Cognitive Effects of Soy Isoflavones in Patients with Alzheimer's Disease.

BACKGROUND: In a previous trial, treatment with soy isoflavones was associated with improved nonverbal memory, construction abilities, verbal fluency, and speeded dexterity compared to treatment with placebo in cognitively healthy older adults. OBJECTIVE: The current trial aimed to examine the potential cognitive benefits of soy isoflavones in patients with Alzheimer's disease. METHODS: Sixty-five men and women over the age of 60 were treated with 100 mg/day soy isoflavones, or matching placebo capsules for six months. APOE genotype was determined for all participants. Cognitive outcomes and plasma isoflavone levels were measured at baseline, and at two additional time points: three and six months after baseline. RESULTS: Of the sixty-five participants enrolled, thirty-four (52.3% ) were women, and 31 (47.7% ) were APOEɛ4 positive. Average age was 76.3 (SD = 7.2) years. Fifty-nine (90.8% ) subjects completed all study visits. Plasma isoflavone levels increased in subjects treated with soy isoflavones compared to baseline and to placebo, although intersubject variability in plasma levels was large. No significant differences in treatment effects for cognition emerged between treatment groups or genders. Exploratory analyses of associations between changes in cognition and plasma isoflavone levels revealed an association between equol levels, and speeded dexterity and verbal fluency. CONCLUSIONS: Six months of 100 mg/day treatment with soy isoflavones did not benefit cognition in older men and women with Alzheimer's disease. However, our results suggest the need to examine the role of isoflavone metabolism, i.e., the ability to effectively metabolize soy isoflavones by converting daidzen to equol when attempting to fully clarify the cognitive effects of isoflavones.

Hypothalamic-pituitary-gonadal axis homeostasis predicts longevity.

The reproductive-cell cycle theory of aging posits that reproductive hormone changes associated with menopause and andropause drive senescence via altered cell cycle signaling. Using data from the Wisconsin Longitudinal Study (n = 5,034), we analyzed the relationship between longevity and menopause, including other factors that impact "ovarian lifespan" such as births, oophorectomy, and hormone replacement therapy. We found that later onset of menopause was associated with lower mortality, with and without adjusting for additional factors (years of education, smoking status, body mass index, and marital status). Each year of delayed menopause resulted in a 2.9% reduction in mortality; after including a number of additional controls, the effect was attenuated modestly but remained statistically significant (2.6% reduction in mortality). We also found that no other reproductive parameters assessed added to the prediction of longevity, suggesting that reproductive factors shown to affect longevity elsewhere may be mediated by age of menopause. Thus, surgical and natural menopause at age 40, for example, resulted in identical survival probabilities. These results support the maintenance of the hypothalamic-pituitary-gonadal axis in homeostasis in prolonging human longevity, which provides a coherent framework for understanding the relationship between reproduction and longevity.

Identification of a regulatory loop for the synthesis of neurosteroids: a steroidogenic acute regulatory protein-dependent mechanism involving hypothalamic-pituitary-gonadal axis receptors.

Brain sex steroids are derived from both peripheral (primarily gonadal) and local (neurosteroids) sources and are crucial for neurogenesis, neural differentiation and neural function. The mechanism(s) regulating the production of neurosteroids is not understood. To determine whether hypothalamic-pituitary-gonadal axis components previously detected in the extra-hypothalamic brain comprise a feedback loop to regulate neuro-sex steroid (NSS) production, we assessed dynamic changes in expression patterns of steroidogenic acute regulatory (StAR) protein, a key regulator of steroidogenesis, and key hypothalamic-pituitary-gonadal endocrine receptors, by modulating peripheral sex hormone levels in female mice. Ovariectomy (OVX; high serum gonadotropins, low serum sex steroids) had a differential effect on StAR protein levels in the extrahypothalamic brain; increasing the 30- and 32-kDa variants but decreasing the 37-kDa variant and is indicative of cholesterol transport into mitochondria for steroidogenesis. Treatment of OVX animals with E(2), P(4), or E(2) + P(4) for 3 days, which decreases OVX-induced increases in GnRH/gonadotropin production, reversed this pattern. Suppression of gonadotropin levels in OVX mice using the GnRH agonist leuprolide acetate inhibited the processing of the 37-kDa StAR protein into the 30-kDa StAR protein, confirming that the differential processing of brain StAR protein is regulated by gonadotropins. OVX dramatically suppressed extra-hypothalamic brain gonadotropin-releasing hormone 1 receptor expression, and was further suppressed in E(2)- or P(4)-treated OVX mice. Together, these data indicate the existence of endocrine and autocrine/paracrine feedback loops that regulate NSS synthesis. Further delineation of these feedback loops that regulate NSS production will aid in developing therapies to maintain brain sex steroid levels and cognition.

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.

Gonadotropins: a cohesive gender-based etiology of Alzheimer disease.

While there is ample experimental evidence supporting the role of estrogen in the pathogenesis of Alzheimer disease, recent inconclusive data regarding hormone replacement therapy (HRT), specifically, the unexpected results of the Women's Health Initiative (WHI) Memory Study has raised serious questions regarding the protective effects of estrogen. Because of this and other inconsistencies in the estrogen hypothesis, we propose that another hormone of the hypothalamic-pituitary-gonadal axis, luteinizing hormone, is a major factor in the pathogenesis of Alzheimer disease. Specifically, we suspect that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a primary causative factor for the development of Alzheimer disease. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, Alzheimer disease.

Estrogen bows to a new master: the role of gonadotropins in Alzheimer pathogenesis.

Epidemiological data showing a predisposition of women to develop Alzheimer disease (AD) led many researchers to investigate the role of sex steroids, namely estrogen, in disease pathogenesis. Although there is circumstantial support for the role of estrogen, the unexpected results of the Women's Health Initiative (WHI) Memory Study, which reported an increase in the risk for probable dementia and impaired cognitive performance in postmenopausal women treated with a combination of estrogen and progestin, have raised serious questions regarding the protective effects of estrogen. Although explanations for these surprising results vary greatly, the WHI Memory Study cannot be correctly interpreted without a complete investigation of the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely, the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. We propose that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of AD. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, AD. On this basis, we suggest that the results of the WHI Memory Study are not only predictable but also avoidable by therapeutically targeting the gonadotropins instead of the sex steroids.

Novel D-penicillamine carrying nanoparticles for metal chelation therapy in Alzheimer's and other CNS diseases.

Metal ions accumulate in the brain with aging and in several neurodegenerative diseases. Aside from the copper storage disease, Wilson's disease, recent attention has focused on the accumulation of zinc, copper and iron in the Alzheimer's disease (AD) brain and the accumulation of iron in Parkinson's disease. In particular, the parenchymal deposition of beta-amyloid (Abeta) and its interaction with metal ions has been postulated to play a role in the progression of AD. Thus, the strategy of lowering brain metal ions and targeting the interaction of Abeta peptide and metal ions through the administration of chelators has merit. Our recent finding that nanoparticle delivery systems can cross the blood-brain barrier has led us to investigate whether chelators delivered conjugated to nanoparticles could act to reverse metal ion induced protein precipitation. In the present studies, the Cu (I) chelator D-penicillamine was covalently conjugated to nanoparticles via a disulfide bond or a thioether bond. Nanoparticle-chelator conjugates were stable between pH 6-8 in aqueous suspension if stored at 4 degrees C, and did not aggregate when challenged with salts and serum. Release of D-penicillamine from the nanoparticles was achieved using reducing agents such as dithiothreitol (as a model for glutathione). Nanoparticles treated only under reducing conditions that released the conjugated D-penicillamine were able to effectively resolubilize copper-Abeta (1-42) aggregates. These results indicate that nanoparticles have potential to deliver D-penicillamine to the brain for the prevention of Abeta (1-42) accumulation, as well as to reduce metal ion accumulation in other CNS diseases.

The role of beta amyloid in Alzheimer's disease: still a cause of everything or the only one who got caught?

The beta amyloid (A beta) protein is a key molecule in the pathogenesis of Alzheimer's disease (AD). The tendency of the A beta peptide to aggregate, its reported neurotoxicity, and genetic linkage studies, have led to a hypothesis of AD pathogenesis that many AD researchers term the amyloid cascade hypothesis. In this hypothesis, an increased production of A beta results in neurodegeneration and ultimately dementia through a cascade of events. In the past 15 years, debate amongst AD researchers has arisen as to whether A beta is a cause or an effect of the pathogenic process. Recent in vitro and in vivo research has consolidated the theory that A beta is the primary cause, initiating secondary events, culminating in the neuropathological hallmarks associated with AD. This research has led to the development of therapeutic agents, currently in human clinical trials, which target A beta.

Reduction of inclusion body pathology in ApoE-deficient mice fed a combination of antioxidants.

Clinical studies have shown that the antioxidant vitamin E can slow the progression of Alzheimer's disease (AD). Other antioxidants reported to affect cognitive function include ginkgo biloba, vitamin C, and lipoic acid. To examine the effects of combination antioxidant therapy (CAT) on longevity and neuropathology in mice, we supplemented the diet of ApoE-deficient mice with vitamin E, ginkgo biloba, pycnogenol, and ascorbyl palmitate. ApoE-deficient mice normally exhibit increased numbers of PAS-positive inclusion bodies with aging. However, supplementation with CAT resulted in a significant increase in life span and a marked reduction of inclusion body histopathology in the hippocampus. In addition, while untreated apoE-deficient mice exhibited increased levels of TUNEL staining, a marker of DNA fragmentation, supplementation with CAT resulted in a significant reduction in the levels of TUNEL staining. These findings suggest that oxidative mechanisms, perhaps related to neuronal apoptosis, are integral to inclusion body formation in aging mice. The association between the reduced number of apoptotic cells and the reduction in inclusion bodies may explain in part the increased longevity of mice fed CAT, and supports the contention that the combined actions of selected antioxidants may be therapeutically effective against neurodegenerative diseases.