2%) of overestimators than the diagnosed (73.3%) and control groups (26.1%). Impaired awareness in overestimators of the suspected and diagnosed groups was correlated with deficits in executive function, language or global cognition.
Impaired awareness of memory abilities was prevalent in community-dwelling older adults with suspected and diagnosed dementia or MCI. Those with suspected dementia or MCI were more likely to overestimate their memory abilities than their diagnosed counterparts, suggesting that limited awareness of deficits may hinder utilization of dementia diagnostic services.
Dementia and Geriatric Cognitive Disorders 01/2010; 30(1):83-92. · 2.14 Impact Factor
-
Barbara B Bendlin,
Lisa M Newman,
Michele L Ries,
Luigi Puglielli,
Cynthia M Carlsson,
Mark A Sager,
Howard A Rowley,
Catherine L Gallagher,
Auriel A Willette,
Andrew L Alexander, Sanjay Asthana,
Sterling C Johnson
[show abstract]
[hide abstract]
ABSTRACT: The use of non-steroidal anti-inflammatory drugs (NSAIDs) in humans is associated with brain differences including decreased number of activated microglia. In animals, NSAIDs are associated with reduced microglia, decreased amyloid burden, and neuronal preservation. Several studies suggest NSAIDs protect brain regions affected in the earliest stages of AD, including hippocampal and parahippocampal regions. In this cross-sectional study, we examined the protective effect of NSAID use on gray matter volume in a group of middle-aged and older NSAID users (n = 25) compared to non-user controls (n = 50). All participants underwent neuropsychological testing and T1-weighted magnetic resonance imaging. Non-user controls showed smaller volume in portions of the left hippocampus compared to NSAID users. Age-related loss of volume differed between groups, with controls showing greater medial temporal lobe volume loss with age compared to NSAID users. These results should be considered preliminary, but support previous reports that NSAIDs may modulate age-related loss of brain volume.
Frontiers in aging neuroscience. 01/2010; 2.
-
[show abstract]
[hide abstract]
ABSTRACT: The Women's Health Initiative (WHI) study and its ancillary Memory Study (WHIMS) revealed increased rates of cardiovascular risk, cognitive decline and dementia with opposed conjugated equine estrogens (CEE). As a result, previously accepted observational data suggesting cardiovascular and cognitive benefits and reduced risk for dementia with hormone therapy (HT) were largely attributed to 'healthy-user' bias. The present observational, community-based, case-controlled study examined the 'healthy-user' bias theory by comparing cognitive task performance in two groups of postmenopausal women, who were either HT users or non-users.
Participants were 213 non-demented, postmenopausal women residing in the community and in assisted-living facilities who completed a self-report health questionnaire and underwent a 1-h cognitive test battery. To study the independent contribution of variables in the prediction of cognitive performance, we employed a series of hierarchical regression models adding terms in three stages. The first stage included only HT, the second stage added demographics, and the last stage added alcohol, depression and a cardiovascular risk factor (CVRF) composite derived from a confirmatory factor analysis. The CVRF composite consisted of: stroke, diabetes, hypertension, and hypercholesterolemia.
Although independent samples t-tests revealed no statistically significant differences in the CVRF composite and its individual components between the two groups, HT users tended to possess fewer CVRF than non-users. Conversely, HT users were younger and more educated than non-users. HT users outperformed non-users on 7/9 cognitive variables. The full regression model controlling for CVRF, demographic variables, and mood showed HT users outperformed non-users on measures of verbal memory and abstract reasoning.
While there is some evidence HT users possess fewer preexisting CVRF than non-users, the observed positive association between HT and cognition is not completely explained by this trend.
Maturitas 11/2009; 64(3):182-7. · 2.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Both insulin alone and the somatostatin analogue octreotide alone facilitate memory in patients with Alzheimer's disease (AD). Since octreotide inhibits endogenous insulin secretion, the cognitive effects of insulin and octreotide may not be independent. This study tested the individual and interactive effects of insulin and octreotide on memory and plasma growth hormone (GH) levels in older adults. Participants were 16 memory-impaired (AD = 7, amnestic mild cognitive impairment = 9; apolipoprotein E [APOE] epsilon4- [no epsilon4 alleles] = 9, epsilon4+ [1-2 epsilon4 alleles] = 7), and 19 cognitively-intact older adults (APOE epsilon4- = 17, epsilon4+ = 1). On separate days, fasting participants received counterbalanced infusions of: 1) insulin (1 mU.kg(-1).min(-1)) and dextrose to maintain euglycemia; 2) octreotide (150 microg/h); 3) insulin, dextrose, and octreotide; or 4) saline. Story recall was the principal endpoint. Insulin alone facilitated delayed recall for epsilon4- patients, relative to epsilon4+ patients (P = 0.0012). Furthermore, epsilon4- patients with higher Mattis Dementia Rating Scale (DRS) scores had greater octreotide-induced memory facilitation (P = 0.0298). For healthy adults, octreotide facilitated memory (P = 0.0122). Unexpectedly, hyperinsulinemia with euglycemia increased GH levels in healthy controls (P = 0.0299). Thus, insulin and octreotide appear to regulate memory in older adults. APOE epsilon4 genotype modulates responses to insulin and octreotide. Finally, insulin may regulate GH levels during euglycemia.
Journal of Alzheimer's disease: JAD 08/2009; 18(3):595-602. · 3.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Over a decade of converging findings from clinical, observational and basic science research indicate that estrogen administration during the menopausal transition exerts beneficial effects on cognition and decreases a woman's risk of developing Alzheimer's disease (AD) later in life. This review article stresses the research focus of AD prevention, and introduces hormone therapy (HT) as a probable catalyst that may achieve this goal. Furthermore, this article outlines 3 mechanisms proposed to mediate estrogen's beneficial effects, discusses the controversy surrounding HT administration, and presents the most promising estrogen related research in AD prevention and treatment. Although controversial, cumulative evidence suggests that the potential of estrogen initiated during perimenopause to prevent AD needs to be systematically evaluated.
American Journal of Translational Research 01/2009; 1(2):131-47.
-
[show abstract]
[hide abstract]
ABSTRACT: a small number of reports exist on the cognitive effects of soy isoflavones, the findings from which are mixed. Isoflavone efficacy is dependent upon conversion of glycosides contained in soy foods and supplements to the biologically active aglycons. Of particular interest is the production of the metabolite, equol, which is dependent upon intestinal microflora and an integrous digestive system, both being altered by age and age-associated conditions. Unfortunately, few studies enrolled adults over the age of 70, and none included older men.
we examined safety, feasibility and cognitive efficacy of soy isoflavone administration in older nondemented men and women (age 62-89 years).
in this randomised, placebo-controlled, double-blind pilot study, subjects ingested either 100 mg/day soy isoflavones (glycoside weight) or matching placebo tablets for 6 months.
active and placebo-treated subjects exhibited a comparable side-effect profile. Plasma levels of genistein and daidzein (P < 0.001), but not equol, increased with isoflavone administration. While similar at baseline, the two groups differed across 6 months of treatment on 8 of 11 cognitive tests administered. Isoflavone-treated subjects improved on tests of visual-spatial memory (P < 0.01) and construction (P = 0.01), verbal fluency (P < 0.01) and speeded dexterity (P = 0.04). Placebo-treated participants were faster than isoflavone-treated subjects on two tests of executive function (P < 0.05).
these data suggest that administration of 100 mg/day of isoflavones was well tolerated. Plasma genistein and daidzein levels, but not equol, increased with isoflavone administration. Finally, data support the potential cognitive effects of soy isoflavones in older adults.
Age and Ageing 01/2009; 38(1):86-93. · 3.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: First-degree family history (FH) of sporadic Alzheimer's disease and the apolipoprotein E epsilon4 allele (APOE4) are risk factors for Alzheimer's disease that may affect brain function prior to onset of clinical symptoms. In this functional MRI (fMRI) study, we used an episodic recognition task that required discrimination of previously viewed (PV) and novel (NV) faces to examine differences in blood oxygen level dependent (BOLD) signal due to risk factors in 74 middle-aged cognitively normal individuals. The group effects on this recognition task were tested with a 2 x 2 ANCOVA factorial design (+FH/-FH and +APOE4/-APOE4). There were significant APOE4 and FH effects in the left dorsal posterior cingulate cortex and precuneus, where decreased risk resulted in greater activity during recollection. Recognition performance was positively correlated with BOLD signal in the left posterior hippocampus, parahippocampal-retrosplenial gyrus and left superior frontal cortex regardless of risk factors. To examine condition-specific group effects, both the PV and NV faces were tested further in separate 2 x 2 ANCOVAs. Both models revealed an APOE effect, with the -APOE4 group showing stronger signal than the +APOE4 group in anterior cingulate cortices, while a FH effect was found in the dorsal cuneus and medial frontal cortices with the -FH group showing stronger signal than the +FH group. Finally, interactions between APOE4 and FH effects were found bilaterally in the fusiform gyrus. These results suggest that risk factors and cognitive performance each influence brain activity during recognition. The findings lend further support to the idea that functional brain changes may begin far in advance of symptomatic Alzheimer's disease.
Brain 11/2008; 132(Pt 2):383-91. · 9.46 Impact Factor
