The purpose of this study was to investigate the reading comprehension abilities of those with mild and moderate dementia of the Alzheimer's type (DAT) and compare their performance to that of a sample of non-demented elderly. Thirty-eight male subjects were used, 20 non-demented elderly, nine mild DAT and nine moderate DAT. All were administered level B of the NRST. This test contains questions requiring three levels of inference: literal, translational, and high-level inference.

Reversible adenosine methylation (N6-methylation; m6A) at the RNA level was described in connection to the regulation of RNA fate. The N6-methyladenosine pathway is important for cognitive function and mechanisms related to memory, including the regulation of adult neurogenesis and synaptic plasticity. The objective of this study was to test the hypothesis that a decreased activity of the RNA-demethylase FTO is associated with improved cognitive function in rats. The RNA-demethylase FTO is a key regulator of the m6A pathway. In this study, we administered MO-I-500, a pharmacological inhibitor of FTO in TgF344-AD transgenic rats, which resulted in an improvement of spatial cognition. We further investigated the cognitive enhancement induced by a caloric restriction as a possible compensatory mechanism of cognitive disorders and its effect on the proteins regulating the N6-methyladenosine pathway. Long-term caloric restriction ameliorated cognitive functions and led to changes in the expression of the major proteins controlling the m6A pathway (FTO, METTL3) which are consistent with the aforementioned hypothesis. Although we do not know the exact mechanism of action, these findings support the hypothesis that m6A pathway regulators, such as the FTO demethylase, may be a promising molecular target for...

Genetic susceptibility test results have been found to cause differences in coping behavior following testing for the APOE-ε4 gene, associated with Alzheimer's disease. Coping behaviors differ within the first 12 months of testing. Currently, no studies have been conducted beyond the first 12 months comparing positive (P) and negative (N) groups or how sex relates to coping behavior based on positive test results. Based on the theory of primary and secondary control, and theory of stress, appraisal, and coping this study compared differences in coping strategies based on genetic test results and between sexes with positive test results beyond the first 12 months. Participants (n = 280) were selected who had undergone testing for the APOE-ε4 gene 12 or more months prior to the study and had a relative diagnosed with AD. Coping strategies were measured using the Brief COPE scale. Independent measures t test results were significant, indicating differences in coping between P and N groups. The P group reported significantly higher levels of cognitive and emotional coping strategies than did the N group 12 or more months after receiving test results. These findings were consistent with previous studies that produced significances in cognitive and emotional coping strategies between groups in the first 12 months. The findings were non significant for cognitive and emotional coping strategies for sex in the positive group. This study contributes to social change by informing impact decision making by individuals with positive test results for the APOE-ε4 gene in making financial changes, life styles changes, and family and work adjustments affecting their community and society.

Embora a doença de Alzheimer (DA) tenha sido descoberta há mais de 100 anos, muitas questões acerca dela, sobretudo sobre o seu diagnóstico, resistem ao tempo. Algumas delas, inclusive, nunca foram de fato investigadas, o que se aplica à preservação ou não, nos idosos acometidos, da capacidade de compreensão de informação pragmática. A busca pela elucidação desse tópico perpassa, necessariamente, o desenvolvimento de um método capaz de aferir quão preservada está tal capacidade, e foi a isso que se prestou esta pesquisa. Com o embasamento teórico propiciado pelos princípios funcionalistas e cognitivistas da linguagem, atestou-se que a função pragmática relaciona-se com os âmbitos do processamento cognitivo, do envolvimento da corporeidade e da linguagem verbal. Assim, esses domínios foram convertidos em critérios de análise, cada qual composto por três subitens que, por sua vez, podem ser avaliados segundo uma gradação tripartida. A partir da soma dos resultados de cada um desses elementos, obtêm-se valores para o desempenho dos idosos com DA que, contrastados com os resultados de idosos cognitivamente sadios, dão pistas a respeito de a capacidade de compreensão de informação pragmática nos indivíduos com demência estar preservada ou não. A elaboração do método, portanto, constitui o objetivo principal deste trabalho, que apresenta, também, a sua aplicação a um conjunto de seis informantes, todas do sexo feminino, divididas igualmente entre grupo focal e de controle, cujos resultados são interpretados sobretudo no sentido de testar a validade do próprio método. Não se sabe muito sobre a complexidade da linguagem em sua perda, e foi intenção aqui diminuir, ao menos um pouco, essa lacuna de conhecimento. / Although Alzheimer\'s disease (AD) has been discovered more than 100 years ago, many questions about it, especially about its diagnosis, stand the test of time. Some of them, even, have never really been investigated, what applies to the preservation or not, in the affected elderly, of the capacity of understanding pragmatic information. The search for the elucidation of this topic necessarily leads to the development of a method capable of checking how well this capacity is preserved, and that is what this research was done for. With the theoretical foundation provided by the functionalist and cognitivist principles of language, it was demonstrated that the pragmatic function is related to the scopes of cognitive processing, the involvement of corporeity and verbal language. Thus, these domains have been converted into analysis criteria, each composed of three factors that can be evaluated according to a tripartite gradation. From the sum of the results of each of these elements, values are obtained for the performance of the elderly with AD, which, contrasted with the results of cognitively healthy elderly, give clues about the capacity to understand pragmatic information in individuals with dementia. The elaboration of the method, therefore, is the main objective of this work, which also presents its application to a group of six female informants, equally divided between the focal group and the control group, whose results are interpreted mainly for the test of the method. Not much is known about the complexity of language in its loss, and it was intended here to decrease, at least a little, this knowledge gap.

Desorption electrospray ionization (DESI) is an ambient ionization technique used for mass spectrometric imaging of biological samples. When coupled with isotopic ratio measurements of deuterium-labeled tissues, DESI provides a means of measuring metabolic rates on a spatially resolved basis. In vivo metabolic rates are desired to better understand diseases such as Alzheimer's, Parkinson's, Huntington's, and various forms of cancer that negatively impact metabolic rates within different organs of the human body. Although DESI has been used to image lipids and metabolites of a variety of tissues and other imaging techniques, such as NIMS, have been used to study kinetic turnover rates, DESI has not yet been used to study in vivo metabolic rates using deuterium labeled tissue. This thesis describes how we optimized our DESI source for imaging of biological tissue, how we developed a MATLAB graphical user interface (GUI) to process and interpret the large mass spectral data files, how we conducted our initial mouse brain study for proof-of-concept, and how we plan to implement our DESI imaging in a study with mouse models of Alzheimer's disease. Our initial mouse brain study involved labeling mice with deuterium enriched water, preparing tissue slices for DESI analysis, imaging the tissue slices using DESI coupled with a Bruker mass spectrometer, analyzing the mass spectral data using our custom-designed image_inspector program, confirming identification of lipids using MS/MS, and creating incorporation curves to measure in vivo metabolic rates.

Large-scale neuroimaging data is becoming increasingly available, providing a rich data source with which to study neurological conditions. In this thesis, I demonstrate the utility of large-scale neuroimaging as it applies to Alzheimer’s disease (AD) and normal aging, using univariate parametric mapping, regional analysis, and advanced machine learning. Specifically, this thesis covers: 1) validation and extension of prior studies using large-scale datasets; 2) AD diagnosis and normal aging evaluation empowered by large-scale datasets and advanced deep learning algorithms; 3) enhancement of cerebral blood volume (CBV) fMRI utility with retrospective CBV-fMRI technique. First, I demonstrated the utility of large-scale datasets for validating and extending prior studies using univariate analytics. I presented a study localizing AD-vulnerable regions more reliably and with better anatomical resolution using data from more than 350 subjects. Following a similar approach, I investigated the structural characteristics of healthy APOE ε4 homozygous subjects screened from a large-scale community-based study. To study the neuroimaging signatures of normal aging, we performed a large-scale joint CBV-fMRI and structural MRI study covering age 20-70s, and a structural MRI study of normal aging covering the full age-span, with the elder group screened from a large-scale clinic-based study ensuring no evidence of AD using both longitudinal follow-up and cerebrospinal fluid (CSF) biomarkers evidences. Second, I performed deep learning neuroimaging studies for AD diagnosis and normal aging evaluation, and investigated the regionality associated with each task. I developed an AD diagnosis method using a 3D convolutional neural network model trained and evaluated on ~4,600 structural MRI scans and further investigated a series of novel regionality analyses. I further extensively studied the utility of the structural MRI summary measure derived from the deep learning model in prodromal AD detection. This study constitutes a general analytic framework, which was followed to evaluate normal aging by performing deep learning-based age estimation in cognitively normal population using more than 6,000 scans. The deep learning neuroimaging models classified AD and estimated age with high accuracy, and also revealed regional patterns conforming to neuropathophysiology. The deep learning derived MRI measure demonstrated potential clinical utility, outperforming other AD pathology measures and biomarkers. In addition, I explored the utility of deep learning on positron emission tomography (PET) data for AD diagnosis and regionality analyses, further demonstrating the broad utility and generalizability of the method. Finally, I introduced a technique enabling CBV generation retrospectively from clinical contrast-enhanced scans. The derivation of meaningful functional measures from such clinical scans is only possible through calibration to a reference, which was built from the largest collection of research CBV-fMRI scans from our lab. This method was validated in an epilepsy study and demonstrated the potential to enhance the utility of CBV-fMRI by enriching the CBV-fMRI dataset. This technique is also applicable to AD and normal aging studies, and potentially enables deep learning based analytic approaches applied on CBV-fMRI with similar pipelines used in structural MRI. Collectively, this thesis demonstrates how mechanistic and diagnostic information on brain disorders can be extracted from large-scale neuroimaging data, using both classical statistical methods and advanced machine learning.

The neurodegenerative disorders Alzheimer??s Disease (AD) and Parkinson??s Disease (PD) are characterised by the accumulation of misfolded amyloid beta 1-42 peptide (Aβ1-42) or α-synuclein, respectively. In both cases, there is extensive evidence to support a central role for these aggregation-prone molecules in the progression of disease pathology. However, the precise mechanisms through which Aβ1-42 and α-synuclein contribute to neurodegeneration remain unclear. Organismal, cellular and in vitro models are under development to allow elucidation of these mechanisms. A cellular system for the study of intracellular Aβ1-42 misfolding and localisation was developed, based on expression of an Aβ1-42-GFP fusion protein in the model eukaryote Saccharomyces cerevisiae. This system relies on the known inverse relationship between GFP fluorescence, and the propensity to misfold of an N-terminal fusion domain. To discover cellular processes that may affect the misfolding and localisation of intracellular Aβ1-42, the Aβ1-42-GFP reporter was transformed into the S. cerevisiae genome deletion mutant collection and screened for fluorescence. 94 deletion mutants exhibited increased Aβ1-42-GFP fluorescence, indicative of altered Aβ1-42 misfolding. These mutants were involved in a number of cellular processes with suspected relationships to AD, including the tricarboxylic acid cycle, chromatin remodelling and phospholipid metabolism. Detailed examination of mutants involved in phosphatidylcholine synthesis revealed the potential for phospholipid composition to influence the intracellular aggregation and localisation of Aβ1-42. In addition, an existing S. cerevisiae model of α-synuclein pathobiology was extended to study the effects of compounds that have been hypothesized to be environmental risk factors leading to increased risk of developing PD. Exposure of cells to aluminium, dieldrin and compounds generating reactive oxygen species enhanced the toxicity of α- synuclein expression, supporting suggested roles for these agents in the onset and development of PD. Expression of α-synuclein-GFP in phosphatidylcholine synthesis mutants identified in the Aβ1-42-GFP fluorescence screen resulted in dramatic alteration of α-synuclein localisation, indicating a common involvement of phospholipid metabolism and composition in modulating the behaviours of these two aggregation-prone proteins.

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<p>Alzheimer’s disease (AD) is the most common cause of dementia. A characteristic feature of AD is the presence of amyloid plaques in the cortex and hippocampus of the brain. The principal component of these plaques is the amyloid-β (Aβ) peptide, a cleavage product from proteolytic processing of amyloid precursor protein (APP). A central event in AD pathogenesis is the ability of Aβ monomers to aggregate into amyloid fibrils. This process involves the formation of various Aβ intermediates, including protofibrils. Protofibrils have been implicated in familial AD, as the Arctic APP mutation is associated with enhanced rate of protofibril formation <i>in vitro.</i></p><p>This thesis focuses on Aβ aggregation and neurotoxicity <i>in vitro</i>, with special emphasis on protofibril formation. Using synthetic Aβ peptides with and without the Arctic mutation, we demonstrated that the Arctic mutation accelerated both Aβ1-42 protofibril- and fibril formation, and that these processes were affected by changes in the physiochemical environment. </p><p>Oxidation of Aβ methionine delayed trimer and protofibril formation <i>in vitro</i>. Interestingly, these oxidized peptides did not have the neurotoxic potential of their un-oxidized counterparts, suggesting that formation of trimers and further aggregation into protofibrils is necessary for the neurotoxic actions of Aβ. In agreement, stabilization of Aβ wild type protofibrils with the omega-3 (ω3) fatty acid docosahexaenoic acid (DHA) sustained Aβ induced neurotoxicity; whereas in absence of DHA, neurotoxicity was reduced as Aβ fibrils were formed. These results suggest that the neurotoxic potential of Aβ is mainly confined to soluble aggregated forms of Aβ, not Aβ monomer/dimers or fibrillar Aβ. </p><p>Stabilization of Aβ protofibrils with DHA might seem contradictory, as ω3 fatty acids generally are considered beneficial for cognition. However, we also demonstrated that DHA supplementation reduced Aβ levels in cell models of AD, providing a possible mechanism for the reported beneficial effects of DHA on cognitive measures <i>in vivo</i>.</p>