The Role of Basal Cortisol Elevations in Alzheimer’s Disease: Presence and Prediction of Associated Pathology

Elevations in the glucocorticoid steroid hormone cortisol have long been suspected to be characteristic of Alzheimer’s disease, and there is a renewed interest in the contribution of cortisol to the progression of the disease. However, to date, no systematic examination of basal cortisol levels in AD has been conducted. Further, although cortisol elevations are hypothesized to facilitate cerebral amyloid-beta accumulation, direct examinations of this relationship have been restricted to samples already showing evidence of amyloid accumulation. The two studies included in this dissertation directly addressed these issues. First, a comprehensive meta-analysis was conducted to compare basal cortisol levels between cognitively normal and demented older adults. The cortisol levels in the demented samples were significantly higher than those of the cognitively normal samples (d = 0.39, QM = 34.73, p < 0.001) and this difference was not moderated by the age, sex, or cognitive performance of the included samples. The second study applied a Cox regression analysis to data collected from the Baltimore Longitudinal Study of Aging to test whether basal cortisol measures collected prior to imaging evidence of amyloid-beta deposition would predict the risk of subsequent amyloid-beta accumulation. Both the cortisol slope and the cortisol level measured nearest to the estimated event time were significantly positively associated with the risk of amyloid-beta accumulation (HR = 1.31, p = 0.04 and HR = 1.03, p = 0.01 respectively). Taken together these studies suggest that basal cortisol elevations are often observed in Alzheimer’s disease and that the influence of cortisol on disease progression may begin even before detection by neuroimaging markers.Ph.D

The recruitment of stromal cells to the site of tumor formation

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, February 2010.This electronic version was submitted by the student author. The certified thesis is available in the Institute Archives and Special Collections.Cataloged from student submitted PDF version of thesis. Vita.Includes bibliographical references.Myofibroblasts are an alpha-smooth muscle actin ([alpha]-SMA)-expressing cell type found within human mammary carcinomas, but not in the normal mammary gland. Myofibroblasts can enhance tumor formation by promoting angiogenesis and invasion, and we therefore sought to better understand how myofibroblasts are incorporated into breast carcinomas. By identifying secreted factors that recruit myofibroblasts as well as the physical niche where they originated, we aimed to identify possible therapeutic targets to inhibit their incorporation. Using a newly developed mammary carcinoma model, termed BPLER, we identified CXCL1, VEGF, CCL5, and IL-6 as factors that may be important for the recruitment of myofibroblasts. We tested the ability of CXCL1, VEGF164, or CCL5 to affect tumor formation and induce the incorporation of a-SMApositive cells. We show that the expression in MCF-7-Ras modified human breast cancer cells of VEGF164, but not CXCL1 or CCL5, results in the promotion of primary tumor growth and the increased incorporation of [alpha]-SMA-positive cells. Furthermore, we demonstrate that these a-SMA-positive cells do not correlate with cells expressing CD34, a marker of endothelial cells, suggesting that these cells are not [alpha]-SMA-positive smooth muscle cells. Thus, we propose that VEGF is a critical factor that recruits myofibroblasts to the site of breast cancer formation. In another line of experiments, we examined the source of the [alpha]-SMA-positive cell population recruited to another mammary tumor model, termed BPHER-3.(cont.) In order to investigate whether these cells are derived from the bone marrow, we utilized chimeric mice that express green fluorescent protein (GFP) in their bone marrow and blood cells in order to look for incorporation of GFP-labeled cells within the stroma of a subcutaneously grown tumor. We demonstrated that green bone marrow-derived cells are robustly recruited to the site of BPHER-3 tumor formation; however strikingly, almost 100% of the [alpha]-SMA positive cells analyzed were GFP negative. Our results demonstrate that the [alpha]-SMA-positive cell population recruited to BPHER-3 tumors is not bone marrow-derived, but is instead recruited from the adjacent tissue microenvironment.by Matthew P. Saelzler.Ph.D

The relationship between basal cortisol levels and cognitive functioning across the adult lifespan

Age-related declines in cognitive functioning have been well documented, however, there are vast individual differences in the age of onset and magnitude of these changes. This observation has spurred the investigation of the potential risk factors for cognitive decline. Chronic elevations of the steroid hormone cortisol have been shown to compromise hippocampal- and frontal cortex- dependent cognitive tasks in rodents, non-human primates and Cushing’s disease patients. Several studies have extended these findings to investigate possible associations between cortisol and cognition in aging human populations. However, these previous examinations of the role of cortisol in cognitive aging have been hampered by the predominant use of single time-point measures of cortisol, small sample sizes, limited age ranges and/or constrained cognitive testing batteries. The present cross-sectional study investigated the relationship between basal cortisol levels, indexed by a 24-hr free cortisol to creatinine ratio, and cognitive functioning on twelve cognitive outcomes in a sample of 1,853 non-demented adults aged 18 to 93 years. The results showed that elevated cortisol levels had small but significant negative effects on verbal learning and working memory performance across the lifespan and significant negative effects limited to older age on a measure of speeded processing. Longitudinal investigation is warranted to examine if within-person changes in cortisol level predict cognitive change.M.S

3D-Printed lightweight ceramics using capillary suspensions with incorporated nanoparticles

status: publishe

Volkswirtschaftliche Betrachtung des Arbeitsausfalls berufstaetiger Muetter infolge akuter respiratorischer Erkrankungen ihrer Kinder im Krippen- und Kindergartenalter Studie in Thale fuer das Jahr 1976/77

SIGLEHUB(11) - 89 HB 9588 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekDEGerman

The role of testosterone, the androgen receptor, and hypothalamic-pituitary–gonadal axis in depression in ageing Men

Considerable research has shown that testosterone regulates many physiological systems, modulates clinical disorders, and contributes to health outcome. However, studies on the interaction of testosterone levels with depression and the antidepressant effect of testosterone replacement therapy in hypogonadal men with depression have been inconclusive. Current findings indicate that low circulating levels of total testosterone meeting stringent clinical criteria for hypogonadism and testosterone deficiency induced by androgen deprivation therapy are associated with increased risk for depression and current depressive symptoms. The benefits of testosterone replacement therapy in men with major depressive disorder and low testosterone levels in the clinically defined hypogonadal range remain uncertain and require further investigation. Important considerations going forward are that major depressive disorder is a heterogeneous phenotype with depressed individuals differing in inherited polygenic determinants, onset and clinical course, symptom complexes, and comorbidities that contribute to potential multifactorial differences in pathophysiology. Furthermore, polygenic mechanisms are likely to be critical to the biological heterogeneity that influences testosterone-depression interactions. A genetically informed precision medicine approach using genes regulating testosterone levels and androgen receptor sensitivity will likely be essential in gaining critical insight into the role of testosterone in depression

Systemic Endocrine Instigation of Indolent Tumor Growth Requires Osteopontin

The effects of primary tumors on the host systemic environment and resulting contributions of the host to tumor growth are poorly understood. Here, we find that human breast carcinomas instigate the growth of otherwise-indolent tumor cells, micrometastases, and human tumor surgical specimens located at distant anatomical sites. This systemic instigation is accompanied by incorporation of bone-marrow cells (BMCs) into the stroma of the distant, once-indolent tumors. We find that BMCs of hosts bearing instigating tumors are functionally activated prior to their mobilization; hence, when coinjected with indolent cells, these activated BMCs mimic the systemic effects imparted by instigating tumors. Secretion of osteopontin by instigating tumors is necessary for BMC activation and the subsequent outgrowth of the distant otherwise-indolent tumors. These results reveal that outgrowth of indolent tumors can be governed on a systemic level by endocrine factors released by certain instigating tumors, and hold important experimental and therapeutic implications

Association of Age at Menopause and Hormone Therapy Use With Tau and β-Amyloid Positron Emission Tomography

Importance: Postmenopausal females represent around 70% of all individuals with Alzheimer disease. Previous literature shows elevated levels of tau in cognitively unimpaired postmenopausal females compared with age-matched males, particularly in the setting of high β-amyloid (Aβ). The biological mechanisms associated with higher tau deposition in female individuals remain elusive. Objective: To examine the extent to which sex, age at menopause, and hormone therapy (HT) use are associated with regional tau at a given level of Aβ, both measured with positron emission tomography (PET). Design, setting, and participants: This cross-sectional study included participants enrolled in the Wisconsin Registry for Alzheimer Prevention. Cognitively unimpaired males and females with at least 1 18F-MK-6240 and 11C-Pittsburgh compound B PET scan were analyzed. Data were collected between November 2006 and May 2021. Exposures: Premature menopause (menopause at younger than 40 years), early menopause (menopause at age 40-45 years), and regular menopause (menopause at older than 45 years) and HT user (current/past use) and HT nonuser (no current/past use). Exposures were self-reported. Main outcomes and measures: Seven tau PET regions that show sex differences across temporal, parietal, and occipital lobes. Primary analyses examined the interaction of sex, age at menopause or HT, and Aβ PET on regional tau PET in a series of linear regressions. Secondary analyses investigated the influence of HT timing in association with age at menopause on regional tau PET. Results: Of 292 cognitively unimpaired individuals, there were 193 females (66.1%) and 99 males (33.9%). The mean (range) age at tau scan was 67 (49-80) years, 52 (19%) had abnormal Aβ, and 106 (36.3%) were APOEε4 carriers. There were 98 female HT users (52.2%) (past/current). Female sex (standardized β = -0.41; 95% CI, -0.97 to -0.32; P 5 years following age at menopause) was associated with higher tau PET compared with early initiation (β = 0.49; 95% CI, 0.27-0.43; P = .001). Conclusions and relevance: In this study, females exhibited higher tau compared with age-matched males, particularly in the setting of elevated Aβ. In females, earlier age at menopause and late initiation of HT were associated with increased tau vulnerability especially when neocortical Aβ elevated. These observational findings suggest that subgroups of female individuals may be at higher risk of pathological burden