A challenge in the treatment of central nervous system (CNS) diseases is the transport of drug candidates into the brain. Inositol stereoisomers have show promise as therapeutic agents for CNS disorders. scyllo-Inositol was an effective prophylactic and therapeutic for Alzheimer’s disease (AD) in TgCRND8 mice, a model of AD. This suggests inositol stereoisomers have excellent CNS bioavailability. They enter the brain through inositol transporters, of which there are three: one hydrogen myo-inositol transporter (HMIT) and two sodium myo-inositol transporters (SMIT1, SMIT2). HYPOTHESIS: Given the high CNS bioavailability of inositol stereoisomers, it may be possible to use inositol transporters to shuttle other compounds into the CNS. OBJECTIVES: 1. To confirm the CNS bioavailability of the two main inositol stereoisomers, myo- and scyllo-inositol, in both TgCRND8 and wild-type mice. 2. To examine inositol transporter expression in the brains, as a function of time and disease pathology, in both groups. 3. To evaluate the flexibility of the inositol transporters for transporting compounds by determining the substrate structural features required for active transport. RESULTS: myo-Inositol and scyllo-inositol accumulated in the brain following oral administration. Disease pathology did not alter baseline inositol levels or uptake. Brain subregional transporter expression was unaltered as a function of age or disease pathology. In vitro cell culture experiments found HMIT inactive and therefore not a contender for drug transport. In contrast SMIT1 and SMIT2 were both active and competitive transport assays, revealed distinct criteria for active transport through each system. However, both were stringent in the substitutions to the structure of myo-inositol possible to maintain active transport. CONCLUSION: Active transport through the inositol transporters is very sensitive to changes in the structure of myo-inositol and only conservative changes are possible. Therefore, these transporters would not make effective shuttling systems for drug transport into the brain.

Alzheimer'€™s disease (AD) is the fifth leading cause of death among the elderly. This study uses National Center for Health Statistics (NCHS) Multiple Cause of Death data for the United States for the years 1998 to 2002, examining the 9.5 million death records of all decedents of age 60 and over, and determines their incidence of AD. Seven independent variables are used: age, sex, race, ethnicity, marital status, education level and whether or not they lived in a metropolitan area. This study uses logistic regression, modeling five nested models, to determine the likelihood of mortality by AD and the direction of the relationship between AD and each of the variables. A Bayesian analysis, used to determine the best fit model, found that the full model was the best fit. The major findings of the study are that the incidence of AD increases significantly with increasing age in decedents aged 60-90. However, this peaks for decedents aged 85-89. Those who survive past age 90 begin to have a lesser likelihood of mortality by AD. With the exceptions of marital status and education, the hypotheses were supported. Females are more likely to die of AD than males. NonHispanic Whites are more likely to die of AD than Hispanics and NonHispanic Blacks. There is an increased risk of dying in a nursing home if one dies of AD. Future research as outlined above is needed to learn further about this fifth leading cause of mortality of those over age 60.

Thesis (M.Med.Sc.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 92-102).

Thesis (M.A.)--Central Connecticut State University, 2001. / Thesis advisor: C. Charles Mate-Kole. " ... in partial fulfillment of the requirements for the degree of Master of Arts in Psychology." Includes bibliographical references (leaves 36-44). Also available via the World Wide Web.

Thesis (M.A.)--Central Connecticut State University, 2000. / Thesis advisor: Charles Mate-Kole. " ... in partial fulfillment of the requirements for the degree of Master of Arts in [in Psychology]." Includes bibliographical references (leaves 46-60).

Thesis (M.A.)--Central Connecticut State University, 2000. / Thesis advisor: Charles Mate-Kole. " ... in partial fulfillment of the requirements for the degree of Master of Arts in Psychology." Includes bibliographical references (leaves 40-47).

Thesis (Ph. D.)--University of Texas at Austin, 2001. / Vita. Includes bibliographical references (leaves 159-173). Available also in a digital version from Dissertation Abstracts.

Thesis (Ph. D.)--Oregon State University, 2002. / Typescript (photocopy). Includes bibliographical references. Also available on the World Wide Web.

On the basis of neuropathological, neurochemical, genetic, and clinical profile studies on patients, distinct forms of dementia, such as dementia with Lewy bodies (DLB), have been distinguished which were originally thought to be Alzheimer's disease (AD). Dementia with Lewy bodies is probably the second most common form of dementia in the elderly. In this thesis, a well characterised and investigated cohort of DLB and AD patients were compared to non-demented elderly controls in order to establish profiles of cognitive decline in these groups. Initially, comprehensively matched experimental groups were compared using the Cambridge Neuropsychological Test Automated Battery (CANTAB). The DLB group was less impaired than the AD group on a test of visual pattern recognition memory. However, the DLB group performed worse on a number of cognitive tests. Comparison of larger, carefully matched, experimental groups using the Cognitive Drug Research Computerised Assessment Battery (CDR) also revealed differences in the profile of cognitive impairment in DLB and AD. The DLB group showed more marked deficits in attentional abilities than the AD group. In particular, the DLB group were unable to sustain attention. Conversely, the DLB group were less impaired on a test of visual secondary recognition memory than the AD group. Further division of the DLB group into cases with and without persistent visual hallucinations revealed distinct patterns of cognitive impairment in these two groups. Generally, DLB cases with persistent visual hallucinations showed greater attentional and spatial working memory deficits than the DLB cases without persistent visual hallucinations. A final study compared decline in cognitive function over 1 year in DLB, AD and control groups. Similar rates of cognitive decline were identified in a number of cognitive domains in AD and DLB groups. In addition, disproportionate decline in the ability to sustain attention was identified in the DLB group. A comparative model relating known neuropsychological, neurochemical, and neuropathological features of DLB and AD was proposed.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, with genetic factors playing critical roles in its pathogenesis. Mutations in APP, PSEN1 and PSEN2 genes are confirmed to be causative risk factors for early-onset Alzheimer’s disease (EOAD). For late-onset Alzheimer’s disease (LOAD), growing evidence suggests it is caused by multiple genetic risk factors in corporation with the environmental exposures. Although, so far, APOE is the most well recognized common genetic risk factor for LOAD, other susceptible candidate genes, such as CR1, CLU and PICALM, have recently been identified in Caucasians using genome-wide association approach. In order to have a better understanding on the genetic components of LOAD in Chinese as well as identify other potential genetic risk factors for Chinese ethnic population, we conducted a case-control study using candidate gene association approach. In view of increasing evidence on the neural protective effects of sex steroid hormones both in vivo and in vitro, we hypothesized variations on sex steroid metabolic pathway genes were associated with LOAD. Four candidate genes (ESR1, ESR2, CYP19A1, CYP11A1) were evaluated based on 462 cases and 350 non-demented controls. Apart from consistent result for APOE, polymorphisms in ESR2 and CYP11A1 were found to be significantly associated with the disease. When stratification according to gender, marginally significant associations were detected for ESR1 and ESR2 variants in men while CYP11A1 variants relevant to LOAD risk were detected exclusively in women. Additionally, genotypic and phenotypic correlation analysis revealed CYP19A1 was significantly relevant to serum 17-estradiol (E2) levels in 689 subgroup participants, especially in 400 LOAD patients of subgroup. Further gene-level analyses based on whole sample confirmed above disease association for ESR2 and CYP11A1 and pathway-level analyses highlighted the impact of sex steroid metabolic pathway on disease predisposition. The independent follow-up study for CR1, CLU and PICALM previously reported by genome-wide association study (GWAS) in Caucasians was conducted in the same Chinese cohort. Similar to the Caucasian cohort, polymorphisms in CR1 and CLU were found to be significantly different between cases and non-demented controls. However, significant disease association for PICAML was detected only in the APOE ε4 (-) subgroup of our Chinese cohort. In conclusions, genetic abnormalities were founded in Chinese LOAD patients. In addition to confirmation disease susceptibility for APOE, CR1, CLU and PICALM, we were first to report the associations between several sex steroid metabolic pathway genes and LOAD. This valuable genetic information obtained from Chinese patients may lead to the development of novel diagnostic strategies and therapeutic interventions in LOAD. / published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy