This qualitative study is an attempt to explore the adaptive experiences of elderly Chinese caregivers who have to take care of their spousal partners who are suffering from Alzheimer’s disease (AD). As the illness is known to be chronic and degenerative in nature, caregivers are thus faced with many stressful situations and adjustments are necessary. The purpose of this study is to examine how these caregivers in AD situations are interpreting the factors that might have influenced their adjustments. The sample consists of 26 participants aged 60 and above that have been a primary caregiver for not less than a year. Three in-depth interviews were conducted with each participant during the study period, which lasted for about two years. Findings show that most of them had to adjust to stressful situations in various aspects of life. They also developed many strategies for life adaption, which can be summarized in the following six adjustment themes. First, after hearing the AD diagnosis, they initially experienced a series of shocks and false hopes, and subsequent adjustments include eliminating uncertainty, establishing reasonable expectations toward both the disease and treatment, learning to take on the caregiver role, and finally, separating the disease from their partner’s personality. Second, these elderly caregivers gradually learned to attain inner peace through converting to various religions, searching for meanings within their stressful situations, and reconstructing rational explanations for their negative emotions. Third, in the area of spousal interaction, adaptive strategies included staying connected with their sick partners, reinforcing their caregiving motivations, completing the “familiar-strange-familiar” cycle, and re-establishing daily routines. Fourth, in situations involving other family members, such as adult children, the adjustment strategies included sharing economic burdens, re-allocating housework chores, delegating care responsibilities, and emotionally supporting one another. Fifth, in terms of social network, the main support that caregivers received usually came from informal sources; formal support is extremely limited. Findings further show a connection between the input and output of social support and personal capacity. Sixth, elderly spousal caregivers often possessed the ability to re-position and re-construct their self-confidence while adjusting to their new life rhythm. They were also able to achieve a balance between their private lives and their care responsibilities, which helps to maintain their well-being and neutralize their distresses. In summary, participants of the study often utilized more than one strategy in adjusting to their situations. The six aspects of adjustments are thus put together in this study as an integrated model of life adaptation and survival tactics adopted by elderly Chinese AD spousal caregivers. Also, whether these caregivers are successful in adapting depends on their abilities to accept changes in themselves and their environment, and achieve a compromise between the two. Based on the above findings, a culturally sensitive perspective is thus put forward to enhance the understanding of studied phenomenon within the contemporary Chinese context. Recommendations are also made regarding the needed policy changes and the revisions of social work practices in support of the elderly suffering from AD and their caregiving spouses. / published_or_final_version / Social Work and Social Administration / Doctoral / Doctor of Philosophy

Presenilin-1 (PS1) mutations caused by the PSEN1 gene mutations are the major cause of early onset familial Alzheimer’s disease (EOFAD). Two Chinesespecific EOFAD related PS1 mutations, V97L and A136G, have been found. Studies suggested that V97L mutation lead to the overexpression of Aβ42 and tau hyperphosphorylation, which are the major hallmarks of Alzheimer’s disease (AD), while properties of A136G were unclear. Since calcium dysregulation was suggested to play an important role in AD, the research project investigated if V97L and A136G mutations also lead to altered endoplasmic reticulum (ER) 〖Ca〗^(2+) regulation. SH-SY5Y cells transduced with retrovirus carrying V97L mutant or A136 mutant PSEN1 were used as the experiment models. In Western blotting, while the PS1 expression level was unaffected in V97L mutant, the expression level was significantly lower in A136G mutant. In carbachol (CCh) perfusion experiment, V97L mutant was found to exaggerate ER 〖Ca〗^(2+) release when stimulated by higher concentration (30, 100 and 300 μM) CCh, while A136G mutant exaggerated ER Ca2+ release when stimulated by 30 μM and 300 μM CCh, but not 100 μM CCh. In 5% fetal bovine serum (FBS) perfusion experiment, both V97L and A136G mutants were found to sensitize 〖Ca〗^(2+) oscillation, which the sensitization effect of V97L was 3 folds of A136G. The results suggested that V97L mutation exaggerates ER 〖Ca〗^(2+) release, possibly via interaction with IP3R. However the results of A136G were inconclusive and contradicting, therefore further investigation is needed. / published_or_final_version / Physiology / Master / Master of Medical Sciences

Alzheimer's disease (AD) is the most common form of dementia, a disease that gradually destroys brain cells and leads to progressive decline in mental function. The presence of high densities of neuritic plaques composed of Abeta in the cerebral cortices is a criterion for the post-mortem diagnosis of AD. The view that Abeta deposition drives the pathogenesis of AD (amyloid hypothesis) has received support from a wide range of molecular, genetic, and animal studies. This hypothesis has been the focus of therapeutic intervention leading to the development of anti-Abeta immunotherapy as a potential treatment. There is a great deal of evidence that supports the capacity of immunization against Abeta to reduce amyloid pathology and restore memory function in transgenic mouse models of amyloidogenesis. However, as a result of anti-Abeta immunotherapy, many investigators have reported increased severity of cerebral amyloid angiopathy (CAA) and increased incidences of microhemorrhage. The mechanism/s responsible for the redistribution of Abeta to the vasculature is unclear. We examine two possible mechanisms that may influence the severity of CAA following immunization; the rate of Abeta clearance with deglycosylated antibodies via a dose response study and anti-Abeta antibody epitope specificity. Dose response results with a deglycosylated antibody showed that lower doses resulted in greater clearance of amyloid and significant improvements in cognition, suggesting that clearance mechanisms become saturated with high doses of antibody. Treatment with antibodies directed against different epitopes of Abeta implied that the degree of parenchymal Abeta clearance determines the extent of vascular Abeta accumulation; epitope specificity is not critical in directing the vascular accumulation. Passive anti-Abeta immunization can prevent Abeta deposition in APP transgenic mice. We investigated amyloid accumulation after immunization was terminated, and discovered that after treatment, amyloid began to accumulate as a factor of time and gradually built up but never reached the Abeta levels in control APP mice. These data suggest that delayed deposition of amyloid leads to long term delays in AD associated pathology. These data strongly support the use of prophylactic immunotherapy treatments, and it appears that existing amyloid deposits will require interventions that actively clear amyloid as the only means to efficiently reduce brain Abeta in AD.

OBJECTIVE: The brain reserve hypothesis was examined in a secondary analysis of cross-sectional data from a community-based sample of 468 older adults residing in Charlotte County, Florida. The objective of the analysis was to determine the association between head circumference and eight cognitive outcomes and to assess any potential effect modification of existing associations by Apolipoprotein E (APOE) genotype. METHODS: Cognitive outcomes include scores from the Modified Mini-Mental State Exam (3MS), the Hopkins Verbal Learning Test-Revised (HVLT-R), Stroop Color-Word Test, Trail-Making Test A and B, and a word-stem completion task measuring implicit memory. Descriptive statistics were calculated for each variable. Head circumference and dependent cognitive outcomes were modeled as dichotomous variables using logistic regression, adjusting for gender, age, education, income, height, and Spot The Word test score, a measure of pre-morbid IQ. For dichotomized test scores, poor outcomes (cases) were defined as having scores in the lowest quintile; the remaining top four quintiles were considered non-cases. RESULTS: small head circumference was significantly associated with low 3MS scores [OR(95%CI): 2.97 (1.12, 7.89), p=0.03], after adjustment for age, income and pre-morbid IQ. The association remained statistically significant after adjustment for gender and education as well. After adjustment, head circumference was not found to be statistically significantly associated with any other cognitive outcome. No effect modification was found by APOE genotype or years of education. CONCLUSION: This analysis confirms previous findings that exposure to low head circumference significantly impacts cognition in late life.

Alzheimer's disease (AD) is associated with decreased brain energy metabolism. Hypometabolism in the posterior cingulate cortex (PCC) occurs before the onset of memory deficits in subjects at genetic risk for AD who are not yet cognitively impaired. There is a specific inhibition in cytochrome oxidase (C.O.) in the PCC, an area involved in spatial navigation. Creating an animal model that exhibits the early pathophysiology of AD is important for developing and testing drugs that could reverse memory problems associated with such deficits. Methylene blue (MB) is a compound that improves C.O. activity and memory retention in rats. This dissertation had three specific aims: 1) to examine if isolated PCC hypometabolism causes spatial memory deficits in rats; 2) to find a dose of MB that improves memory without nonspecific behavioral effects; and 3) to prevent memory deficits from PCC hypometabolism with low dose MB. PCC hypometabolism was produced by focal administration of sodium azide, an inhibitor of C.O. activity. PCC hypometabolism resulted in impaired spatial memory in a hole board food-search task, increased oxidative damage, and neurotoxicity in the PCC. In addition, PCC hypometabolism resulted in reduced inter-regional correlations in brain activity. Our second set of studies examined the dose-response effects of MB. Our findings demonstrated that a low dose of MB: 1) enhanced memory in open field habituation and object recognition tasks; 2) did not affect general locomotor activity, exploration, motivation, or anxiety; and 3) increased brain oxygen consumption 24 hr after in vivo administration. Finally, our last study found that low dose MB prevented the deficits caused by PCC hypometabolism. MB did not prevent PCC inhibition or cell loss caused by sodium azide. Inter-regional correlations of brain metabolic activity suggested that rats treated with MB were using a different, but equally efficient, strategy for memory retrieval. This animal model of C.O. hypometabolism in the PCC can provide information to understand the mechanisms that regulate early pathological degeneration and reveal new therapeutic strategies aimed at reducing or preventing cognitive decline. Studies of low dose MB in humans are needed to examine its effects in AD patients.

This dissertation consists of three quantitative papers addressing contemporary issues in health policy. The first paper draws on a survey of 2,678 adults from the United States and four European countries to assess demand for a hypothetical early medical test for Alzheimer's disease (AD). Overall, 67% of respondents reported that they would be "very" or "somewhat" likely to get the test if it were available. Through logistic regression analysis, we find that interest was higher among those worried about developing AD, with an immediate blood relative with AD, and who have provided care for AD patients. Knowing that AD is fatal did not influence demand, except among those with an affected blood relative. We expect that a test becoming available could precipitate the creation of a large constituency of asymptomatic, diagnosed adults, affecting a range of health policy decisions. The second paper utilizes Current Population Survey data to explore state-level Medicaid enrollment rates among eligible parents between 2003 and 2010, focusing on the interaction of race and ethnicity and political ideology. Using logistic regression analysis, we find that average take-up for Hispanics in conservative states was 23%, whereas take-up was 38% for both whites and blacks in those states, adjusting for state and individual demographics. These differences abated in liberal and moderate states. Among eligible Hispanics, enrollment rates were less than half as high in conservative states than in liberal states (23% versus 61%). Adjusting for differences in state Medicaid policies narrowed these disparities significantly, highlighting the importance of new provisions aimed at streamlining enrollment procedures across all states. The last paper draws on public and private data from 2007 to 2010 to analyze how administrative spending by health insurers and providers varied across states with different levels of insurance and hospital market concentration. Using regression analysis, we find that in provider offices, high levels of insurance concentration were associated with lower administrative costs. If all states were as concentrated as the most concentrated state in our sample, we would expect nationwide savings of $3.6 billion in administrative expenses. However, market concentration did not reduce administrative spending by insurers or hospitals.

Despite intense interest in the proteolysis of Amyloid Precursor Protein (APP) in Alzheimer’s disease (AD), how the normal processing and function of this type I receptor-like glycoprotein is regulated remains ill-defined. APP is reported to function in neurodevelopment, including migration of neuronal precursor cells into the cortical plate. In recent years, several candidate ligands for APP, including F-spondin, Reelin, \(\beta1\) Integrin, Contactins, and Lingo-1 have been reported. However, a cognate ligand for APP that regulates its function or processing has yet to be widely confirmed in multiple laboratories. First, in an unbiased approach to reveal novel ligands, Pancortin was identified by a mass spectrometry-based screen for factors that bind to the APP ectodomain in rodent brain. Each of the Pancortin isoforms was confirmed to interact with APP. However, only specific Pancortin isoforms reduced \(\beta\)-secretase but not \(\alpha\)-secretase cleavage of endogenous APP. Using in utero electroporation to overexpress or knockdown Pancortin isoforms in rodent cortex, a previously unidentified role for Pancortin in cortical cell migration with evidence for a functional interaction with APP was discovered. Next, I developed new assays in an effort to confirm a role for one or more of the published candidate ligands in regulating APP ectodomain shedding in a biologically relevant context. A comprehensive quantification of APPs\(\alpha\) and APPs\(\beta\), the immediate products of secretase processing, in both non-neuronal cell lines and primary neuronal cultures expressing endogenous APP yielded no evidence that any of these published candidate ligands stimulate ectodomain shedding. Rather, Reelin, Lingo-1 and Pancortin emerged as the most consistent ligands for significantly inhibiting ectodomain shedding. These studies clarify mechanisms regulating the function and processing of APP, which is needed to understand consequences of chronically altering APP proteolysis to treat AD and to develop new potential drug targets.

Focused ultrasound (FUS) can temporarily increase blood-brain barrier (BBB) permeability and locally deliver therapeutic agents to the brain. To date, applications of FUS for treatment of Alzheimer’s disease (AD) have not been explored. Here, I propose that FUS can facilitate a rapid reduction in amyloid-β peptide (Aβ) pathology in a mouse model of AD. Firstly, FUS was used to enhance delivery of an antibody directed against Aβ, which aggregates and forms extracellular plaques. FUS mediated the delivery of antibodies to the targeted right cortex by 4 hours post-treatment and antibodies remained bound to Aβ plaques for 4 days. At 4 days post-treatment, stereological quantification of plaque burden demonstrated a significant reduction of 23%. Secondly, FUS treatment alone resulted in a significant reduction in plaque load (13%). I then investigated effects of FUS that may contribute to Aβ plaque reduction, specifically the delivery of endogenous antibodies to the brain and, activation of microglia and astrocytes. Endogenous immunoglobulin was found bound to plaques within the treated cortex at 4 days post-FUS. Western blot analysis confirmed that immunoglobulin levels were increased significantly. Further, FUS led to a time-dependent increase in glial response. The expression of ionized calcium-binding adaptor molecule 1, a marker of phagocytic microglia, was increased at 4 hours and 4 days, and it was resolved by 15 days. Astrocytes had a slightly delayed response, with an increase in the expression of glial fibrillary acidic protein at 4 days, which declined by 15 days. After 4 days, microglia and astrocytes had significantly greater volumes and surface areas, signifying enhanced activation in the FUS-treated cortex, without an apparent increase in cell count. Co-localization of Aβ within activated glia revealed a significant increase in Aβ internalization following FUS. In conclusion, it was demonstrated that the delivery of exogenous antibodies by FUS, and FUS alone can lead to plaque reduction. Mechanisms by which FUS alone reduces plaque load may include entry of endogenous antibodies to the brain and the induction of a transient glial response. This work details acute effects of FUS that highlight the promise of this delivery method for AD treatment.

Cholinesterase inhibitors (ChEIs) are the first line pharmacotherapy for the symptoms of Alzheimer’s disease (AD). Though ChEIs offer modest cognitive benefits in early AD, literature addressing their continued use in severe AD is scarce. This study assessed the safety of discontinuing ChEIs in institutionalized moderate-severe AD patients. Twenty-six patients were randomized, double-blind to ChEI continuation or placebo for 8-weeks. Vitals, weight (kg) and adverse events (AEs) were monitored biweekly. Chi-square test revealed no significant association between semi-blinded treatment allocation and AE occurrence (χ²=(1,26)=0.99, p=0.32). Groups showed no differences on clinically significant weight loss (χ²=(1,26) =1.9, p=0.17), mean weight loss (F=.531, p= .473), pulse rate (F=.624, p=.437), or side effects (F=.224, p=.640). Preliminary results suggest that either ChEIs are well tolerated or that these drugs are no longer providing therapeutic benefit. Study completion (recruitment of 60 patients and unblinding) will generate more comprehensive data for determination of safe ChEI discontinuation guidelines.

The effects of exogenous estrogen administration on aspects of memory and cognition in women were examined in two studies. In Study 1, women receiving estrogen replacement therapy were compared to untreated women on four measures of verbal memory. Those receiving estrogen had significantly better scores on a measure of delayed memory for propositional material. In Study 2, women in the early stages of Alzheimer's Disease (AD) were administered either estrogen or placebo on a double-blind basis for six months. Women given estrogen showed improvement on a measure of verbal memory and spatial attention compared to the placebo controls. The combined results of these studies provide evidence that estrogen enhances aspects of verbal memory in both healthy postmenopausal women and in postmenopausal women in the early stages of AD as measured by neuropsychological tests. These effects might be mediated by actions of estrogen on neuronal morphology and physiology in brain areas important for memory and cognition.