Alzheimer's disease (AD) is the most common form of dementia, currently affecting around 17--25 million people worldwide. The typical neuropathological hallmarks of AD are amyloid beta (Abeta) deposition, presence of neurofibrillary tangles and neuronal cell death. Evidence from ongoing studies on the pathogenesis of AD, suggests that several different mechanisms are involved in neurons loss and thus decline of cognitive function. These include the metabolism of amyloid peptide, inflammation, cholesterol metabolism, and hormonal factors. / I have focused on the role of inflammation in the progression of AD. The inflammation hypothesis is based on findings of (1) elevated levels of inflammatory cytokines, such as IL-1, IL-6, TNFalpha, (2) the reduced levels of anti-inflammatory cytokines, like IL-10 in CSF and the blood of AD patients, and (3) activated microglia in the histological section of the patient's brain. On the other hand, the effects of the ApoE gene and differential age of onset between the two sexes suggested a modulation role for cholesterol and sex hormone like estrogen, which may influence the inflammatory response in the brain, so as to modulate the risk of AD. / In this project, the genetic risk factors predisposing to AD were investigated by genetic association studies of candidate genes. Candidate genes were shortlisted by two approaches. (I) Linkage-based candidate genes: Candidate genes were identified from reported loci with linkage to AD genome scan studies. Previous linkage studies of AD families revealed linked loci at 1p36, 1q23, 3p14, 4q32, 6p21, 6q27, 9q22, 10q24, 13q32, 15q26, 19q13 and 21q22. Several candidate genes from these loci including TNFalpha-related genes, TLR2, IGF-1, IFNalpha and MTHFR were selected for this project. (II) Hypothesis-based candidate genes: Candidate genes were selected according to their possible involvement in the inflammation hypothesis of AD. Under the hypothesis-based candidate gene approach, genes that might contribute to the inflammatory response of amyloid deposition were identified. These genes were validated by their expression level in the central nervous system. A further priorization step was carried out to select those genes showing a higher degree of inter-individual variation. Therefore, these genes were more likely to have a genetic/inherited variation at the population level. In other words, they are more likely to be the predisposition genes than genes without inter-individual variation (house-keeping genes are examples of genes showing little inter-individual variation). In this project, genes involved in the inflammatory pathway in the brain, such as IL-10 and HLA-A, and also genes that interact with the inflammatory pathway such as cholesterol related enzymes and estrogen receptors were investigated under the hypothesis-based approach. / This project is based on a case-control genetic association study which comprised of NINCDS-ADRDA diagnosed Chinese patients with AD (n=259) and age-matched non-demented subjects (n=248). Three genes PTGS2 (encoding for COX-2), MxA and ESR1 were selected for an intensive study by investigating their linkage disequilibrium pattern and using tagSNP strategy. TagSNPs selected for each gene were genotyped to investigate their association with the risk of AD. / This study showed that MTHFR, IL-10, HLA-A, CYP46A1, PTGS2 (COX-2) and ESR1 were associated with the risk of AD, and MxA, identified for the first time, was associated with the age of onset of AD. In conclusion, the results of my study further suggested the roles of inflammation in the pathogenesis of AD. / Ma Suk Ling. / "June 2006." / Advisers: Linda C. W. Lam; Nelson L. S. Tang. / Source: Dissertation Abstracts International, Volume: 68-03, Section: B, page: 1417. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 169-204). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstracts in English and Chinese. / School code: 1307.

<p>This dissertation examines lead exposure and effects across the lifespan among vulnerable populations. The vulnerable population that this dissertation focuses on are the elderly, newcomers to the US, which represents immigrants, as well as adolescents and women of childbearing age. The first chapter gives an introduction and highlights the history of lead as it relates to environmental and occupational exposure having deleterious effects on the human system. The second chapter highlights the association between blood lead level and subsequent Alzheimer’s disease (AD) mortality in those 65 years and older. Chapter 3 looks at whether length of time in the United States is a predictor of adolescent and adult blood lead levels. The fourth chapter assesses whether early life lead exposure is associated with AD mortality later in life. Adaptations of Chapter 2 and Chapter 3 of this dissertation have been submitted for publication.</p><p>Chapter 2 presents a longitudinal study of 8080 elders (≥60 years) with BLL data from the 1999-2008 National Health and Nutrition Examination Survey, where mortality was determined from linked 1999-2014 National Death Index data. In this study, a causal diagram presented causal assumptions and identified a sufficient set of confounders: age, sex, poverty, race/ethnicity, and smoking. Cox proportional hazard models were used to determine the association between BLL and subsequent AD mortality. Impacts of competing risks and design effect were also assessed. Adjusted hazard rate ratio (HRR) and 95% confidence interval (CI) were reported. Results showed that those with BLL of 1.5 μg/dL and 5 μg/dL had 1.2 (95% CI: 0.70, 2.1) and 1.4 (95% CI: 0.54, 3.8) times the rate of AD mortality compared to those with BLL of 0.3 μg/dL, respectively, after accounting for competing risks. Adjusted HRRs were 1.5 (95% CI 0.81, 2.9) and 2.1 (95% CI 0.70, 6.3), respectively, after considering design effect. This longitudinal study demonstrated a positive, albeit statistically non-significant association between BLL and AD mortality, after adjustment for competing risks or design effect.</p><p>Chapter 3 included cross-sectional 1580 women of childbearing age (15-45 years) and 5933 men and women (≥15 years) from the 2013-2016 United States National Health and Nutrition Examination Survey. Linear regression models adjusted for race/ethnicity, education, blood cotinine, age, sex (as appropriate) and accounted for complex survey design. Results showed that women of childbearing age who have lived 0-4 years in the US have, on average, a 43% (95% confidence interval (CI): 31%, 56%) higher BPb compared to women born in the US. Corresponding results for all adults and adolescents was 40% (95% CI: 28%, 51%). Similar, statistically significant, results were observed for other time periods (5-9 years, 10-19 years, and ≥20 years); the magnitude of the association decreased with increasing time in the US. Higher BPb was also significantly associated with Asian (vs. white), lower education, higher age, and male (vs. female).</p><p>Chapter 4 is an ecologic study utilizing data from the United States Census Bureau and American Fact Finder. This ecologic study uses publicly available data from the 1930s US census and the Centers for Disease Control and Prevention to compare estimated historic lead exposure with AD mortality rates among US states and Indiana counties. Occupations were assigned a numeric weight based on the likelihood of lead exposure. The proportion of workers in each occupation multiplied by this weight was used to create a historic lead exposure index; quintiles of this index were used in analyses. AD mortality rates among persons ≥ 65 years old from 1999-2016 were obtained from the Centers for Disease Control and Prevention. The relationship between the historic exposure index and mortality was evaluated using correlation coefficients and linear regression models adjusting for age, sex, education, socioeconomic status (SES). Maps to characterize spatial pattern of historic lead exposure and AD mortality were completed using Geographic Information System (GIS) spatial analysis tools for the U.S. at state level and at county level for Indiana. Results showed that among states, the average AD mortality rate was 202.2 per 100,000 (SD=44.4). Within Indiana, the average AD mortality rate was 209.6 per 100,000 (SD= 64.9). Among Indiana counties, the unadjusted model shows an association of higher HEI with higher AD mortality, with the fifth quintile reaching statistical significance. Results for the adjusted model were not statistically significant. Results for US states for both unadjusted and adjusted regression models show that the third, fourth, and fifth quintiles of the historic exposure index were associated with a significantly lower AD mortality rate when compared to the lowest quintile.</p><p>Conclusion: The first study, using a longitudinal design, shows a positive but non-significant association between BLL and subsequent AD mortality after adjustments for competing risks or design effects. The second study, using a cross-sectional design, showed that newcomers to the US may be a population at higher risk for elevated BPb. The third, ecological study, did not find any significant association between historic lead exposure and AD mortality rates for Indiana counties, however there was a significant association of higher historic lead exposure index with lower AD mortality rates for states in the US.</p>

In conclusion, gene expression profiling in blood may have potential to be an adjuvant marker for early detection of AD. Expression marker panel is more informative than single gene expression signature. Further validation in prospective studies will substantiate its clinical application and explore its potential to differentiate AD from other dementias and to predict the progression from MCI to AD. (Abstract shortened by UMI.) / In the study, the profile of 12 target gene expression levels in peripheral blood cells were determined in 96 AD, 145 MCI and 167 normal controls (NC) by quantitative real-time RT-PCR. The genes were identified with (i) high expression in blood and brain; (ii) differential expression between AD and control; (iii) AD related candidate genes. Then, a list of genes were selected including CTSB, CTSD, DDT, ITPKB, NDUFA6, NRD1, PIN1, SNX2, TSC1, UQCRC1, CNR2, GSTM3. Seven genes were found to be differentially expressed between AD and NC group, with upregulation of CTSB, CTSD, DDT, TSC1 and UQCRC1, and downregulation of ITPKB and PIN1 in AD patients. Expression levels of two genes were increased in the MCI compared with NC group, including CTSB and CTSD. In addition, an upregulation of CTSD, UQCRC1, NRD1 and downregulation of ITPKB were observed in AD subjects in comparison to the MCI group (Mann-Whitney U test, p&lt;0.05). After adjusting for confounding factors of age, gender, education level, ApoE4 status and the total CIRS score, expression level of any single gene was not associated with the classfication of AD or MCI (Logistic regression, p>0.05). A five gene biomarker panel, including DDT, ITPKB, PIN1, TSC1 and UQCRC1 was identified with logistic regression analysis. The function of Logit(P)= ln(P/(1-P))= b0+b1RatioDDT+ b2RatioITPKB + b3Ratio PIN1 +b4 RatioTSC1+b5Ratio UQCRC1 were defined as the probability of a subject to be diagnosed as "AD" or "MCI' by using 5-gene biomarker panel. ROC analysis showed that the AUC for the 5-gene biomarkers panel in differentiating between AD and NC, between MCI and NC, between AD and MCI were 0.79 (95% CI, 0.72-0.86; p&lt;0.001), 0.61 (95% CI, 0.53-0.69; p=0.007) and 0.68 (95% CI, 0.60-0.76; p&lt;0.001) respectively. The 5-gene combination was found to discriminate AD subjects from normal controls with good sensitivity and specificity of 70.7% and 86.7% respectively at an optimal cut-off point of 0.486. Low sensitivity (42.4%) and acceptable specificity (76.2%) were observed at a cut-off threshold of 0.505 when differentiating MCI from NC subjects. Between AD and MCI subjects, gene combination showed a sensitivity of 61% and specificity of 73.7% at a cut-off value of 0.496. / Several genes including CTSD, DDT, NDUFA6, TSC1 and UQCRC1 were found in association with the cognitive and psychiatric symptoms, indicating the role of genetic factors in moderating the presence of cognitive and NP profiles in demented individuals. / The aim of the present study is to evaluate the gene expression profiling of peripheral leukocytes in Chinese subjects with Alzheimer's disease (AD) and explored its potential of clinical application. Behavioral phenotypes of cognitive performance and neuropsychiatric assessment were also investigated in association with gene expression in AD. Persons with mild cognitive impairment (MCI), as an at-risk state between normal aging and clinical dementia, was also assessed in consideration that the information may provide a better understanding of the mechanisms involved in clinical progression of AD. / The genes identified in this study were involved in processes implicated in neurodegneration, including protein isomerization (PIN1), calcium disequilibrium and mitochondria insufficiency (ITPKB and UQCRC1), increased inflammatory response (DDT), apoptosis (CTSB and CTSD) and neurogeneration (NRD1 and TSC1). / Fu, Yan. / Adviser: Chiu Wa Lam. / Source: Dissertation Abstracts International, Volume: 73-02, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 132-168). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Alzheimer’s disease (AD) is the leading cause of dementia but despite being identified over a century ago, current treatments remain limited. To date, no disease-modifying therapies are available. Soluble, intracellular forms of β-amyloid (Aβ), a protein associated with AD, have been identified and intracellular targets of Aβ are being investigated as potential targets for new drugs. Amyloid binding alcohol dehydrogenase (ABAD) was previously identified as a mitochondrial target of Aβ and is known to be up-regulated in AD. This interaction results in production of reactive oxygen species and cell death. Using a small peptide, known as the “decoy peptide”, disruption of this interaction has been shown to reverse biochemical and behavioural symptoms in an AD mouse model. The work reported in this thesis describes the approaches taken to develop methods for in vitro and ex vivo study of the interaction between ABAD and Aβ. A fluorogenic assay for measuring the intracellular activity of ABAD in living cells was developed and using this technique, the intracellular inhibition of ABAD by Aβ was observed for the first time. Surface plasmon resonance was used to measure binding between ABAD and Aβ and also showed the first quantitative analysis of direct binding of the decoy peptide to Aβ42. In order to synthesise small molecule inhibitors of ABAD activity with the aim of developing a molecular probe of the enzyme’s activity, compounds were identified by screening a fragment-based library. Subsequent optimisation of the compound structure led to a 10-fold improvement in the IC50 and has resulted in a lead compound for future development. A similar screening strategy was employed to identify potential small molecule inhibitors of the ABAD-Aβ interaction. This research has resulted in a range of tools and methods for studying ABAD activity and interactions, which will greatly benefit future work on developing compounds that inhibit the ABAD-Aβ interaction to provide a novel method for treating Alzheimer’s disease.

The purpose of this study was to examine the relationship between life stressors, resources, and psychological symptomatology of 20 family caregivers of Alzheimer's patients. Stressors were categorized as stressors specific to the caregiving role and general life stressors. Resources were also categorized as resources specific to the caregiving role and general life resources. Multiple regression determined which stressors, resources, and demographic variables predicted psychological symptomatology. Specific stressors that were significant predictors included: caregiving events, caregiving event chronicity, and mean burden scores. Significant general stressors included: size of caregivers' household, non-caregiving events and non-caregiving event chronicity. Significant resources included: other caregivers, the duties other caregivers provided, and caregiver's educational level. No Other Demographic Variables were found to be significant predictors.

The purpose of this study was to examine the effect of an intervention program for Alzheimer's patients on coping efficacy of their family caregivers. Using a pre-post repeated measures design, 16 family caregivers were interviewed before and after a medical, nursing, and social service intervention. Self-report measures, adjusted for caregiver satisfaction and caregiver mastery, were used to determine if there was a change in: resources, burden, and coping efficacy with caregiver specific and general life events. Results showed a marginal effect [F = 2.6, df(4,10), p<.10] for the omnibus MANCOVA. Most of this change was due to an increase in resources. Covariates of caregiver satisfaction and mastery were correlated with average burden. Results suggest that interventions such as this will be helpful for family caregivers of Alzheimer's patients.

Early detection of Alzheimer's disease (AD) and related dementias in the elderly is critical for improving treatment methods and is a necessary component for improving public health interventions. One of the earliest and most common behavioral syndromes of AD is apathy and is associated with executive dysfunction. Apathy in AD is often misdiagnosed as depression due to an overlap in symptoms. Studies that have found depression to be associated with executive dysfunction have not always controlled for the presence of apathy. The Geriatric Depression Scale (GDS) is a widely used instrument designed to assess depression in the elderly. This study utilized the GDS and a set of standard neuropsychological instruments to investigate the relationship between apathy, depression, and executive functions in individuals with AD and related dementias. The first objective of this study was to determine if apathy has a greater impact on executive functions compared to depression in AD and related dementias. The second objective was to determine the effectiveness of the GDS as a screen for apathy. The results of the analyses did not support the hypotheses. However, exploratory analyses suggested a possible non-linear relationship with apathy and various levels of dementia severity. Exploratory analysis also suggested mean levels of endorsement for apathy varied by diagnosis. Further research is warranted to investigate this relationship and the GDS endorsement patterns for caregivers regarding their impression of the demented individual.

Indiana University-Purdue University Indianapolis (IUPUI) / Although cancer and treatment-associated cognitive dysfunction has been well-documented in the literature, much work remains to elucidate the biological mechanisms driving this effect, hampering current therapeutic efforts. To address this gap, we first reviewed studies utilizing neuroimaging to characterize cognitive dysfunction in cancer, as studies of neurodegenerative diseases point to neuroimaging as a sensitive measure of cognitive dysfunction. This review highlighted the need for longitudinal imaging studies of cancer and treatment-related changes in cerebral structure and function. Subsequently, we utilized multimodal neuroimaging techniques in a female breast cancer cohort to investigate the longitudinal impact of cancer and chemotherapy treatment on cerebral perfusion and gray matter. Our findings indicate that chemotherapy is associated with elevated perfusion, primarily in posterior brain regions, as well as depressed frontal perfusion associated with decreased frontal gray matter density. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. We also investigated the relationship of cognitive dysfunction and chemotherapy-induced peripheral neuropathy (CIPN), another type of chemotherapy-related nervous system sequelae, again utilizing multimodal, longitudinal neuroimaging, and found that peripheral neuropathy symptoms following chemotherapy were associated with changes in cerebral perfusion and gray matter density. Together, these findings support the hypothesis that multiple biological mechanisms drive cancer and treatment-related cognitive dysfunction. Interestingly, although cancer is associated with cognitive dysfunction, epidemiological studies have shown that cancer and Alzheimer's disease (AD) are inversely correlated. To extend our imaging analysis beyond breast cancer, we leveraged the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to investigate the inverse relationship of cancer and AD and investigate the impact of both of these diseases on gray matter density. We found that though the inverse relationship of these diseases was replicated in the ADNI cohort, cancer history was associated with lower gray matter density, similar to findings from breast cancer studies, independent of AD diagnostic group. Finally, we reviewed microRNA studies, as microRNAs are important regulators of many cell signaling pathways and have been actively investigated in relation to both diseases. This review suggests several pathways that may be driving the inverse association and may contribute to cognitive dysfunction.

Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer’s disease (AD) is a neurological disorder defined by the presence of plaques comprised mostly of amyloid-β (Aβ), and neurofibrillary tangles consisting of hyperphosphorylated microtubule associated protein tau (MAPT). AD is also characterized by widespread synapse loss and degeneration followed by death of neurons in the brain. Inflammatory processes, such as glial activation, are also implicated. In order to study mechanisms of neurodegeneration and evaluate potential therapeutic agents that could slow or reverse this process, a tissue culture system was developed based on primary embryonic cerebrocortical neurons. This culture system was observed to exhibit time-dependent neurodegeneration, glial proliferation, and synaptic marker loss consistent with AD-affected brains. The regulatory promoter regions of several genes implicated in AD, including the Aβ precursor protein (APP), β-amyloid cleaving enzyme (BACE1), and MAPT, were studied in this culture model. The MAPT gene promoter activity followed the pattern of neuronal maturation and degeneration quite closely, increasing in the initial phase of the tissue culture, then reducing markedly during neurodegeneration while APP and BACE1 gene promoters remained active. Deletion series of these promoters were tested to give an initial indication of the active regions of the gene promoter regions. Furthermore, the effects of exogenous Aβ and overexpression of p25, which are two possible pathogenic mechanisms of gene regulation in AD, were studied. Response to Aβ varied between the promoters and by length of the Aβ fragment used. Overexpression of p25 increased MAPT, but not APP or BACE1, promoter activity. This neurodegeneration model was also used to study the putative neuroprotective action of the NMDA receptor antagonist memantine. Treatment with memantine prevented loss of synaptic markers and preserved neuronal morphology, while having no apparent effect on glial activation. The protective action on synaptic markers was also observed with two other structurally distinct NMDA receptor antagonists, suggesting that the effects of memantine are produced by its action on the NMDA receptor. It is concluded that this tissue culture model will be useful for the study of gene regulation and therapeutic agents for neurodegeneration, and that the efficacy of memantine may result from preservation of synaptic connections in the brain.

One of the most foundational and personal philosophical questions one can ask is what makes you, you? In large part, you are made up of your relationships, experiences, and memories. The hippocampus, a brain region which is critical for the formation of memories, has been the focus of neuroscience research for decades due partially to this function, which is foundational to our individuality. In Alzheimer’s disease (AD), one of the most common and well-researched neurodegenerative diseases in the world, the hippocampus is one of the earliest targets. Despite extensive work on AD, we still lack a coherent understanding of what is causing the disease, the mechanisms by which it is causing neuronal dysfunction and death within the hippocampus and other brain regions, and how it ultimately causes deficits in cognition and behavior, leading to an erosion of our selves. In this thesis, I explore three independent but related questions: 1) what molecular mechanisms are causing early synaptic loss in AD, specifically within the hippocampus, 2) what molecular effectors are responsible for establishing and maintaining intracellular architecture in hippocampal neurons, which are exploited in early AD, and 3) how and when does the hippocampal circuit dysfunction in AD progression? Using a variety of experimental techniques, ranging from in utero and ex utero electroporation, primary murine and human neuronal cell culture, longitudinal confocal microscopy, immunohistochemistry, biochemistry, cell and molecular biology, in vivo two-photon calcium imaging, and behavioral assays, I have found that, within CA1 of the hippocampus, synapse loss requires degradation of the dendritic mitochondrial network, activity and input specificity are driving mitochondrial compartmentalization within CA1 neurons through the same pathway that is aberrantly overactivated in AD, and the hippocampal circuit is overly rigid in encoding the environment as the disease progresses.