Diss. (sammanfattning) Stockholm : Karol. inst., 2001. / Härtill 5 uppsatser.

by Lan Chen. / "June 1999." / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

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.

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<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<0.001), 0.61 (95% CI, 0.53-0.69; p=0.007) and 0.68 (95% CI, 0.60-0.76; p<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.

Objetivos: Analisar a relevância dos polimorfismos da APOE, -491 e -219 e do LRP na ocorrência de doença de Alzheimer (DA) em indivíduos brasileiros. Metodologia: Realizou-se o estudo em 120 pacientes com DA provável e em 120 controles. Resultados: Houve diferença quanto à freqüência do alelo e4 da APOE, (31% dos pacientes e 10% dos controles). A presença do alelo e2 conferiu efeito protetor. Os polimorfismos das posições -219 e -491 da APOE e do gene LRP não mostraram correlação com DA. Conclusões: O alelo e4 do gene APOE mostrou-se associado a maior risco de DA e o alelo e2 conferiu efeito protetor. Não foi encontrada correlação entre DA e os outros polimorfismos / OBJETIVE: To investigate the role of polymorphisms APOE,-491 and -219 and LRP patients with Alzheimer's disease (AD) and controls in Brazilian individuals.METHODS: One hundred twenty patients and 120 controls were selected for the assessment. RESULTS: The frequency of the e4 allele was 0.31 in patients and 0.10 in controls. The presence of allele e2 was protective factor. No significant difference emerged for the polymorphisms of the localization -219 and -491 of APOE and of the LRP gene. CONCLUSION: These results confirm the relevance of the e4 allele like genetic risk factor and the protective role of the e2 allele in AD. We did not notice any difference in patients and controls for polymorphisms of the LRP and APOE promoter region polymorphism in this study

Objetivos: Analisar a relevância dos polimorfismos da APOE, -491 e -219 e do LRP na ocorrência de doença de Alzheimer (DA) em indivíduos brasileiros. Metodologia: Realizou-se o estudo em 120 pacientes com DA provável e em 120 controles. Resultados: Houve diferença quanto à freqüência do alelo e4 da APOE, (31% dos pacientes e 10% dos controles). A presença do alelo e2 conferiu efeito protetor. Os polimorfismos das posições -219 e -491 da APOE e do gene LRP não mostraram correlação com DA. Conclusões: O alelo e4 do gene APOE mostrou-se associado a maior risco de DA e o alelo e2 conferiu efeito protetor. Não foi encontrada correlação entre DA e os outros polimorfismos / OBJETIVE: To investigate the role of polymorphisms APOE,-491 and -219 and LRP patients with Alzheimer's disease (AD) and controls in Brazilian individuals.METHODS: One hundred twenty patients and 120 controls were selected for the assessment. RESULTS: The frequency of the e4 allele was 0.31 in patients and 0.10 in controls. The presence of allele e2 was protective factor. No significant difference emerged for the polymorphisms of the localization -219 and -491 of APOE and of the LRP gene. CONCLUSION: These results confirm the relevance of the e4 allele like genetic risk factor and the protective role of the e2 allele in AD. We did not notice any difference in patients and controls for polymorphisms of the LRP and APOE promoter region polymorphism in this study