Carey E. Gleason

Activation of brain regions vulnerable to Alzheimer's disease: the effect of mild cognitive impairment.

This study examined the functionality of the medial temporal lobe (MTL) and posterior cingulate (PC) in mild cognitive impairment amnestic type (MCI), a syndrome that puts patients at greater risk for developing Alzheimer disease (AD). Functional MRI (fMRI) was used to identify regions normally active during encoding of novel items and recognition of previously learned items in a reference group of 77 healthy young and middle-aged adults. The pattern of activation in this group guided further comparisons between 14 MCI subjects and 14 age-matched controls. The MCI patients exhibited less activity in the PC during recognition of previously learned items, and in the right hippocampus during encoding of novel items, despite comparable task performance to the controls. Reduced fMRI signal change in the MTL supports prior studies implicating the hippocampus for encoding new information. Reduced signal change in the PC converges with recent research on its role in recognition in normal adults as well as metabolic decline in people with genetic or cognitive risk for AD. Our results suggest that a change in function in the PC may account, in part, for memory recollection failure in AD.

Effects of Hormone Therapy on Cognition and Mood in Recently Postmenopausal Women: Findings from the Randomized, Controlled KEEPS-Cognitive and Affective Study.

Background Menopausal hormone therapy (MHT) reportedly increases the risk of cognitive decline in women over age 65 y. It is unknown whether similar risks exist for recently postmenopausal women, and whether MHT affects mood in younger women. The ancillary Cognitive and Affective Study (KEEPS-Cog) of the Kronos Early Estrogen Prevention Study (KEEPS) examined the effects of up to 4 y of MHT on cognition and mood in recently postmenopausal women. Methods and Findings KEEPS, a randomized, double-blinded, placebo-controlled clinical trial, was conducted at nine US academic centers. Of the 727 women enrolled in KEEPS, 693 (95.3%) participated in the ancillary KEEPS-Cog, with 220 women randomized to receive 4 y of 0.45 mg/d oral conjugated equine estrogens (o-CEE) plus 200 mg/d micronized progesterone (m-P) for the first 12 d of each month, 211 women randomized to receive 50 μg/d transdermal estradiol (t-E2) plus 200 mg/d m-P for the first 12 d of each month, and 262 women randomized to receive placebo pills and patches. Primary outcomes included the Modified Mini-Mental State examination; four cognitive factors: verbal learning/memory, auditory attention/working memory, visual attention/executive function, and speeded language/mental flexibility; and a mood measure, the Profile of Mood States (POMS). MHT effects were analyzed using linear mixed-effects (LME) models, which make full use of all available data from each participant, including those with missing data. Data from those with and without full data were compared to assess for potential biases resulting from missing observations. For statistically significant results, we calculated effect sizes (ESs) to evaluate the magnitude of changes. On average, participants were 52.6 y old, and 1.4 y past their last menstrual period. By month 48, 169 (24.4%) and 158 (22.8%) of the 693 women who consented for ancillary KEEPS-Cog were lost to follow-up for cognitive assessment (3MS and cognitive factors) and mood evaluations (POMS), respectively. However, because LME models make full use all available data, including data from women with missing data, 95.5% of participants were included in the final analysis (n = 662 in cognitive analyses, and n = 661 in mood analyses). To be included in analyses, women must have provided baseline data, and data from at least one post-baseline visit. The mean length of follow-up was 2.85 y (standard deviation [SD] = 0.49) for cognitive outcomes and 2.76 (SD = 0.57) for mood outcomes. No treatment-related benefits were found on cognitive outcomes. For mood, model estimates indicated that women treated with o-CEE showed improvements in depression and anxiety symptoms over the 48 mo of treatment, compared to women on placebo. The model estimate for the depression subscale was −5.36 × 10−2 (95% CI, −8.27 × 10−2 to −2.44 × 10−2; ES = 0.49, p < 0.001) and for the anxiety subscale was −3.01 × 10−2 (95% CI, −5.09 × 10−2 to −9.34 × 10−3; ES = 0.26, p < 0.001). Mood outcomes for women randomized to t-E2 were similar to those for women on placebo. Importantly, the KEEPS-Cog results cannot be extrapolated to treatment longer than 4 y. Conclusions The KEEPS-Cog findings suggest that for recently postmenopausal women, MHT did not alter cognition as hypothesized. However, beneficial mood effects with small to medium ESs were noted with 4 y of o-CEE, but not with 4 y of t-E2. The generalizability of these findings is limited to recently postmenopausal women with low cardiovascular risk profiles. Trial Registration ClinicalTrials.gov NCT00154180 and NCT00623311

Estrogen and Alzheimer's Disease The Story So Far

The ovarian hormone estrogen has long been used to treat the physical symptoms of menopause and to aid in the prevention of osteoporosis in postmenopausal women. Cumulative evidence from basic science and clinical research suggests that estrogen also plays a significant neuromodulatory and neuroprotective role. The numerous estrogenic effects in the brain include the modulation of synap-togenesis, increased cerebral blood flow, mediation of important neurotransmitters and hormones, protection against apoptosis, anti-inflammatory actions, and antioxidant properties. These multiple actions in the central nervous system support estrogen as a potential treatment for the cognitive decline associated with Alzheimer’s disease (AD), the most common form of dementia. Evidence from epidemiological studies supports enhanced cognitive function in women with AD taking estrogen replacement therapy (ERT) as well as a reduced risk for developing AD in healthy women receiving ERT. Additional clinical evidence suggests that estrogen may modulate specific cognitive functions such as working memory and verbal learning and memory. However, results from more recent controlled trials have not consistently shown a beneficial effect of estrogen on the cognitive function of women with AD. Future research should focus on examining the influence of multiple potential mediators of ERT including the route of estrogen administration, form of estrogen (conjugated estrogens vs estradiol), duration of treatment, opposed versus unopposed estrogen and the use of estrogen analogues. Further, sensitive neuropsychological measures may provide more detailed information concerning the specific effects of estrogen on cognitive function. These important issues must be addressed in order to establish the role of estrogen for the prevention and treatment of AD in women.

Magnetic Resonance Imaging Characterization of Brain Structure and Function in Mild Cognitive Impairment: A Review

Given the predicted increase in prevalence of Alzheimers disease (AD) in the coming decades, early detection and intervention in persons with the predementia condition known as mild cognitive impairment (MCI) is of paramount importance. Recent years have seen remarkable advances in the application of neuroimaging and other biomarkers to the study of MCI. This article reviews the most recent developments in the use of magnetic resonance imaging (MRI) to characterize brain changes and to prognosticate clinical outcomes of patients with MCI. The review begins with description of methods and findings in structural MRI research, delineating findings regarding both gross atrophy and microstructural brain changes in MCI. Second, we describe the most recent findings regarding brain function in MCI, enumerating findings from functional MRI and brain perfusion studies. Third, we will make recommendations regarding the current clinical use of MRI in identification of MCI. As a conclusion, we will look to the future of neuroimaging as a tool in early AD detection.

Increased Risk for Falling Associated with Subtle Cognitive Impairment: Secondary Analysis of a Randomized Clinical Trial

Background/Aims: Having dementia increases patients’ risk for accidental falls. However, it is unknown if having mild cognitive deficits also elevates a person’s risk for falls. This study sought to clarify the relationship between subtle cognitive impairment, measured with a widely-used, clinic-based assessment, the Mini Mental State Exam (MMSE), and risk for falls. Methods: In a secondary analysis of the Kenosha County Falls Prevention Study, a randomized controlled trial targeting older adults at risk for falls, we examined the association between baseline MMSE and prospective rate of falls over 12 months in 172 subjects randomized to control group. Results: Using univariate analysis, the rate of falls increased with each unit decrease in MMSE score down to at least 22 (rate ratio 1.25, 95% confidence interval (CI) 1.09–1.45, p = 0.0026). Using stepwise multivariate regression, controlling for ability to perform activities of daily living, use of assistive device, current exercise, and arthritis, the association between MMSE score and falls rate persisted (rate ratio 1.20, 95% CI 1.03–1.40, p = 0.021). Conclusion: Minimal decrements on the MMSE were associated with elevations in rate of falls, suggesting that subtle cognitive deficits reflected in MMSE scores above a cut-off consistent with a diagnosis of dementia, can influence risk for falls.

Effects of Simvastatin on Cerebrospinal Fluid Biomarkers and Cognition in Middle-Aged Adults at Risk for Alzheimer's Disease

BACKGROUND Statins reduce amyloid-beta (Abeta) levels in the brain and cerebrospinal fluid (CSF) in animals and may thereby favorably alter the pathobiology of AD. It is unclear if statins modify Abeta metabolism or improve cognition in asymptomatic middle-aged adults at increased risk for AD. METHODS In a 4-month randomized, double-blind, controlled study, we evaluated the effects of simvastatin 40 mg daily vs. placebo on CSF Abeta42 levels and cognition in 57 asymptomatic middle-aged adult children of persons with AD. RESULTS Compared to placebo, individuals randomized to simvastatin for 4 months had similar changes in CSF Abeta42 (p=0.344) and total tau levels (p=0.226), yet greater improvements in some measures of verbal fluency (p=0.024) and working memory (p=0.015). APOE4 genotype, gender, and vascular risk factors were associated with CSF biomarker levels, but did not modify treatment effects. CONCLUSION In asymptomatic middle-aged adults at increased risk for AD, simvastatin use improved selected measures of cognitive function without significantly changing CSF Abeta42 or total tau levels. Further studies are needed to clarify the impact of higher dose and/or longer duration statin therapy on not only Abeta metabolism, but also other preclinical processes related to the development of AD.

A preliminary study of the safety, feasibility and cognitive efficacy of soy isoflavone supplements in older men and women

BACKGROUND 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. OBJECTIVE we examined safety, feasibility and cognitive efficacy of soy isoflavone administration in older nondemented men and women (age 62-89 years). DESIGN AND METHODS 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. RESULTS 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). CONCLUSIONS 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.

Clinical Pharmacology and Differential Cognitive Efficacy of Estrogen Preparations

Abstract: Menopause is associated with a significant decline in levels of estrogen, which reportedly leads to several distressing symptoms and adverse health effects on various target tissues including those on bones, heart, and brain. Although effective, the long‐term safety and feasibility of therapy with both unopposed and opposed oral conjugated equine estrogen has been questioned by the recent findings of both the Womens Health Initiative (WHI) and the Womens Health Initiative Memory Study (WHIMS). The findings of both these studies have raised several critical issues related to hormone therapy that need to be systematically evaluated in clinical studies. Specifically, these issues relate to the differential efficacy and adverse‐effects profile of various forms of estrogen and progestins, the importance of the route of administration of estrogen, the best timing to initiate postmenopausal hormone therapy, and the efficacy of cyclic versus continuous hormone therapy. This article focuses on estrogen and discusses issues related to selecting the best form and route of administration of the hormone. It includes information on basic clinical pharmacology of various forms of estrogen, neuroendocrinology of the menopause, neurobiology of estradiol and estrone, and results of selected basic science and human intervention studies with relevance to identifying the best form and route of administration of estrogen.

Short-term Hormone Therapy with Transdermal Estradiol Improves Cognition for Postmenopausal Women with Alzheimer’s Disease: Results of a Randomized Controlled Trial

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 Alzheimers 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 Womens 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.

Rationale and design of the Kronos Early Estrogen Prevention Study (KEEPS) and the KEEPS cognitive and affective sub study (KEEPS Cog)

This manuscript describes the study design and rationalle 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 Womens Health Initiative (WHI) and the Womens Health Initiative Memory Study (WHIMS). Here we also describe the most recent results and ongoing HT-related research studies designed to address similar issues. This article is part of a Special Issue entitled Hormone Therapy.