Diss. (sammanfattning) Stockholm : Karol. inst., 2004. / Härtill 5 uppsatser.

Thesis (Ph.D.)--University of South Florida, 2004. / Includes vita. Includes bibliographical references (leaves 183-193). Also available online.

published_or_final_version / abstract / Anatomy / Doctoral / Doctor of Philosophy

The pathology of Alzheimer's disease (AD) remains elusive. Competing evidence links amylois \U+fffd\-peptide (A\U+fffd\) amyloid formation to the phenotype of AD (1). The mechanism of amyloid fibril formation has been an ongoing investigation for many years. A\U+fffd\10-23 peptide, a fragment of A\U+fffd\1-42 peptide, contained crucial hydrophobic core residues (2). In this study, an investigation was launched to study the aggreagation process of A\U+fffd\1023 peptide and its ability to form amyloid fibrils. Furthermore, the presence of its hydrophobic core showed importance for its ability to aggregate and form amyloid fibrils. Thereafter, the inhibition of A\U+fffd\1-42 peptide aggregation was studied by using pyrimidine-based compounds. A\U+fffd\1-42 peptides, known to be neurotoxic, aggregate to form amyloid fibrils (3). This investigation may provide insight into the development of novel small molecular candidates to treat AD. / by Ahmad Alex Hijazi. / Thesis (M.S.)--Florida Atlantic University, 2012. / Includes bibliography. / Mode of access: World Wide Web. / System requirements: Adobe Reader.

Protein aggregation, oligomer and fibril formation is one of the dominant characteristics in the pathogenesis of a number of neurodegenerative diseases, such as Alzheimer’s disease (AD). Inhibition of toxic oligomer and fibril formation is one of the approaches to find potential drug candidates for AD. Additionally, early diagnosis of these amyloid species can provide mechanistic understanding of protein aggregation and thus can pave the way for preventing the onset of AD. The aim of this dissertation was 1) to explore the effects of charged cholesterol derivatives on the aggregation kinetic behavior of Amyloid-β40 (Aβ40), 2) to probe Aβ40 oligomer and amyloid formation in vitro using gold nanoparticles (AuNPs), and 3) to monitor the kinetic effect of various natural product molecules on Aβ40 aggregation in vitro. In the first chapter, a general introduction about AD as an amyloidogenic disease, amyloid cascade hypothesis, and the manipulation of Aβ peptides aggregation kinetics using different approaches was presented. In the second chapter, we studied the effects of oppositely charged cholesterol derivatives on the aggregation kinetics of Aβ. In the third chapter, we developed a gold nanoparticles (AuNPs) assay to probe Aβ40 oligomers and amyloid formation. In chapter IV, we monitored the effects of various small molecules on the aggregation kinetics of Aβ40. In chapter V, we discussed the methods and experimental details. / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2018. / FAU Electronic Theses and Dissertations Collection

No description available.

Cognitive impairment after stroke or transient ischemic attack (TIA) is a prototype of vascular cognitive impairment (VCI). 30% of subjects with poststroke cognitive impairment are detected Alzheimer’s disease (AD)-like amyloid-beta (Aβ) retention with reference to ¹¹C-Pittsburgh compound B (PiB) positron emission tomography (PET). Therefore, poststroke cognitive impairment provides a good clinical context for the study about contribution of comorbid Alzheimer’s and cerebrovascular disease (CVD) pathologies to cognition. In this thesis, there are four studies addressing the effect of Aβ on poststroke cognitive impairment. / The first study investigated the accuracy of diagnosing cognitive impairment subtype in subjects with stroke/TIA using current clinical diagnostic criteria with reference to ¹¹C-PiB PET. We found the agreement between the pre and the post-PET diagnoses was poor (Kappa=0.194). The overall accuracy of clinical diagnosis of pure VCI (pVCI) was 66.7%, while that of mixed (i.e., AD with CVD) VCI (mVCI) was 68.0%. / Dementia may occur after stroke/TIA within 3-6 months (early poststroke dementia [PSD]) or from 3-6 months onward (delayed PSD). In the second study, apart from age and history of diabetes mellitus, chronic small vessel disease (SVD) lesions including lacunes and white matter changes (WMC) predicted delayed PSD as they did for early PSD. With comparable levels of SVD, the presence of acute infarcts and AD-like Aβ retention were associated with the early dementia after stroke/ TIA. / So far, there is a lack of research on the long-term effect of Alzheimer’s pathology on cognitive impairment in the context of stroke/TIA. We hypothesized that comorbid AD-like Aβ deposition played a key role in progressive cognitive decline after stroke/TIA. To test this hypothesis, we conducted a 3-year longitudinal study as study 3. Over 3 years, there was significant difference between mVCI and pVCI on the changes of the Mini-Mental State Examination (MMSE) score over time. We observed a significant decline in MMSE in the mVCI group but not the pVCI group. The annual rates of decline in MMSE and Montreal Cognitive Assessment (MoCA) score were greater in the mVCI group compared to the pVCI group. Of all MoCA domains measured, memory, executive and visuospatial functions were related to Aβ deposition. / In study 4, we investigated the relative contribution of Aβ deposition and CVD lesions to neuropsychological profiles in subjects with cognitive impairment after stroke/TIA. We found that in mVCI, Aβ retention in deep region or parietal lobe was predominantly associated with memory or executive function, respectively. In pVCI, frontal WMC and global large acute infarcts could affect memory or executive function via brain atrophy. / The conclusion of these studies reported herein can be summarized as follows: First, the overall accuracy of clinical diagnosis for cognitive impairment subtypes after stroke/TIA was low. Second, subjects with AD-like Aβ deposition tended to have dementia early after stroke/TIA, and they were more likely to experience a continuous and more severe cognitive decline 3 years later. Finally, Aβ deposition could affect both memory and executive function directly as a predominant factor in subjects with mixed Alzheimer’s and CVD pathologies. / 中風或短暫性腦缺血發作後的認知障礙被普遍視為血管性認知障礙的一種原型。通過澱粉樣蛋白正電子發射計算機斷層掃描技術（¹¹C-PiB PET），30%的中風或短暫性腦缺血發作後認知障礙患者具有阿爾茲海默氏病型的澱粉樣蛋白(Aβ)沈積。因此，中風或短暫性腦缺血發作後認知障礙是一種研究共存的阿爾茲海默氏病和腦血管疾病對認知功能的影響的良好模型。該論文通過四個研究，闡述了Aβ對中風或短暫性腦缺血發作後認知功能的影響。 / 第一個研究通過藉助¹¹C-PiB PET,調查了臨床診斷中對中風或短暫性腦缺血發作後認知障礙的分型的準確性。我們發現，對不同認知障礙類型的臨床診斷準確率較低（Kappa=0.194）。其中，對血管性認知障礙的臨床診斷準確率為66.7％，對混合性(阿爾茲海默氏病和腦血管疾病混合型)認知障礙的臨床診斷準確率為68.0％。 / 通常，我們把於中風或短暫性腦缺血發作後3至6個月內發生的癡呆定義為早髮型中風或短暫性腦缺血發作後癡呆，3至6個月后發生的癡呆定義為晚髮型中風或短暫性腦缺血發作後癡呆。在第二個研究中，我們發現，慢性小血管病（腔隙性梗塞和腦白質病變）不僅可以導致早髮型中風或短暫性腦缺血發作後癡呆，而且和晚髮型中風或短暫性腦缺血發作後癡呆也有關聯。然而，如果在相同程度的小血管病損傷的情況下，具有急性缺血性損傷和阿爾茲海默氏型Aβ沈積的患者更易提早發生中風或短暫性腦缺血發作後癡呆。 / 迄今，尚無關於共存的阿爾茲海默氏病和腦血管疾病對認知功能的長期影響的研究。我們假設合併的阿爾茲海默氏病可以導致患者中風或短暫性腦缺血發作後認知功能持續下降。為了驗證這一假設，我們進行了一個為期3年的長期隨訪研究（研究三）。在三年的隨訪中，混合性認知障礙患者和血管性認知障礙患者的簡短認知檢測（MMSE）評分變化有著顯著不同：混合性認知障礙患者的MMSE評分顯著下降，而血管性認知障礙患者的MMSE評分則無明顯改變。而且，混合性認知障礙患者的MMSE和蒙特利爾認知評估量表（MoCA）評分每年下降的平均速度皆高於血管性認知障礙患者。此外，藉助MoCA，我們發現中風或短暫性腦缺血發作後認知障礙患者的記憶、執行能力和視覺空間能力的損傷都和Aβ沉積有關。 / 在第四個研究中，我們研究了Aβ和腦血管病損傷對中風或短暫性腦缺血發作後患者不同認知功能的影響。我們發現，在混合性認知障礙患者中，腦深部的Aβ沉積和記憶功能損害直接相關，腦頂葉的Aβ沉積則和執行功能損害直接相關。在血管性認知障礙患者中，額葉腦白質病變和全腦大型腦梗病灶則可通過腦萎縮的介導，影響記憶或執行功能。 / 總之，我們的研究發現: 1.目前關於中風或短暫性腦缺血發作後患者認知障礙分型的臨床診斷的準確性較低。2.具有阿爾茲海默氏型Aβ沉積的患者不僅易於在中風或短暫性腦缺血發作後早期發生認知障礙，而且其認知水平在長期隨訪中也會不斷下降。3. Aβ沉積可以作為主導因素直接影響混合性認知障礙患者的記憶和執行功能。 / Liu, Wenyan. / Thesis Ph.D. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 164-187). / Abstracts also in Chinese; appendixes in Chinese. / Title from PDF title page (viewed on 12, October, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

published_or_final_version / Medicine / Master / Master of Philosophy

Major depression and Alzheimer’s disease (AD) are highly prevalent psychiatric disorders. Further investigation demonstrated that depression itself is a risk factor for AD, and several associated genetic mutations have been found Moreover, significant proportion of AD patients suffer also suffer from depression. These findings generated interests in finding the neurobiological linkages between depression and AD. The elucidation of pathophysiological mechanisms common in both disorders would be important, as the knowledge could provide additional insights regarding the pathogeneses of the disorders and possible interventions. The present study proposes that synaptic degeneration plays a central role in the pathogenesis of depression and AD. Using in vitro disease models, this study demonstrated abnormalities in pre-synaptic and cytoskeletal proteins, which leads to impaired synaptic function. Further investigation into the upstream events demonstrated the involvement of ubiquitin-mediated protein degradation mechanism and the preferential activation of the autophagic-lysosomal pathway. This study also investigated the neuroprotective properties of the antidepressants imipramine and escitalopram. Antidepressants have originally been thought to exert their therapeutic effects through monoaminergic system modulation. Interestingly, results in this study showed that these two agents were able to ameliorate the observed synaptic protein changes, thereby implicating other possible mechanism of action for antidepressants. In conclusion, this study provides evidence that similar synaptic pathologies exist between depression and AD, which could be responsible for the development of these two disorders. Furthermore, antidepressants may be exerting its effects through alleviating synaptic degeneration. / published_or_final_version / Psychiatry / Doctoral / Doctor of Philosophy

No description available.