BONE LOSS IN RELATION TO HYPOTHALAMIC ATROPHY IN ALZHEIMER'S DISEASE

Epidemiologic projections indicate that the incidence of Alzheimer's disease (AD) will increase dramatically in the coming decades due largely to the demographics of the disease and our aging population. Associated cognitive and physical decline greatly contributes to disability in older adults and places considerable burden on the health system, patients, and caregivers. Bone loss and increased risk of fractures are associated with AD, however little is known about mechanisms of this association. The body of presented work extends the literature on a relationship between bone loss and AD. Overall, the presented work provides initial evidence that accelerated bone loss observed in individuals in the early stages of AD may be partially due to distortion of central regulatory mechanisms by neurodegeneration. This is the first work to demonstrate that hypothalamic atrophy is related to bone loss and this relationship may be mediated by leptin-dependent mechanisms in humans in the early stages of AD. The work in Chapter 2 assessed bone health in the earliest clinical stages of AD in comparison to non-demented aging and examined the relationship of bone mineral density (BMD) with cognitive performance and brain atrophy, both of which are used as surrogate markers of neurodegeneration. We tested the hypothesis that bone density would be lower in early AD and associated with brain atrophy and cognitive decline. The results of this cross-sectional study supported our hypothesis and found that BMD is reduced in men and women in the earliest clinical stages of AD and associated with brain atrophy and memory decline, suggesting that central mechanisms may contribute to bone loss in early Alzheimer's disease. AD is associated with pathological changes in the hypothalamus, a key regulatory structure of bone remodeling. The aim of Chapter 3 was to extend previous findings of the association between BMD and neuroimaging markers of neurodegeneration by looking at global and regional, hypothalamus specifically, measures of brain volume in early AD and non-demented aging. The results demonstrated that in early AD, low BMD was associated with low volume of gray matter in brain structures predominantly affected by AD early in the disease, including the hypothalamus, cingulate, and parahippocampal gyri and in the left superior temporal gyrus and left inferior parietal cortex. No relationship between BMD and regional gray matter volume was found in non-demented controls. These results suggest that central mechanisms of bone remodeling may be disrupted by neurodegeneration. There is very limited guidance in the literature regarding useful and reliable techniques for studying hypothalamic anatomy using neuroimaging. In Chapter 4, we compared an automated neuroimaging technique - voxel-based morphometry (VBM) - to a "gold standard" manual method assessing volumetry of the hypothalamus. The atlas-based VBM volumetry showed promise as a useful tool for regional volumetry of the hypothalamus and has advantages over manual tracing as it is currently used. The results of this study provided guidance for method selection in future work. In Chapter 5, we further examined the hypothesis that AD may influence bone density in cortical skeletal sites directly through atrophy of the hypothalamus, the major central regulatory structure of bone remodeling. We previously reported in cross-section that BMD was lower in those with early AD and suggested that brain atrophy, specifically of the hypothalamus, was associated with lower BMD in AD. We now examined if similar results were apparent in a two year longitudinal study to extend our previous finding of an association between hypothalamic atrophy and bone density. We also explore predictors of bone loss in AD and healthy aging. Our results demonstrate that bone loss may be accelerated in AD compared with non-demented controls. For AD participants, bone loss was associated with hypothalamic atrophy over two years. Additionally, bone loss was associated with baseline levels of the vitamin D. For non-demented participants, bone loss was associated with age, female gender and decline in physical activity. Different predictors of bone loss may suggest that mechanisms of bone loss may differ in aging and AD and that neurodegeneration may contribute to bone loss in early AD. These results extend and strengthen the cross-sectional observations in Chapters 2&3. The purpose of the work presented in Chapter 6 was to further extend previous observations by assessing the roles of leptin, growth hormone (GH) and insulin-like growth factor-1 (IGF-1) , two important regulators of hypothalamic control of bone remodeling, in mediating relationship between hypothalamic structural changes and bone loss in AD. We used a hypothetical model with statistical structural equation or path modeling to examine if leptin, GH, and IGF-I may mediate the relationship between hypothalamic structural changes. The model demonstrated that hypothalamic atrophy had a direct relationship with bone loss. There was no apparent association between baseline IGF-1 and leptin with bone loss but we observed changes in both leptin and IGF-1 over two years that were associated with hypothalamic atrophy. Leptin increased over two years in AD and increase in leptin was associated with hypothalamic atrophy. On the other hand, IGF-1 declined over two year and this decrease was associated with increase in leptin. These results suggest that it is conceivable that central regulatory mechanisms of bone mass may be disturbed by neurodegeneration leading to bone loss in participants in the early stages of AD. In summary, this body of work demonstrates that bone density is reduced in women and men with early stages of AD and continues to decline over time, exceeding bone loss in non-demented older adults. While the causes of bone loss in AD remain unclear, the observed association of hypothalamic atrophy with bone loss suggests neurodegeneration may play a role in bone loss observed in AD and highlights a need for further studies. This work also corroborates other studies on the importance of vitamin D and physical activity for bone health. The findings of this body of work are important because evidence that bone loss in AD is associated with the atrophy in regions involved in the central regulation of bone mass may be relevant to therapeutic strategies to prevent or treat bone loss in AD and neurodegenerative diseases

Metabolic Syndrome and Cognitive Decline in Early Alzheimer’s Disease and Healthy Older Adults

This is the author's accepted manuscript. The original is available at http://content.iospress.com/articles/journal-of-alzheimers-disease/jad121168Metabolic syndrome (MetS) is a cluster of risk factors (i.e., abdominal obesity, hypertension, dyslipidemia, glucose and insulin dysregulation) that is associated with cardiovascular disease, diabetes, and dementia. Recent studies addressing the association of MetS with cognitive performance and risk for dementia report mixed results. An important step in clarifying these conflicting results is determining whether cognition is influenced by the effects of individual MetS components versus the additive effects of multiple components. We assessed the effect of MetS on cognitive performance and decline over two years in 75 cases of early Alzheimer’s disease (AD) and 73 healthy older adult controls in the Brain Aging Project. Using factor analytic techniques, we compared the effect of a combined MetS factor to the effect of individual MetS components on change in attention, verbal memory, and mental status. In healthy controls, a combined MetS factor did not significantly predict cognitive performance, though higher insulin predicted poorer cognitive performance outcomes. In the AD group, higher scores on a combined MetS factor predicted better cognitive outcomes. Our findings suggest that MetS does not have the same association with cognitive decline in healthy older adults and those with early AD. We suggest that individual MetS components should not be evaluated in isolation and that careful methodological approaches are needed to understand the timing and non-linear relationships among these components over time

Measuring Physical Activity in Older Adults with and without Early Stage Alzheimer’s Disease

This is the author's accepted manuscript. The original is available at http://www.tandfonline.com/doi/abs/10.1080/07317115.2013.788116#.VvMAj_krK70We compared subjective reports of physical activity with objective measures of physical fitness including cardiorespiratory capacity, body composition, and physical performance in 146 older adults with and without early stage Alzheimer’s disease (ESAD). Respondents reported primarily unstructured and low-intensity activities, including walking and housework. Individuals with ESAD participated in fewer and lower intensity physical activities than those without ESAD. In those without ESAD, housework was related to lower body mass index, leisure walking was related to faster speed on a timed walking test, and participation in sports was related to higher peak oxygen intake. In individuals with ESAD, reported physical activities did not predict any of the physical fitness, body composition, or physical performance measures. We conclude that measures of physical activity require expansion of unstructured and low intensity activities to improve sensitivity in sedentary populations, especially in older adults with ESAD

Patient Navigators Connecting Patients to Community Resources to Improve Diabetes Outcomes

BACKGROUND: Despite the recognized importance of lifestyle modification in reducing risk of developing type 2 diabetes and in diabetes management, the use of available community resources by both patients and their primary care providers (PCPs) remains low. The patient navigator model, widely used in cancer care, may have the potential to link PCPs and community resources for reduction of risk and control of type 2 diabetes. In this study we tested the feasibility and acceptability of telephone-based nonprofessional patient navigation to promote linkages between the PCP office and community programs for patients with or at risk for diabetes. METHODS: This was a mixed-methods interventional prospective cohort study conducted between November 2012 and August 2013. We included adult patients with and at risk for type 2 diabetes from six primary care practices. Patient-level measures of glycemic control, diabetes care, and self-efficacy from medical records, and qualitative interview data on acceptability and feasibility, were used. RESULTS: A total of 179 patients participated in the study. Two patient navigators provided services over the phone, using motivational interviewing techniques. Patient navigators provided regular feedback to PCPs and followed up with the patients through phone calls. The patient navigators made 1028 calls, with an average of 6 calls per patient. At follow-up, reduction in HbA1c (7.8 ± 1.9% vs 7.2 ± 1.3%; P = .001) and improvement in patient self-efficacy (3.1 ± 0.8 vs 3.6 ± 0.7; P < .001) were observed. Qualitative analysis revealed uniformly positive feedback from providers and patients. CONCLUSIONS: The patient navigator model is a promising and acceptable strategy to link patient, PCP, and community resources for promoting lifestyle modification in people living with or at risk for type 2 diabetes