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1
Branca, Caterina, Darren M. Shaw, Ramona Belfiore, et al. "Dyrk1 inhibition improves Alzheimer's disease-like pathology." WILEY, 2017. http://hdl.handle.net/10150/626504.
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There is an urgent need for the development of new therapeutic strategies for Alzheimer's disease (AD). The dual-specificity tyrosine phosphorylation-regulated kinase-1A (Dyrk1a) is a protein kinase that phosphorylates the amyloid precursor protein (APP) and tau and thus represents a link between two key proteins involved in AD pathogenesis. Furthermore, Dyrk1a is upregulated in postmortem human brains, and high levels of Dyrk1a are associated with mental retardation. Here, we sought to determine the effects of Dyrk1 inhibition on AD-like pathology developed by 3xTg-AD mice, a widely used animal model of AD. We dosed 10-month-old 3xTg-AD and nontransgenic (NonTg) mice with a Dyrk1 inhibitor (Dyrk1-inh) or vehicle for eight weeks. During the last three weeks of treatment, we tested the mice in a battery of behavioral tests. The brains were then analyzed for the pathological markers of AD. We found that chronic Dyrk1 inhibition reversed cognitive deficits in 3xTg-AD mice. These effects were associated with a reduction in amyloid-beta (Ab) and tau pathology. Mechanistically, Dyrk1 inhibition reduced APP and insoluble tau phosphorylation. The reduction in APP phosphorylation increased its turnover and decreased Ab levels. These results suggest that targeting Dyrk1 could represent a new viable therapeutic approach for AD.
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Tilley, Louise. "Genetic risk factors in sporadic Alzheimer's disease." Thesis, University of Nottingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311748.
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Devall, Matthew Adrian Michael. "Epigenetic modification of mitochondrial genes in Alzheimer's disease (AD)." Thesis, University of Exeter, 2017. http://hdl.handle.net/10871/28434.
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Alzheimer’s disease is a chronic, neurodegenerative disease characterised by amyloid plaque accumulation, neurofibrillary tangles and eventual neuronal cell loss. The complex aetiology exhibited in late-onset Alzheimer’s disease presents a considerable challenge in the field of genetics, with identified variants from genome-wide association studies collectively only explaining about a third of disease incidence. As such, new avenues are being explored to elucidate underlying mechanisms associated with disease onset and progression. In 2014, the first epigenome-wide association studies in Alzheimer’s disease were published, identifying several, novel differentially methylated loci in the nuclear genome in cortical brain samples, highlighting that epigenetic mechanisms may play a role in disease aetiology. Further, a growing body of evidence has implicated mitochondrial dysfunction as an early feature of disease pathogenesis. Despite this, few studies have investigated the role of mitochondrial DNA epigenetics in Alzheimer’s disease. Indeed, the relatively nascent field of mitochondrial epigenetics has largely been restricted to candidate-based gene approaches to identify differential methylation associated with disease. The main aim of this thesis was therefore to design an experimental and bioinformatic pipeline for the analysis of mitochondrial DNA methylation in post- mortem human brain tissue; first in healthy non-demented control donors, and subsequently in individuals with Alzheimer’s disease. Our work therefore represents the first epigenome wide studies of mitochondrial DNA methylation at single nucleotide resolution, providing a framework not only for mitochondrial DNA methylation in Alzheimer’s disease, but also in a number of complex diseases characterised by mitochondrial dysfunction.
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Soman, Sony. "OXIDATIVE DAMAGE TO DNA IN ALZHEIMER'S DISEASE." UKnowledge, 2013. http://uknowledge.uky.edu/chemistry_etds/28.
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Previous studies from our laboratory and others show a significant increase in levels of both nuclear and mitochondrial DNA and RNA oxidation in vulnerable brain regions in the progression of Alzheimer’s disease (AD). Although total DNA oxidation is increased in AD it remains unclear whether oxidative damage is widespread throughout the genome or is concentrated to specific genes. To test the hypothesis that specific genes are more highly oxidized in the progression of AD, we propose to quantify the percent oxidative damage in genes coding for proteins shown to be altered in the progression of AD using quantitative/real-time polymerase chain reaction (qPCR/ RT-PCR). To further test the hypothesis that diminished DNA repair capacity in the progression of AD contributes to increased DNA oxidation we will use custom PCR arrays and qPCR, Western blot analysis and activity assays to quantify changes in enzymes involved in base excision repair (BER).
In order to carry out these studies tissue specimens from superior and middle temporal gyri (SMTG) and inferior parietal lobe (IP), as well as, a non-vulnerable region, the cerebellum (CER) will be analyzed from normal control (NC) subjects and subjects throughout the progression of AD including those with preclinical AD (PCAD), mild cognitive impairment (MCI), and late stage AD (LAD). We will also analyze specimens from diseased control subjects (DC; Frontotemporal dementia (FTD) and dementia with Lewy bodies (DLB)) to determine if the changes we observe in AD are specific.
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Lyubartseva, Ganna. "Alterations of zinc transporters in Alzheimer's disease." Lexington, Ky. : [University of Kentucky Libraries], 2009. http://hdl.handle.net/10225/1072.
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Thesis (Ph. D.)--University of Kentucky, 2009.<br>Title from document title page (viewed on October 27, 2009). Document formatted into pages; contains: x, 128 p. : ill. (some col.). Includes abstract and vita. Includes bibliographical references (p. 111-127).
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Irvine, Karen. "Sex differences in cognition in Alzheimer's disease." Thesis, University of Hertfordshire, 2014. http://hdl.handle.net/2299/13879.
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Inspection of the published research shows that sex differences in cognition in the general population have been widely cited with the direction of the advantage depending on the domain being examined. The most prevalent claims are that men are better than women at visuospatial and mathematical tasks whereas women have superior verbal skills and perform better than men on tasks assessing episodic memory. There is also some evidence that women are more accurate than men at identifying facial expressions of emotion. A more in-depth examination of the literature, however, reveals that evidence of such differences is not as conclusive as would at first appear. Not only is the direction and magnitude of sex differences dependent on the cognitive domain but also on the individual tasks. Some visuospatial tasks show no difference (e.g. figure copying) whist men have been shown to be better than women at confrontation naming (a verbal task). Alzheimer’s disease is a heterogeneous illness that affects the elderly. It manifests with deficits in cognitive abilities and behavioural difficulties. It has been suggested that some of the behavioural issues may arise from difficulties with recognising facial emotion expressions. There have been claims that AD affects men and women differently: women have been reported as being more likely to develop AD and showing a greater dementia severity than men with equivalent neuropathology. Despite this, research into sex differences in cognition in AD is scarce, and conflicting. This research was concerned with the effect of sex on the cognitive abilities of AD patients. The relative performance of men and women with AD was compared to that of elderly controls. The study focused on the verbal, visuospatial and facial emotion recognition domains. Data was collected and analysed from 70 AD patients (33 male, 37 female), 62 elderly controls (31 male, 31 female) and 80 young adults (40 male, 40 female). Results showed those with AD demonstrate cognitive deficits compared to elderly controls in verbal and visuospatial tasks but not in the recognition of facial emotions. There were no significant sex differences in either the young adults or the healthy elderly controls but sex differences favouring men emerged in the AD group for figure copying and recall and for confrontation naming. Given that elderly men and women perform equivalently for these tasks, this represents a deterioration in women’s cognitive abilities, relative to men’s. Further evidence of such an adverse effect of AD was apparent in other tasks, too: for most verbal and visuospatial tasks, either an effect favouring women in the elderly is reversed or a male advantage increases in magnitude. There is no evidence of sex differences in facial emotion recognition for any group. This suggests that the lack of published findings reporting on sex differences in this domain is due to the difficulty in getting null findings accepted for publication. The scarcity of research examining sex differences in other domains is also likely to be due to this bias.
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Casali, Brad Thomas. "Disease-Modifying Effects of Microglia Depletion and Nuclear Receptor Deletion inMyeloid Cells in Alzheimer's Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1599047858196611.
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McNicoll, Marie-Michelle. "Early Defects in Neurogenesis in the 3xTg Mouse Model of AD." Thesis, Université d'Ottawa / University of Ottawa, 2021. http://hdl.handle.net/10393/42665.
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Smith, Adam Robert. "Epigenetic characterisation of ANK1, a novel gene implicated in Alzheimer's disease (AD)." Thesis, University of Exeter, 2018. http://hdl.handle.net/10871/33208.
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Alzheimer’s disease is a progressive neurodegenerative disorder that affects approximately twenty eight million people worldwide. Collectively DNA mutations only explain approximately 33% of Alzheimer’s disease incidence. Therefore, Alzheimer’s disease has been hypothesised to have both an environmental and epigenetic contribution to disease aetiology. Epigenetics refers to the heritable changes in gene expression that do not involve changes to the underlying DNA sequence. Epigenetic changes can be transient, varying in levels according to a person’s age, sex, environmental exposure, genetics and disease status. The identification of robust epigenetic changes in Alzheimer’s disease would give the potential to open up a variety of new treatment options for the disease. Previous epigenome-wide association studies in Alzheimer’s disease have highlighted neuropathology-associated DNA hypermethylation in the ANK1 gene. To date, however, no studies have examined whether other epigenetic mechanisms are altered in this gene in Alzheimer’s disease pathology, or whether these ANK1 epigenetic changes are seen in other neurodegenerative diseases. The aim of this thesis was to characterise the epigenetic profile (DNA methylation, DNA hydroxymethylation and histone modifications) of ANK1 in Alzheimer’s disease. In addition, it sought to determine whether the previously identified ANK1 DNA methylation changes in Alzheimer’s disease are specific to this dementia, or are observed in a number of other neurodegenerative diseases. The results provide further support for a role for epigenetic dysfunction of ANK1 in Alzheimer’s disease as well as some other neurodegenerative diseases. In summary, the work presented in this thesis represents the first epigenome-wide association study of DNA methylation and DNA hydroxymethylation simultaneously in Alzheimer’s disease across two brain regions, highlighting changes in DNA modifications in ANK1. The thesis then highlights ANK1 DNA methylation changes in other neurodegenerative diseases and explores the histone modification profile of the ANK1 locus in Alzheimer’s disease.
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Lalande, Maryline. "The Role of Sigma-1 Receptors in an Alzheimer's Disease Mouse Model." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/37034.
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Alzheimer's disease (AD) is an incurable disease characterized by a slow, progressive decline in cognitive functions as well as the presence of amyloid-beta (Aβ) plaques and neurofibrillary tangles. Interestingly, two thirds of AD patients are women who have a faster disease progression. Despite this clinical profile, sex differences in AD pathophysiology are largely ignored at the basic and clinical levels. Current therapies provide only mild to moderate improvement in patient symptoms. There is, therefore, an urgent need to expand our understanding of the underlying pathophysiology of AD, and to obtain alternative hypotheses and therapeutics. A recent and promising development involves the sigma-1 receptor (Sig1R), a protein regulated by steroid hormones, which has been implicated in AD. Most interestingly, Sig1R agonists have been shown to ameliorate cognitive deficits in an AD mouse model. Here, we investigated the role of Sig1Rs in an Aβ25-35-infusion mouse model of AD, using behavioural paradigms. Previous studies employing this model have demonstrated Aβ-induced impairments in learning and memory in young male rodents, while no work has been done on females. We examined cognitive function following Aβ25-35 infusion in wild-type and knock-out Sig1R adult male and female mice using the Morris water maze, spontaneous alternation in the Y-maze, and forced alternation in the Y-maze tasks. Overall, the data unexpectedly shows that genotype, Aβ25-35-treatment, and sex had no effect on cognitive functions. These results suggest that additional efforts are required to obtain a working Aβ25-35-infusion model in our Sig1R mice and behavioural tasks. Future experiments will hopefully shed some light on the link between Sig1Rs and AD, which could lead to the development of therapeutics and disease prevention.
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Savage, Julie C. "Nuclear Receptors License Phagocytosis in Mouse Models of Alzheimer's Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=case1430907654.
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Norton, Lauren E. "Performance on perceptual-structural priming tasks in patients with probable Alzheimer's Disease (AD) /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1998. http://wwwlib.umi.com/cr/ucsd/fullcit?p9907594.
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Voorhees, Jaymie Richelle. "Cognitive impairment and neuronal damage in Alzheimer's disease are malleable: occupational chlorpyrifos exposure exacerbates phenotypes, while the neuroprotective compound P7C3 ameliorates effects in a transgenic model of Alzheimer's disease." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5871.
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Alzheimer’s disease (AD) is a devastating neurodegenerative disease that affects millions of peoples’ lives worldwide. While the consequences of AD are recognizable, the etiology is unclear. Gene-environment interactions have been implicated in the development of the disease, and exposure to organophosphorus (OPs) compounds is one of the environmental factors associated with AD. Evidence links exposure to levels of OPs encountered in agriculture, horticulture, and other work places with neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Unfortunately, the mechanisms underlying these effects have yet to be established. Here, we set out to examine the long-term consequences of exposure to a commonly applied OP insecticide, chlorpyrifos (CPF), in an attempt to identify a causal link between occupational exposures and chronic illnesses. We exposed a transgenic rodent model of AD, TgF344-AD, to levels of CPF representing occupational exposures and examined ensuing behaviors and neuropathologies. We observed a sex-specific, biphasic response in CPF-exposed animals, including acute neurotoxicities, followed by intermediate recovery, and finally, chronic cognitive impairments. CPF exposure exacerbated neuronal damage in brain regions critical to the impaired behaviors, and neuroinflammatory pathways were identified as facilitators of this damage. This work emphasizes the long-term consequences of early life repeated exposures to OPs and identifies dysregulated microglia as a potential deleterious modifier of disease.
Additionally, we investigated the efficacy of a neuroprotective compound, (-)-P7C3-S243 in TgF344-AD rats. P7C3 compounds exert protection by preventing young hippocampal neurons from dying prematurely and also enhancing flux of nicotinamide adenine dinucleotide (NAD), thereby aiding in neuron survival under conditions that normally cause axon degeneration and cell death. These compounds have proven effective in preclinical models of Parkinson’s disease, amyotrophic lateral sclerosis, and traumatic brain injury. Thus, we sought to investigate the neuroprotective efficacy of P7C3 compounds in AD, as well. (-)-P7C3-S243 was administered to wild-type and transgenic male and female rats daily for 9 and 18 months, and classic hallmarks of the disease were assessed. Transgenic rats developed a spectrum of AD pathologies and behaviors, as expected, and (-)-P7C3-S243 ameliorated early depression-like behaviors, late learning and memory deficits, and progressive neuronal damage in this model, without influencing amyloid plaque deposition, tauopathies, or neuroinflammation. This data suggests that targeting neuronal cell death pathways is a promising treatment strategy in AD.
Taken together, the research presented here expands our current understanding of pathways of regulation in Alzheimer’s disease—organophosphates are capable of exacerbating the severity of AD, while P7C3 compounds are promising therapeutic candidates for neuronal death in the disease. Given the overlapping molecular pathways of modulation in CPF-induced toxicity and (-)-P7C3-S243 neuroprotection in AD, future studies will investigate the efficacy of (-)-P7C3-S243 in cognitive deficits induced by CPF exposure. Ultimately, this body of work highlights the plasticity of neuronal cell death and cognitive impairment in AD, thus indicating a better understanding of these pathways could facilitate vastly improved intervention strategies in Alzheimer’s disease.
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Kanyenda, Limbikani J. "Investigating the impact of CD147 and its expression on neurodegenaration and Alzheimer's disease (AD)." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2012. https://ro.ecu.edu.au/theses/499.
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CD147, also known as basigin, extracellular matrix metalloproteinase inducer, neurothelin, tumour cell-derived collagenase stimulatory factor, M6, HT7, OX47 or gp42, is a transmembrane glycoprotein of the immunoglobulin super-family. It is expressed in many neuronal and non-neuronal tissues with high expression in the hippocampus, pre-frontal cortex, thyroid, heart, early erythroid, amygdala and placenta. This protein is involved in various cellular and biological functions such as lymphocyte migration and maturation, tissue repair, cancer progression, T and B lymphocyte activation and induction of extracellular matrix metalloproteinase. The CD147 protein interacts with with cyclophilin A, cyclophilin B, sterol carrier protein, caveolin-1 and integrins, and can influence beta amyloid peptide levels, a protein that is central to Alzheimer’s disease pathology.
Mechanisms through which CD147 regulates bata amyloid levels still remain unclear, thus the current study investigated the impact of high cholesterol and beta amyloid 42 loading on CD147 expression in rat primary cortical neuronal cultures. Its expression in human brain tissue from Alzheimer’s disease and non-Alzheimer’s disease dementias and APPswe transgenic mice fed on a high fat/high cholesterol diet were also determined. CD147 over expression experiments in rat primary cortical neuronal and SH-SY5Y cultures using recombinant adenoviruses (AdRSV-CD147 and AdRSV-Empty) in the presence and/or absence of cyclophilin A were employed to determine level of proection against oxidative stress and toxicity. Finally sequencing of the CD147 promoter region (-392 to -242 nucleotides) was perfomed to identify possible single neucrotide polymorphysims that may be linked to Alzheimer’s disease pathology.
The in vitro experiments conducted in this study have shown that cholesterol and beta amyloid loading and oxidative stress result in increased CD147 expression in rat primary cortical neuronal cultures and that CD147 protects neuronal cultures from beta amyloid toxicity only in the presence of cylophilin A. However in vivo experiments in animal model have shown that a high fat/high cholesterol diet does not affect brain CD147 levels as evidenced by unchanged expression levels in APPswe mice.
Human studies have revealed a correlation between CD147 and γ-secretase complex components (nicastrin and presenilin 1) in the hippocampus. However, there is no difference in CD147 protein expression between hippocampus and frontal cortex from Alzheimer’s disease patients. Sequencing of the CD147 promoter region, where sterol carrier protein binds to initiate CD147 transcription, has identified two novel single neucrotide polymorphysims (-61A>G and 37C>G). However, single neucrotide polymorphysims within this region are not associated with Alzheimer’s disease pathology.
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Pedrini, Steve. "An overview of blood-based biomarkers in AD." Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2023. https://ro.ecu.edu.au/theses/2623.
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Alzheimer’s disease (AD) is the most common form of dementia in the elderly whose main neuropathological features are the presence of extracellular senile plaques in the brain and the intracellular accumulation of hyperphosphorylated tau filaments. However, a relatively cheap and non-invasive method for the diagnosis of AD remains elusive. Recent studies have indicated that cerebral biochemical changes take place decades before the clinical onset of the disease, but current methodologies, brain scan (PET amyloid imaging) and cerebrospinal fluid (CSF) analysis, are unsuited for community-wide screening. Brain scanning methods non-invasively assess amyloid load but are extremely expensive and cannot be used for clinical routine analyses. Conversely, CSF analysis measuring specific AD-related biomarkers (Aβ and tau) are invasive and require trained personnel. While these methodologies are considered the best options for identifying individuals at risk for AD, neither technique is suitable for community-wide screening. These problems could be solved by developing an AD-related blood-based biomarker panel that could reflect the amount of amyloid deposition in the brain, identifying individuals at risk for AD, thereby bypassing the need for current methodologies. This blood analysis would be a cheap and non-invasive community screen, and thus suitable for use in clinical pathology laboratories.
In this thesis, I am presenting my work on specific blood-based AD-related biomarkers. The first part of the thesis is focused on High Density Lipoprotein (HDL) subclasses and its protein cargo. Previous studies have indicated that small HDL subclass is linked to anti-inflammatory and anti-oxidative features, while many of the molecules associated to HDL, have been related to AD. My initial analysis has indicated that protective small HDL subclass is reduced in AD and positively correlate with cognitive functions. Furthermore, I have also isolated HDL particles and shown that HDL composition is changed in AD, with a significant increase of cholesterol/ApoA-I and ApoD/ApoA-I ratios and reduced ApoA-II/ApoA-I ratio.
Additionally, cholesterol/ApoA-I ratio is also positively associated to increased ventricular volume, while ApoA-II/ApoA-I and ApoJ/ApoA-I ratios are positively associated with grey matter volume, hippocampal volume and are negatively associated with ventricular volume. Taken together, these data indicate that plasma HDL composition is related to brain volumetric data and has the potential to be used as part of a broader AD-related biomarker panel.
In the second part of this thesis, in collaboration with colleagues, I have evaluated the levels of specific AD-related biomarkers (Aβ1-42, Aβ1-40, t-tau, p-tau181, glial fibrillary acidic protein (GFAP) and neurofilament light chain (NFL)) in two different cohorts. Our results have indicated that Aβ1-42/Aβ1-40 ratio, p-tau181 and GFAP levels are reliable biomarkers for identifying individuals with ongoing brain amyloidosis and could also be used in a broader AD-related biomarker panel.
While additional studies are necessary, these early data indicate that the development of a specific biomarker panel for AD is achievable. This discovery would allow for the detection of individuals at risk for AD before the clinical onset of the disease, thereby allowing for early medical intervention(s).
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Dong, Mia, Masud Husain, David Brooks, et al. "Alzheimer’s Disease (AD) Detect & Prevent: presymptomatic AD detection and prevention." TUDpress, 2019. https://tud.qucosa.de/id/qucosa%3A36693.
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Alzheimer’s disease (AD) is a major cause of the rapidly growing and crushing aging challenge that threatens to economically undermine today’s healthcare system. AD prevalence will grow to over 100 million cases in 2050. AD is incurable but can be prevented. Therefore, the most viable solution may be to detect very early signs of AD (presymptomatically) in citizens-at-risk and to intervene in time to reduce AD risk or prevent it entirely. The present project will refine and validate two breakthrough innovations for AD detection and AD prevention and commercialize them as a one-stop digital medical device, named ‘AD Detect & Prevent’. The first innovation is a highly sensitive cognitive assessment method recently pioneered by a group of researchers that has been shown to detect subtle presymptomatic stage cognitive decline specific to AD. This will be integrated with the second innovation – a digital AD prevention programme delivered on an award-winning computerized cognitive training and rehabilitation platform (app + web) that uses high intensity immersive and adaptive ‘neurogames’ and audio-based therapy for behavioural intervention, designed for strengthening core cognitive functions, building cognitive reserve, changing lifestyle and thus reducing the overall AD risk in individuals. The detection and prevention methods will undergo vigorous scientific validation, and the ambition is to create and become the global standard of care for precise presymptomatic detection of AD and effective AD prevention.
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Herrmann, Abigail Grace. "Proteomic response to metabolic stress and cellular dysfunction in relation to Alzheimer's disease." Thesis, University of Edinburgh, 2014. http://hdl.handle.net/1842/9546.
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Vascular risk factors inducing a state of chronic cerebral hypoperfusion and metabolic stress are thought to influence the onset and progression of Alzheimer’s disease (AD). To investigate the complex molecular changes underpinning cellular adaptation to metabolic stress, the first aim of this thesis was to define the proteomic response of the SH-SY5Y human neuroblastoma cell line after exposure to the metabolic challenge of oxygen glucose deprivation (OGD). 958 proteins across multiple subcellular compartments were detected and quantified by label-free liquid chromatography mass spectrometry (LC-MS). The levels of 130 proteins were significantly increased (P<0.01) after OGD and the levels of 63 proteins were significantly decreased (P<0.01) while expression of the majority of proteins (765) was not altered. Ingenuity Pathway Analysis identified novel protein-protein interactomes involved with mitochondrial energy production, protein folding, and protein degradation, indicative of coherent and integrated proteomic responses to the metabolic challenge. Approximately one third (61) of the differentially expressed proteins were associated with the endoplasmic reticulum and mitochondria. Electron microscopic analysis of these subcellular structures showed morphologic changes consistent with the identified proteomic alterations. Pertinent to AD research, amyloid binding alcohol dehydrogenase (ABAD) was found to be significantly increased in response to OGD. ABAD is emerging as a key player in mitochondrial dysfunction in AD, yet full understanding of the biochemical pathways in which this protein is involved remain elusive. Using immunoprecipitation coupled to LC-MS (IP-MS), the second aim of the thesis was to characterise the ABAD protein interactome in SH-SY5Y cells and its response to metabolic stress. 67 proteins were identified as potential ABAD interactors under control conditions, and 69 proteins were identified as potential ABAD interactors under OGD conditions. The Database for Annotation, Visualization and Integrated Discovery (DAVID) was used to determine the subcellular locations and biological functions of the ABAD interacting proteins in control and OGD conditions. DAVID identified the nuclei and mitochondria to contain the greatest number of changes in ABAD interacting proteins following OGD. “Glucose Metabolic Process” (GO:0006006) was the top functional cluster for ABAD interacting proteins in both control and OGD conditions. Independent immunoprecipitations, western blotting, immunohistochemistry and electron microscopy were used to validate specific protein interactions. OGD was found to initiate a novel interaction between ABAD and glucose-regulated protein 75 (GRP75), a finding confirmed in human AD tissue. GRP75 is a mitochondrial protein and marker of the mitochondrial associated membrane (MAM), a specialised region between the mitochondria and the ER. The MAM is known to be enriched with presenilin proteins, involved in the proteolytic cleavage of amyloid precursor protein (APP). These data were used to generate an “ABAD-GRP75-MAM hypothesis of mitochondrial dysfunction in AD”, which might provide a novel link between chronic metabolic stress, ABAD, mitochondrial dysfunction and the onset / progression of AD. The third aim of the thesis was to test this novel hypothesis. Western blotting revealed APP to be significantly decreased following OGD, concurrent with an increase in ABAD protein levels. Over-expression of ABAD protein in SH-SY5Y cells was used to test whether the increased levels of ABAD following OGD were the driving force behind APP down-regulation. ABAD over-expression in SH-SY5Y cells was found to have no detectable effect on APP. Conversely, electron microscopy revealed a dynamic response of the MAM to metabolic stress. This result, along with the interaction of ABAD with GRP75, and the enrichment of presenilins at the MAM, suggests that this specialised membrane region may have an important role to play in AD.
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Raina, Arun K. "Oncogenic Parallels in Alzheimer Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1102023891.
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Rawal, Devika. "Use of a Neurotrophic Factor Mimetic to Block Amyloid Toxicity in Alzheimer's Disease Models." Digital WPI, 2010. https://digitalcommons.wpi.edu/etd-theses/69.
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Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the world. The most accepted hypothesis for the cause of this disease is the amyloid cascade hypothesis, which postulates that the formation of extracellular neurotoxic amyloid-beta binds specific receptors on the surface of neuronal and glial cells to increase cell stress leading to cell death. Our laboratory previously showed that treatment of cultured human SHSY neuronal cells with amyloid beta increases the cellular levels of two key components (caspases-2 and -3) of the extrinsic apoptotic pathway, leading to cell death. The amyloid beta induced caspase elevation was blocked by simultaneously treating the cells with a short mimetic of human ependymin neurotrophic factor, hEPN-1, and the hEPN-1 treatment also blocked cell death. This thesis extends the AD investigation to show that treatment of SHSY cells with amyloid beta may also activate an intrinsic apoptotic mitochondrial stress pathway (assaying caspase-9 as a marker enzyme), and that hEPN-1 treatment significantly lowers this activation. In addition, our laboratory previously showed that treating SHSY cells with amyloid beta increases TUNEL staining, an assay for DNA fragmentation (a hallmark of end stage of apoptosis, and a different apoptotic marker than caspase activation). Treatment with hEPN-1 simultaneously with the amyloid beta, or 6 hrs post amyloid beta, significantly lowered the amyloid beta induced TUNEL signal. This thesis extended the earlier TUNEL experiments to show that hEPN-1 treatment can significantly lower the amyloid beta induced TUNEL staining even when added 18 hrs post amyloid beta. With respect to caspase-8, an initiator caspase in the extrinsic pathway, immunoblot assays of brain lysates from 8 month old transgenic AD mice showed that a 2 week oral delivery of hEPN-1 (conjugated to a carrier to deliver it across the blood brain barrier) significantly lowered caspase-8 levels. Finally, an assay of cellular inhibitors of apoptosis (cIAP) showed a significant increase in their cellular levels in SHSY cells, and in transgenic AD mice treated with hEPN-1, showing for the first time that hEPN-1 may aid cell survival by upregulating proteins known to directly bind specific caspases to block their activity leading to their degradation. The cIAP upregulation occurred in the presence or absence of amyloid beta, indicating that hEPN-1 likely does not block cell death by directly interfering with the interaction of amyloid beta with its cell surface receptors, but instead hEPN-1 may activate an independent cell survival signal transduction pathway in neuronal cells.
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SCADUTO, Pietro. "NEUROINFLAMMATION AND SYNAPTIC IMBALANCE IN ALZHEIMER’S DISEASE." Doctoral thesis, Università degli Studi di Palermo, 2020. http://hdl.handle.net/10447/395023.
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Yin, Haishan. "Triggers and enhancers of tau aggregation implication for AD pathogenesis /." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1155315408.
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ZONA, CRISTIANO. "Design and systhesis of nanoparticles for therapy and imaging of Alzheimer's disease." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2011. http://hdl.handle.net/10281/19222.
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Various types of nanoparticles (NPs), such as Liposomes, Solid Lipid NPs and Polymeric NPs, are being extensively explored for their potentialities in the medical field. NPs are attractive tools in biomedical applications thanks to their biocompatibility, non-immunogenicity, non-toxicity, biodegradability, high physical stability, possibility of drug loading and releasing, and higher probability for surface functionalization.
The project is devoted to the synthesis of NPs functionalized with amyloid-beta ligands (Aβ-ligands), imaging tools and/or blood brain barrier-transporters (BBB-transporters) for the cure and the diagnosis of Alzheimer’s disease (AD).
Amyloid β (Aβ) aggregates are considered as possible targets for therapy and/or diagnosis of Alzheimer disease (AD). It has been previously shown that some small molecules targets Aβ plaques and, among them, curcumin interacts with their precursors, suggesting a potential role for the prevention or the treatment of AD. Herein, a chemoselective ligation procedure was used to generate NPs decorated with a curcumin derivative, designed to maintain all the features required for interaction with Aβ. In summary, this thesis describes the preparation and characterization of new curcumin derivatives and NPs, with affinity for Aβ peptide. They could be exploited as ligands and/or vectors for the targeted delivery of new diagnostic and therapeutic molecules for AD.
The NPs preparations and the biological results were obtained in collaboration with scientists involved in a joint European project:
NAD - Nanoparticles for therapy and diagnosis of Alzheimer’s Disease - 2008-2012, FP7-NMP-2007-LARGE-1-Large-scale integrating project NMP-2007-4.0-4 Substantial innovation in the European medical industry: development of nanotechnology-based systems for in-vivo diagnosis and therapy.
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Wu, Jinfang. "Alzheimer's disease (AD) like pathology following developmental lead exposure in primates and the role of aging in AD-related genes regulation in rodents and primates /." View online ; access limited to URI, 2008. http://0-digitalcommons.uri.edu.helin.uri.edu/dissertations/AAI3314462.
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Forsström, Karin. "Longitudinal Changes in Astroglial and Inflammatory Markers in Patients with MCI and AD." Thesis, Uppsala universitet, Institutionen för farmaceutisk biovetenskap, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-192975.
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Since neuroinflammation is present in patients with mild cognitive impairment (MCI) andAlzheimer's disease (AD) and since cholinesterase inhibitors increases the level ofacetylcholine, the aim was to investigate whether inflammatory markers of cholinoceptive cellsare affected in these patients. Near a biological hallmark of AD, amyloid plaque, activatedastrocytes and microglia can be found and higher levels of proinflammatory cytokines, i.e. IL-1β. To study the inflammatory response, proteins GFAP and S100B are used as CSF glialmarkers. IL-1β can bind to the membrane-bound IL-1 receptor or soluble sIL-1β-RII. When IL-1β binds to the soluble receptor instead of the membrane-bound receptor, no intracellular signalpropagation occur, thereby sIL-1βRII exerts an antagonistic effect and diminishedinflammatory responses. Thus a reduction in ratio of IL-1β to sIL-1RII levels may be indicativeof anti-inflammatory response. Available data on CSF GFAP, S100B, IL-1β and sIL-1β-RIIlevels in AD patients and MCI patients was used. MCI group were longitudinally followedafter start of treatment with a cholinesterase inhibitor (ChEI). AD group had data from baselineand after short-term treatment with a ChEI. The statistics application StatView was used toanalyse data. The activity of the cholinesterase enzymes, BuChE and AChE showed significantinhibition in the CSF of the MCI patients compared to baseline CSF GFAP level wassignificantly lower in MCI than AD patients at baseline. The levels of both GFAP and S100Bwere increased with time in MCI patients to comparable levels in the AD patients, indicative ofastroglial activation in MCI patients. However, the ratio of IL-1β to sIL-1RII showed alongitudinal reduction in the MCI patients after the treatment with the ChEIso that this ratiowas significantly higher in AD than in MCI patients. Thus despite the activation of astroglialcells in the treated MCI patients the proinflammatory effect of IL-1β was prevented byinduction of sIL-1βRII levels indicative of an anti-inflammatory outcome of treatment. Thisstudy suggests that proper activation of astroglial cells may have beneficial effect on ADpathogenesis, and conversion of MCI to AD. It also suggests that cholinesterase inhibitors may have an anti-inflammatory effect.
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Güell, Bosch Jofre. "Diagnòstic i monitorització de la malaltia d’Alzheimer mitjançant tècniques de ressonància magnètica in vivo en el model 3xTg-AD: Avaluació de l’eficàcia del tractament longitudinal amb dos fragments d’anticòs contra el pèptid Aβ". Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/457363.
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La malaltia d’Alzheimer (AD) és, actualment, una malaltia incurable que afecta la major part dels 47 milions de persones que s’estima que pateixen demència arreu del món. Tot i que els mecanismes que donen lloc a desenvolupar l’AD no estan ben definits, hi ha un consens bastant ampli en acceptar la hipòtesi de la cascada amiloide, la qual situa el pèptid Aβ o, més concretament, els oligòmers que forma aquest pèptid, com els responsables principals de l’inici del procés neuropatològic que porta a l’AD.
En els últims anys la immunoteràpia anti-Aβ s’ha erigit com una eina esperançadora per tractar la malaltia. Una de les estratègies és la utilització dels fragments variables de cadena senzilla (scFv), els quals eviten els efectes del fragment cristal·litzable (Fc), que es creu que desencadena una resposta de la micròglia que pot donar lloc a microhemorràgies i edemes vasogènics, com va passar en assajos clínics amb el bapineuzumab, un anticòs sencer dirigit contra l’extrem N-terminal del pèptid Aβ, del qual deriven els scFv-h3D6-WT i scFv-h3D6-EL produïts en el nostre grup de recerca.
En aquesta tesi s’ha tractat longitudinalment el model murí d’AD, 3xTg-AD, amb 1 dosi intraperitoneal mensual de 100 μg de scFv-h3D6-WT, EL o PBS, des dels 5 fins als 12 mesos, edat en la qual s’han sacrificat els ratolins i s’han emmagatzemat les mostres per a poder realitzar anàlisis histològiques i bioquímiques. Durant el tractament, s’han realitzat 4 sessions de monitorització dels animals utilitzant tècniques d’imatge i espectroscòpia per ressonància magnètica (MRI/MRS) als 5, 7, 9 i 12 mesos.
D’una banda, s’ha pogut caracteritzar el 3xTg-AD utilitzant paràmetres in vivo derivats de les tècniques de MRI i MRS, i ex vivo, a partir d’anàlisis bioquímiques i histològiques. Així, s’ha observat que el 3xTg-AD presenta, entre d’altres característiques, un volum més petit en gairebé totes les regions cerebrals i edats analitzades, un increment de l’Aβ tan intra com extracel·lular als 12 mesos i un increment en la inflamació a aquesta mateixa edat, tan a l’hipocamp (IL-6 i mIns) com al còrtex (IL-6).
D’altra banda, s’han pogut analitzar els efectes que els tractaments amb scFv-h3D6-WT o EL provoquen en aquest model i s’ha observat com la variant WT és capaç de recuperar, parcialment, els valors de volumetria, Aβ, IL-6 i mIns, entre d’altres. La variant EL, en canvi, no sembla tenir efectes en volumetria, però sí en les anàlisis histològiques, especialment a l’hipocamp on, fins i tot, aquest efecte sembla superior al del WT.
Per últim, s’han realitzat dos estudis complementaris consistents en (1) aproximar la visualització d’edema vasogènic mitjançant l’administració de l’anticòs sencer mAb-m3D6 i (2) exportar algunes de les tècniques posades a punt, a un projecte extern que té per objectiu veure l’eficàcia de les diferents combinacions de tractaments entre el scFv-h3D6-WT i 2 pèptids mimètics de les apolipoproteïnes E i J.
En resum, aquesta tesi aporta nova informació sobre l’eficàcia i seguretat de dos scFvs contra el pèptid Aβ en el seu afany per combatre l’AD, a l’hora que ajuda a caracteritzar el model 3xTg-AD, aportant informació que, de ben segur, serà molt útil en la recerca preclínica d’aquesta devastadora malaltia.<br>Alzheimer’s disease (AD) is an incurable disease that affects most the 47 million people estimated as living with dementia worldwide. Although the exact mechanisms that drive to AD development are not well known, a wide consensus exists to accept the amyloid cascade hypothesis, which claims that the Aβ peptide oligomers are the main responsible for the triggering of the neuropathological process leading to the disease.
In recent years, Aβ-immunotherapy has been revealed as a hopeful tool in AD treatment. One strategy consists of using single-chain variable fragments (scFvs), which avoid the fragment cristallizable (Fc) effects that are supposed to trigger the microglial response, giving place to microhemorragies and vasogenic edemas, as happened in clinical trials with bapineuzumab. The scFv-h3D-WT and the scFv-h3D6-EL generated in our research group derivate from this antibody targeting the N-terminal of the Aβ peptide.
In the present thesis, 3xTg-AD mice were treated with a 100 μg intraperitoneal monthly dose of scFv-h3D6-WT, EL or PBS, from 5 to 12 months, age at which mice were sacrificed and samples were collected to perform histological and biochemical analyses. During the therapy, 4 monitoring sessions using magnetic resonance image and spectroscopy (MRI/MRS) were performed at 5, 7, 9 and 12 months.
On the one hand, a 3xTg-AD mouse model characterization using the in vivo parameters from MRI/MRS techniques and the ex vivo ones from histological and biochemical analyses has been done. Thus, we have observed that 3xTg-AD presents a smaller volume in almost all cerebral regions and ages examined, an increase in both intra and extracellular Aβ at 12 months, and an inflammation process at this age, in both hippocampus (IL-6 and mIns) and cortex (IL-6).
On the other hand, the effects of both scFv-h3D6-WT and EL have been tested in this model. The WT variant seems to partially recover the values in brain volume, and in Aβ, IL-6 and mIns concentrations, among others. In contrast, the EL variant does not seem to affect the brain volume values. However, it does seem to have positive effects in histology, especially in the hippocampus region, where its effect seems to be greater than the one caused by the WT.
Finally, two complementary studies have been carried out in order to (1) visualize a vasogenic edema by treating the 3xTg-AD with the full-length antibody mAb-m3D6, and (2) to export some of the set up techniques to another project, which aims to study the efficacy of combining the scFv-h3D6-WT treatment with E and J apolipoprotein mimetic peptides.
To sum up, this thesis provides new information about the efficacy and security of two scFvs targeting Aβ peptide in their way to fight AD and, at the same time, it provides new insights in 3xTg-AD characterization, releasing new information which will be very helpful for AD preclinical research.
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Escrig, Monfort Anna. "Interleukin-6 trans-signaling in Alzheimer's disease. A study based on the Tg2576 and 3xTg-AD mouse models." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667955.
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YIN, HAISHAN. "Triggers and enhancers of tau aggregation: implication for ad pathogenesis." The Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=osu1155315408.
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DA, RE FULVIO. "An MRI-based analysis of the longitudinal progression of atrophy in amnestic and non-amnestic phenotypes of Alzheimer’s disease." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2020. http://hdl.handle.net/10281/261941.
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Recenti studi sulla progressione della malattia d’Alzheimer(AD)suggeriscono che la patologia possa essere trasmessa da un’area all’altra del cervello tramite diffusione locale o lungo le fibre assonali.Tuttavia,quest’ipotesi necessita di maggiori conferme ed è ancora meno chiaro se questi modelli possano essere applicabili alle varianti non amnesiche di AD(naAD),un gruppo di fenotipi AD caratterizzati da relativo risparmio all’esordio della memoria episodica e deficit cognitivi dominio-specifici.Pochi studi ad oggi hanno infatti analizzato la progressione longitudinale della malattia in naAD, tutti al massimo con due sole di queste varianti.
Inizialmente abbiamo confrontato 240 RMN pesate in T1 da 129 pazienti AD con RMN di controlli sani per stabilire l’atrofia in 120 regioni di interesse(ROI); poi abbiamo calcolato modelli di progressione di malattia separatamente per ogni fenotipo: AD amnesici(aAD),variante logopenica di afasia primaria progressiva(lvPPA),atrofia corticale posteriore(PCA)e variante frontale di AD(fvAD).Tutti i pazienti avevano evidenza di patologia AD tramite dati autoptici o da liquor cefalorachidiano(CSF).I risultati dalla coorte di aAD sono stati utilizzati per determinare i parametri per l’algoritmo di assegnazione delle fasi,basato sull’associazione con lo staging di patologia di Braak.
Per ogni variante AD,4 fasi di atrofia regionale sono state definite sulla base della frequenza decrescente di atrofia tra i soggetti.Abbiamo osservato pattern unici di atrofia cumulativa per ogni fenotipo.Le ROI di fase 1 nel nostro modello rappresentano l’origine anatomica di ogni fenotipo,inclusi: il lobo temporale mesiale(MTL)per il gruppo aAD(risparmiato negli altri gruppi),il lobo temporale sinistro nella lvPPA,la corteccia parieto-occipitale nella PCA,quella temporo-parietale per la CBS e le aree fronto-temporali per la fvAD.Successivamente abbiamo assegnato una fase ad ogni RMN dei pazienti in base alla somiglianza dei pattern di atrofia regionale con l’atrofia predetta per il fenotipo corrispondente ad ogni fase.Le fasi ROI erano correlate con parametri patologici disponibili,mentre le fasi RMN erano correlate con misure demografiche e cliniche.
Dopodiché abbiamo deciso di studiare le modifiche nel tempo della sostanza grigia(GM)in una coorte di pazienti in parte sovrapposta a quella usata per lo studio trasversale,ad esclusione di CBS: 17 aAD,25 lvPPA,20 PCA e 12 fvAD,con 37 controlli abbinati.Abbiamo analizzato il volume della GM e le sue modifiche longitudinali nelle ROI di fase 1 dallo studio trasversale per naAD e l’MTL per aAD.Abbiamo anche studiato l’atrofia longitudinale al di fuori di queste aree tramite un’analisi accessoria all’intero cervello e abbiamo comparato i fenotipi tra loro.
Abbiamo osservato pattern regionali unici di atrofia iniziale e diffusione longitudinale nella neocorteccia con tassi differenti in lvPPA,PCA e fvAD,che correlavano con i deficit cognitivi.La progressione di atrofia nel tempo ha coinvolto aree sia prossimali sia distanti dal sito d’esordio della malattia,suggerendo quindi più meccanismi di diffusione della patologia coinvolti; per quanto riguarda il secondo,in particolare,una misura di connettività strutturale prediceva la severità di atrofia longitudinale,corroborando quindi l’ipotesi delle vie lunghe.Nell’MTL,i pazienti naAD mostravano al basale meno atrofia dei pazienti aAD,ma i tassi longitudinali non erano diversi tra gruppi; il relativo risparmio dell’MTL in naAD potrebbe quindi essere dovuto a un esordio più tardivo della degenerazione nell’MTL rispetto all’aAD,considerando che l’età più avanzata era associata con atrofia in quest’area,indipendentemente dal gruppo.
Il presente studio ha corroborato probabili aree di malattia precoce in naAD e mostrato che ogni fenotipo ha un diverso pattern di progressione di atrofia lungo la corteccia,fornendo anche dati importanti sulla trasmissione della patologia.<br>Recent studies of Alzheimer’s disease (AD) spread suggest that pathology may be transmitted from one brain area to another either via local diffusion or long-way transport via white matter pathways. However, this hypothesis requires more confirmations, and it’s even more unclear whether such models are applicable in non-amnestic AD (naAD), a group of AD phenotypes characterized by relative spared episodic memory at onset and domain-specific cognitive impairments. Few studies to date have in fact addressed the longitudinal spread of disease in naAD, and all of them considering no more than two variants.
At first we compared 240 T1-weighted anatomical MRIs from 129 AD patients with elderly controls’ scans to assess atrophy in each of 120 regions-of-interest (ROIs); then we computed disease progression models separately for each phenotype: typical amnestic AD (aAD), logopenic variant primary progressive aphasia (lvPPA), posterior cortical atrophy (PCA), corticobasal syndrome (CBS), and frontal-variant AD (fvAD). All patients had autopsy or cerebrospinal fluid (CSF) evidence of AD pathology. Results from the amnestic cohort were used to determine appropriate parameters for the phase assignment algorithm, based on association with Braak pathology staging.
For each AD variant, 4 phases of regional atrophy were defined based on decreasing frequency of atrophy across participants. We observed a unique distribution of accumulating atrophy for each phenotype. Phase 1 ROIs in our model represent the anatomical origin for each phenotype, including: medial temporal lobe (MTL) for the aAD group (spared in the other phenotypes), left lateral temporal lobe for lvPPA, occipito-parietal cortex for PCA, temporo-parietal cortex for CBS, and fronto-temporal cortex for fvAD. We subsequently assigned a phase to each patient MRI scan based on the similarity of regional atrophy patterns with atrophy predicted for the corresponding phenotype at each phase. ROI phases were strongly correlated with available pathological factors, while MRI phase was significantly correlated with demographic and clinical measures.
Then we decided to investigate grey matter (GM) change over time in MRIs within a cohort of patients partly overlapping with the sample used for the cross-sectional study, with the exception of CBS patients (insufficient longitudinal data): 17 aAD, 25 lvPPA, 20 PCA, and 12 fvAD patients, compared to 37 matched controls. We analyzed GM volume and its longitudinal change in phase 1 ROIs from the cross-sectional study for naAD variants, and in MTL for aAD. We also investigated longitudinal atrophy outside these areas through an accessory whole-brain analysis, and we compared phenotypes between each other.
We observed unique regional patterns of initial atrophy and longitudinal neocortical disease spread with different rates in lvPPA, PCA, and fvAD, which correlated with cognitive impairments. Atrophy spread over time included both proximal and distant regions from the hypothesized focus of disease onset, thus suggesting that multiple mechanisms of disease progression may have been involved; for what concerns the second mechanism, in particular, a measurement of structural connectivity predicted the severity of longitudinal atrophy, thus corroborating the hypothesis of long-distance fiber pathways. In MTL regions, naAD patients had less severe atrophy than aAD patients at baseline, but longitudinal rates did not differ between groups; MTL sparing in naAD may be due to later onset of MTL degeneration than in aAD, considering that older age was associated with atrophy in this area, independent of group.
The current study corroborated probable areas of early disease for naAD and showed that each phenotype has a different pattern of atrophy progression across the cortex, providing also important data about pathology transmission.
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Leighty, Ralph E. "Statistical and data mining methodologies for behavioral analysis in transgenic mouse models of Alzheimer's disease : parallels with human AD evaluation." [Tampa, Fla] : University of South Florida, 2009. http://purl.fcla.edu/usf/dc/et/SFE0002869.
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Alsulami, Ohud. "Exploring the Relationship of Knowledge and Perceptions/Attitudes of Alzheimer's Disease (AD) with Perceived Experiences of Working with AD Patients Among Caregivers at Long-Term Care Facilities." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2018. http://digitalcommons.auctr.edu/cauetds/127.
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This study examines how knowledge, perceptions, and attitudes of Alzheimer’s disease (AD) are associated with experiences of caregivers working with AD patients at long-term care facilities in the United States. This study was found understanding the relationships is important to provide a quality of healthcare services for optimal health outcomes among AD patients. This study employed a cross-sectional paper-pencil survey to collect the data. The survey asked participants to self-report quantitative information as to social demographics, knowledge, perceptions, and attitudes (independent variables) of AD, and perceived experiences (dependent variable) of caregivers working with AD patients at long-term care facilities. This result showed positive relationship between the perceived experience of the AD caregivers and all the three variables. While the relationships were not significant. The findings of the study provided implications for scale work practice, police, and research.
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Dhaynaut, Maëva. "PET imaging for the characterization of tauopathies : Alzheimer's disease and chronic traumatic encephalopathy." Electronic Thesis or Diss., Sorbonne université, 2019. http://www.theses.fr/2019SORUS197.
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Les tauopathies sont des maladies neurodégénératives caractérisées par une agrégation intracérébrale de protéines Tau anormales. Au cours de ce travail doctoral, nous avons étudié par tomographie par émission de positons (TEP) l'imagerie des agrégats Tau dans la maladie d'Alzheimer (MA) et l'encéphalopathie traumatique chronique (ETC). Notre premier objectif était de déterminer la capacité de l’imagerie Tau-TEP à améliorer le diagnostic de la MA et de déterminer la viabilité d’un nouveau traitement potentiel. Nous avons établi que l'imagerie Tau-TEP était capable de détecter l'effet bénéfique d'une stimulation cérébrale non invasive, appelée stimulation transcrânienne à courant alternatif (tACS) chez les personnes atteintes de MA. Notre deuxième objectif était de déterminer l'utilité de l'imagerie Tau in vivo dans une population de joueurs de football américains pour aider à la détection précoce de l’ETC. Nous avons démontré que l’imagerie Tau était en mesure de mettre en évidence les premières étapes de la maladie. En outre, nous avons étudié par autoradiographie post-mortem chez des patients diagnostiqués MA et ETC, le schéma de liaison de [18F]-AV-1451 avec [18F]-MK-6240 et [18F]-PI-2620 dans les mêmes échantillons. Ces trois traceurs ont montré un modèle similaire de forte liaison à la protéine Tau dans la MA et un manque de liaison dans le cas de l’ETC. Au total, ces expériences ont permis de confirmer l'utilité potentielle de l’imagerie Tau-TEP pour la détection, quantification des agrégats de Tau avec le suivi de la progression de la maladie dans la MA, tout en restant incertain pour l’ETC<br>Tauopathies are neurodegenerative diseases characterized by intracerebral aggregation of abnormal Tau proteins. During this university thesis, we studied by Positon Emission Tomography (PET) imaging the Tau burden in Alzheimer’s Disease (AD) and Chronic Traumatic Encephalopathy (CTE), two different taupotahies with similar Tau isoforms. In this context, our first objective was to determine the ability of Tau PET imaging to improve the diagnosis of AD and to determine the viability of a new potential treatment. We have established that Tau PET imaging was able to detect the beneficial effect of a non-invasive brain stimulation, called transcranial alternating current stimulation (tACS) in people with AD. Our second objective was to determine the usefulness of Tau PET imaging in vivo in a population of American football players to help the early detection of CTE. We have demonstrated that in our population, Tau PET imaging was able to highlight the Tau pathology in early stages of CTE. In parallel, we have studied by autoradiography post-mortem from patients with neuro-pathological diagnosis of AD and CTE the binding pattern of three radiotracers widely used in research for Tau imaging. We directly compared the binding properties of [18F]-AV-1451 with [18F]-MK-6240 and [18F]-PI-2620 in the same specimens. These three tracers showed similar strong binding pattern to Tau protein in AD and a lack of binding in CTE brain slices. In total, these experiments allow to confirm the potential utility of Tau PET tracers for the reliable detection, quantification of Tau aggregates and disease-progression tracking in AD, while it remains questionable for CTE
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Staley, Lyndsay Ann. "Analysis of Whole Exome Sequence Data in Affected Cousin Pairs from High-Risk Alzheimer's Pedigrees." BYU ScholarsArchive, 2018. https://scholarsarchive.byu.edu/etd/7332.
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Genetic factors account for about half of Alzheimer<'>s Disease (AD) risk and only about a quarter of that heritability is accounted for by known variants. Family based approaches to understanding AD genetics may be an effective way to identify additional risk factors. Here we report the results of whole exome sequencing (WES) and analyses done on pairs of AD affected cousins from 19 families from the Utah Population Database (UPDB) with a statistical excess of AD risk. WES variants passing quality control were additionally filtered by population frequency (minor allele <<> 0.01) and concordance between cousin pairs, resulting in 564 variants shared by at least one pair of cousins. For each of these variants we conducted in depth annotations using Ingenuity Variant Analysis (IVA), Wellderly Data Allele Frequencies, and literature searches. To further aid in variant prioritization we analyzed each variant for association with Age at Onset of AD, AD Risk, CSF AB42, CSF Tau, CSF PTau and Rate of Disease Decline in data from the Alzheimer<'>s Disease Genetics Consortium (ADGC) and from the Knight Alzheimer<'>s disease research center. Statistical analyses were conducted using PLINK. Twelve variants (rs201665195, rs28933981, rs148294193, rs147599881, rs61729902, rs140129800, rs191804178, rs200290640, rs199752248, rs45541434, rs141402160 and rs140914494) in eight genes (ABCA7, TTR, PELI3, FCHO1, SNAP91, COX6A2, MUC16, PIDD1, SYT5 and NOTCH3) were prioritized using a clear pipeline of IVA filters and the additional analysis information. We propose that these genes and variants are the most interesting for follow-up based on current knowledge.This family-based approach to finding rare AD variants adds to a growing body of research suggesting a role for NOTCH3 in late-onset AD. This approach replicated two known AD risk variants and also implicated novel putative risk AD variants and genes. These results suggest that further application of this method of using pairs of cousins may result in additional insights into AD genetics and the ability to find novel rare, causal AD variants.
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Zamboni, Giovanna. "Structural and functional magnetic resonance imaging (MRI) in the prediction and characterization of mild cognitive impairment (MCI) and Alzheimer's disease (AD)." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:8cdd8320-1243-4f85-928c-b03fd4bd1201.
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The aim of the research presented in this thesis was to improve the characterisation of the changes in brain structure and function that occur at different stages of Alzheimer’s disease (AD) progression, from pre-symptomatic AD, to mild cognitive impairment (MCI), to clinically evident dementia, using magnetic resonance imaging (MRI) techniques. Baseline structural MRI data from a cohort of healthy older adults who were followed prospectively for ten years, during which time some developed MCI and some AD, were analysed. It was found that structural MRI could detect volume loss in medial-temporal lobes up to 7-10 years before clinical symptoms of AD appear. In addition, volumetric variability of medial-temporal regions detected by structural MRI across cognitively healthy older adults correlated with their performance on a task of visuospatial associative memory, and functional activation of the same regions occurred during successful performance of the same task on functional MRI (fMRI). Three groups of participants - cognitively healthy controls, people with MCI, and patients with probable AD - were then recruited and underwent a multimodal MRI protocol, which included functional sequences acquired at rest and during the execution of two different cognitive tasks (visuospatial associative memory and self-appraisal). Cross-sectional comparisons showed: (i) that successful visuospatial associative memory performance was associated with increased functional activity (measured with task fMRI) in lateral prefrontal regions in AD patients relative to controls and (ii) that increased functional activity overlapped with frontal brain networks showing increased functional connectivity (measured with resting fMRI) in the same AD patients. Further, by demonstrating group- and condition-specific decreased frontal activity in AD patients relative to controls during a self-appraisal fMRI task, it was shown the specific utility of fMRI to unravel cognitive mechanisms underlying specific neuropsychological symptoms such as unawareness of cognitive impairment (anosognosia) in MCI and AD. In conclusion, structural MRI can detect morphological changes in the preclinical stage of AD, possibly earlier than previously described, and these reliably match cognitive functioning in older adults. In the MCI and AD stages, once symptoms of cognitive impairment are clinically evident and measurable, task-related and resting functional MRI can inform on residual brain function detectable over and above the known changes in brain morphology and cognitive performance that have already occurred at these stages, emerging as a sensitive marker of residual ability that could potentially be used to measure the effect of new treatments.
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Bai, Ge. "Cell Permeability Studies of AApeptides and Novel Molecular Probes for AD." Scholar Commons, 2016. http://scholarcommons.usf.edu/etd/6173.
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Alzheimer's diseases(AD) has been discovered and under research for more than 70 years, However there is no cure for these progressive and devastating diseases. Based on the following hypothsis: Aß metabolite problem/over production result in the accumulation, and lead to aggregation is the cause of Alzheimer’s disease. AApeptide and Melatonin derivatives can bind to Aß and block the aggregation of β amyloid monomers, decrease the toxicity of Aß to neurons and slow the progressive of Alzheimer’s diseases. In addition, AApeptide which mimic transmembrane peptide Tat will have similar transmembrane function. We have set up our goals as follows: 1) Using newly discovered peptidomimetics, AApeptides. We moved on to research to discover their potential of transmembrane activity and anti-Alzheimer's acitiviy. 2) In Addition, studies of small molecule melatonin derivatives were also progressed. Methods include in this research includes bioorganic synthesis, identification of spectroscopy and relative assays targeting on biological efficiency of Anti-Alzheimer’s diseases. The details of which will be described in Chapters. In conclusions, two sets of transmembrane peptidomimetics for drug transportation has been successfully evaluated and potential of AA peptide small molecules, melatonin derivativesare also evaluated. These works have gained good progress in research between AApeptide and Alzheimer’s Diseases. These works also established basis of research in developing peptidomimimetics as potential pharmacies against Alzheimer’s diseases.
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PACE, LORENZO. "Behavioral and neurochemical effects of Palmitoylethanolamide in a murine model of Alzheimer’s Disease." Doctoral thesis, Università di Foggia, 2016. http://hdl.handle.net/11369/338930.
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Abstract
La malattia di Alzheimer è la forma più comune di demenza degenerativa progressivamente invalidante con esordio prevalentemente in età presenile.
Si stima che circa il 60-70% dei casi di demenza sia dovuta a Alzheimer disease (AD). AD è una patologia multifattoriale caratterizzata sia da placche senili extracellulari, costituite dall’accumulo della proteina amiloide, sia da grovigli neurofibrillari intracellulari, composti da filamenti Tau patologici (NFTs).
Inoltre nell’Alzheimer vi è anche perdita neuronale soprattutto a livello delle aree cerebrali che sottendono i processi di apprendimento e memoria, come per esempio la corteccia frontale e l’ippocampo.
L’eziologia dell’AD sembra essere legata a vari meccanismi che non sono stati ancora completamente chiariti. Allo stato attuale, non esistono terapie in uso clinico in grado di influenzare efficacemente il decorso della malattia.
Alla luce della complessità della patologia e ovvio pensare che i nuovi farmaci, per essere ritenuti farmacologicamente promettenti, dovrebbero agire contemporaneamente sui vari meccanismi patogenetici coinvolti nell’AD.
A tal proposito, l'obiettivo di questo progetto di ricerca è stato quello di verificare se la Palmitoiletanolamide (PEA) è in grado di modulare i sintomi presenti nella malattia di Alzheimer.
Per gli obiettivi del progetto, è stato utilizzato un modello transgenico murino della patologia di Alzheimer ed il rispettivo gruppo controllo, non transgenico (NonTg).
I topi transgenici, creati nei laboratori del prof. La Ferla (University of California, Irvine, USA) hanno tre geni umani mutanti (APPswe, PS1M146V, e tauP301L), per questo indicati come 3×Tg-AD, e sono considerati tra i modelli animali di malattia di Alzheimer che meglio simulano la patologia riscontrata nell’uomo.
Infatti, i 3×Tg-AD sono in grado di sviluppare le placche amiloidi e NTF in maniera tempo dipendente, nelle regioni target del cervello, simulando così la progressione della malattia riscontrata negli esseri umani.
Nel nostro protocollo sperimentale, topi a 3 mesi (che presentavano i primi segni di alterazioni neuropatologiche) e 9 mesi (che presentavano evidenti segni di alterazioni neuropatologiche) di vita sono stati trattati con Palmitoiletanolamide (PEA) per 90 giorni e, alla fine del trattamento cronico, i topi sono stati sottoposti a diversi test comportamentali per valutare un eventuale effetto sui deficit cognitivi e non cognitivi riscontrati nel modello transgenico preso in esame.
Alla fine dei test comportamentali gli animali sono stati sacrificati per determinare, mediante analisi di biologia molecolare, l'effetto del trattamento sulle alterazioni istopatologiche tipiche della AD.
I risultati dello studio hanno dimostrato che la PEA è in grado di migliorare le funzioni cognitive e non cognitive nei topi 3×Tg-AD a 6 mesi di vita, mentre sui topi a 12 mesi di vita ha mostrato un miglioramento significativo solo sulla memoria a breve termine.
Circa gli effetti della PEA sulla patologia Aβ e tau nei topi 3xTg-AD, lo studio ha dimostrato che la PEA riduce in modo significativo i livelli di APP nella corteccia di topi 3×Tg-AD a 6 mesi e, cosa ancor più interessante, diminuisce anche i livelli di Aβ*56, un oligomero di Aβ.
Inoltre, il trattamento cronico con PEA ha indotto una significativa riduzione della fosforilazione di tau nei residui di fosforilazione 202/205.
Questi risultati suggeriscono, pertanto, che il miglioramento delle funzioni cognitive e non cognitive potrebbe essere ascritto alle variazioni sui livelli complessivi di Aβ e di tau indotti dal trattamento cronico con PEA. Inoltre, non abbiamo trovato cambiamenti significativi nei topi 3×Tg-AD per quanto riguarda i marcatori neuroinfiammatori presi in considerazione, come, ad esempio, COX-2 o marcatori di attivazione astrocitari e/o microgliali.
Certamente ulteriori studi saranno necessari per determinare i meccanismi molecolari alla base degli effetti della PEA.
In conclusione, i nostri dati indicano che il trattamento cronico con PEA potrebbe essere efficace nelle fasi precoci della patologia, ovvero quando l’accumulo di Aβ è nelle sue fasi iniziali ed i danni nel sistema nervoso centrale sono ancora lievi.
Abstract in English
Alzheimer’s disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. At present, no therapies in clinical use are able to effectively impact the disease course. Therefore, new drugs able to simultaneously ameliorate the numerous pathogenic mechanism involved in AD are therapeutically promising.To this regard, the aim of this research project was to investigate whether the Palmitoylethanolamide (PEA), an endogenous fatty acid amide, might modulate the symptoms of the AD.
To this aim, the triple transgenic mouse model of AD (3xTg-AD) and wild type littermate (NonTg) have been used. The 3×Tg-AD mice harbor three mutant human genes (APPswe, PS1M146V, and tauP301L) and are one of the most thoroughly characterized model of AD. The 3×Tg-AD mice develop amyloid plaques and NTF pathology in a hierarchical manner in AD-relevant brain regions, and closely mimic the disease progression in humans.
The mice at 3-months and 9-months of age have been treated with PEA for 90 days and, at the end of treatment, they were subjected to different behavioral tests in order to investigate their mood and learning/memory domains. At the end of behavioral tests the animals were sacrified to determine, by biochemical analyses, the effect of treatment on neuropathological and neuroinflammatory hallmarks.
Interestingly PEA is able to improve cognitive and non-cognitive functions in 3×Tg-AD at 6 months of age, while has only effect on short-term memory in transgenic mice at 12 months of age.
The present work provides also an extensive investigation of the effect of PEA treatment on the onset and progression of Aβ and tau pathology in 3×Tg-AD
mice. We showed that PEA significantly reduces the levels of full-length APP in cortex of 6-month-old 3×Tg-AD mice and, more interestingly, it decreases also the levels of Aβ*56, an Aβ oligomer. Similarly, PEA treatment is able to reduce steady-state levels of full-length APP also in 3×Tg-AD mice at 12 months of age, suggesting that it could modulate APP processing in these animals.
Interestingly, PEA treatment is also associated with a significant reduction in tau phosphorylation at residues 202/205. These results suggest that cognitive improvement is probably due to changes in overall Aβ levels and tau pathology or to a mixture of both hallmarks.
Furthermore, we did not find significant changes in almost all neuroinflammatory markers taken into account, such as COX-2 or in microglial/astrocytic activation markers.
Although further studies are needed to determine the molecular mechanisms underlying the beneficial effects of PEA against AD neuropathology, our data indicate that the compound may be effective in early AD or when Aβ is accumulating and initiating damage in the central nervous system.
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Borba, Ericksen Mielle. "Associação dos níveis de BDNF com volume do hipocampo no comprometimento cognitivo leve e na doença de Alzheimer." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2016. http://hdl.handle.net/10183/148073.
Full textAbstract:
Introdução: Perda de memória é um dos sintomas mais comuns em pacientes nos estágios iniciais da doença de Alzheimer; esses déficits são um reflexo do envolvimento da formação do hipocampo. O BDNF tem sido relacionado com a plasticidade do hipocampo. Neste sentido, as combinações de biomarcadores, como, por exemplo, a volumetria do hipocampo, pode apresentar um maior valor preditivo para diferenciar doença de Alzheimer do envelhecimento normal em pacientes com comprometimento cognitivo leve. Objetivo: A presente tese de doutorado teve como objetivo avaliar os níveis séricos do BDNF e o volume do hipocampo em pacientes com demência devido à doença de Alzheimer, Comprometimento Cognitivo Leve (CCL) e idosos saudáveis. Métodos: Para realização do estudo foram selecionados 10 idosos saudáveis, 10 CCL e 13 pacientes com demência devido à doença de Alzheimer pelos critérios NIA-AA. Todos participantes foram submetidos a uma avaliação cognitiva. Para as análises do BDNF, foi utilizado método de ELISA e para as análises de volumetria do hipocampo as imagens foram obtidas por meio de equipamento de ressonância de 1.5T e os volumes obtidos por meio do programa NeuroQuant®. Resultados: Idosos saudáveis apresentaram níveis séricos mais elevados de BDNF do que os CCL e pacientes com demência. O grupo de pacientes com demência apresentou menor volume total do hipocampo do que os idosos saudáveis e os CCL. Não houve correlação significativa do BDNF sérico com volume do hipocampo. Conclusão: Considerando nossos resultados em conjunto (baixos níveis de BDNF nos grupos CCL e demência devido à DA e menor volume do hipocampo na demência devido à AD), podemos supor que a diminuição dos níveis de BDNF ocorre antes da lesão neuronal expressa pela redução do hipocampo.<br>Introduction: Memory impairment is the most common symptom in patients in the early stages of Alzheimer's disease; this deficit is a reflection of the involvement of the hippocampal formation. BDNF has been linked to the hippocampal plasticity. Combinations of biomarkers, such as the hippocampal volumetry may have higher predictive value for differentiating Alzheimer's disease from normal aging in patients with mild cognitive impairment. Objective: The objective of present thesis was to evaluate serum levels of BDNF and hippocampal volume in patients with Mild Cognitive Impairment (MCI) and dementia due to Alzheimer's disease, and healthy elderly participants. Method: Ten healthy elderly subjects, 10 MCI and 13 patients with dementia due to Alzheimer's Disease (NIA-AA criteria) were selected for the study. All participants were assessed cognitively. The ELISA method was used for BDNF analysis, and the analysis of hippocampal volumetric images were acquired with 1.5T magnetic resonance equipment and volumes obtained with NeuroQuant® program. Results: Healthy elderly had higher BDNF serum levels than MCI and dementia due to AD patients. The group of dementia patients had lower total hippocampal volume than MCI and healthy elderly participants. No significant correlation between serum BDNF and hippocampal volume was observed. Conclusion: Taking our results together (lower BDNF levels in MCI and dementia due to AD and smaller hippocampal volume in dementia due to AD) we can hypothesize that the decrease of BDNF may start before the establishment of neuronal injury expressed by the hippocampal reduction.
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LOSURDO, MORRIS. "A NEW HOPE FOR ALZHEIMER’S DISEASE FROM PRECONDITIONED BONE MARROW MESENCHYMAL STEM CELL-DERIVED EXTRACELLULAR VESICLES: ANALYSIS OF THE IMMUNOMODULATORY EFFECTS." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2019. http://hdl.handle.net/10281/241093.
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La malattia di Alzheimer (AD), la forma più comune di demenza senile, è caratterizzata da una progressiva degenerazione del sistema nervoso centrale (SNC) che conduce ad un declino della funzione cognitiva e a perdita di memoria. I tratti caratteristici dell’AD includono placche extracellulari di beta amiloide (Abeta), grovigli neurofibrillari (NFTs), neuriti distrofici, morte neuronale e attivazione gliale. In base a quanto affermato dall’ “Ipotesi della cascata della Abeta” - la teoria più corroborata nell’ambito degli studi sull’AD negli ultimi decenni – la neuroinfiammazione veniva supposta come un processo caratterizzante solo le fasi tardive della malattia, e considerata come una mera risposta secondaria agli eventi patologici indotti dall’ A beta. Recentemente, nuovi studi preclinici, epidemiologici e genetici hanno dimostrato un coinvolgimento del sistema immunitario molto più precoce, comportando una rivalutazione del ruolo della principale cellula dell’immunità innata del cervello: la microglia. Dal momento che non vi è cura per l’AD, questi studi hanno motivato lo sviluppo di strategie terapeutiche con l’obiettivo di rallentare i processi degenerativi attraverso un’azione sulle cellule microgliali, in virtù del loro ruolo nell’orchestrare la neuroinfiammazione nelle malattie neurodegenerative. Le cellule staminali mesenchimali (MSC) sono cellule staminali multipotenti che negli ultimi decenni sono emerse per la loro capacità di migliorare il decorso patologico in diversi modelli di malattie neurodegenerative, grazie alla loro attività paracrina, che in gran parte dipende dal rilascio di vescicole extracellulari (EV). Le EV - strutture lipidiche importanti per la comunicazione intercellulare - si sono dimostrate essere mediatori di molti effetti benefici indotti dalle MSC, come l’immunomodulazione. Nello specifico, il concetto che le intrinseche abilità immunoregolatorie delle MSC sono fortemente potenziate dall’ambiente in cui si trovano, ha portato gli scienziati a ridisegnare e ad ottimizzare le condizioni di coltura (precondizionamento, P) di queste cellule, per potenziare le proprietà anti-infiammatorie delle stesse e delle EV da loro rilasciate. L’obiettivo di questo studio è quello di analizzare la capacità delle EV rilasciate da MSC umane precondizionate (p-MSC-EV) di immunoregolare la funzione della microglia in contesti in vitro ed in vivo di AD. Negli studi in vitro abbiamo testato due differenti protocolli di P al fine di isolare un fenotipo altamente immunomodulante di MSC. Le EV derivate da MSC precondizionate con citochine si sono dimostrate in grado di polarizzare il fenotipo microgliale, precedentemente indotto tramite stimoli infiammatori in uno stato funzionale citotossico, verso un fenotipo anti-infiammatorio. Quando abbiamo indagato il potenziale immunomodulatorio delle EV in un modello murino di AD (3xTg AD), abbiamo osservato un forte effetto attenuante sull’attivazione microgliale e sulla prevenzione della perdita di spine dendritiche nelll’ippocampo e nelle cortecce entorinali e prefrontali degli animali trattati con le EV rispetto ai controlli. Questo suggerisce che un effetto neuroprotettivo potrebbe essere ottenuto tramite la modulazione dell’attivazione microgliale in questo modello. Per studiare più selettivamente l’effetto delle EV sulla microglia, stiamo sfruttando un modello di sanguisuga (Hirudo verbana), grazie alla semplice e ben caratterizzata struttura del suo SNC (studio preliminare). In conclusione, i nostri risultati indicano che le p-MSC-EV potrebbero rappresentare uno strumento terapeutico nell’AD, attraverso la riduzione dell’attivazione microgliale e contrastando la perdita di spine dendritiche, tratti neuropatologici tipicamente presenti sia nei modelli transgenici di AD che nei pazienti.<br>Alzheimer’s disease (AD), the most common form of age-related dementia, is characterized by a progressive degeneration of the central nervous system (CNS) that leads to a gradual decline of cognitive functions and memory loss. Neuropathological hallmarks of AD include extracellular beta-amyloid plaques, derived from the altered processing of amyloid precursor protein (APP), neurofibrillary tangles (NFTs, intraneuronal aggregates of hyperphosphorylated and misfolded tau), dystrophic neurites, neuronal loss and glial activation. According to the “Amyloid cascade hypothesis” - the most validated theory in the field of AD for the past few decades - neuroinflammation was assumed to occur only in the late stages of the disease, being considered as a mere secondary response to Abeta-induced pathophysiological events. Recently, new preclinical, epidemiological and genetic studies have demonstrated a much earlier involvement of immune system-related actions, leading to a reassessment of the role of the principal innate immune entities of the brain, that are microglia cells. Since there is still no cure for AD, these studies motivated the design of innovative therapeutic strategies aiming at slowing down degenerative processes by targeting microglia cells, in virtue of their main recognized role in orchestrating neuroinflammatory process in neurodegenerative diseases, including AD. Mesenchymal stem cells (MSCs) are adult multipotent stem cells that over the last decades have been demonstrated to show improvement in various model of neurodegenerative pathologies, thanks to their paracrine ability that is largely dependent on the secretion of extracellular vesicles (EVs). EVs - membrane bound entities known to be important players in intercellular communication - have emerged as mediator of multiple MSC beneficial effects, including immunomodulation. Particularly, the concept that intrinsic immunomoregulatory abilities of MSCs are strongly influenced and strengthened by the environment, has led the scientists to design and optimize culture conditions (preconditioning) in order to enhance the anti-inflammatory properties of these cells and of their derived EVs. The aim of this study is to investigate the ability of preconditioned human bone marrow MSC-derived EVs (p-MSC-EVs) to immunoregulate microglia function in vitro and in vivo AD context.
In in vitro studies we tested two different preconditioning protocols in order to isolate a highly immunomodulant MSC phenotype. Cytokine p-MSC-EVs were shown to switch microglia, previously polarized through inflammatory challenge to the M1 cytotoxic state, toward an anti-inflammatory phenotype. When we delved into the EV immunomodulatory potential in a triple transgenic AD (3xTg AD) mouse model, we observed a strong dampening effect on microglia activation and prevention of dendritic spine loss in hippocampus, entorhinal and prefrontal cortices of EV treated animals compared to controls. This suggests that an EV-dependent neuroprotective effect could be achieved through the modulation of microglia activation in this model.
In order to more selectively study the effect of EVs on microglia, we are taking advantage of a leech animal model (Hirudo verbana), because of its simple and well-characterized CNS structure (preliminary study). In conclusion, our results indicate that p-MSC-EVs may represent a possible therapeutic tool in AD by reducing chronic microglia activation and counteracting dendritic spine loss, which are traits typically observed both in AD transgenic animal models and patients.
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Serra, Lídia Maria Ramos. "Os efeitos do programa musical nos estádios moderados e graves de demência." Master's thesis, Universidade de Évora, 2010. http://hdl.handle.net/10174/19015.
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O objetivo deste estudo foi verificar qual o efeito de um programa musical de 12 semanas, na sintomatologia neuropsiquiátrica e depressiva, e nas expressões emocionais em doentes com Doença de Alzheimer (DA). Participaram 13 sujeitos com diagnóstico de DA em fase moderada-grave da doença: 8 dos participantes integraram o programa musical e, os restantes 5, o grupo de controlo. Para identificar os estádios de demência foi utilizada a Escala de Deterioração Global e para a avaliação dos sintomas foram aplicadas, antes e depois do tratamento, o Inventário Neuropsiquiátrico, a Escala de Cornell para a Depressão na Demência e a Escala de Observação Emocional. Sem resultados significativos, a participação no programa musical melhorou as pontuações das provas utilizadas, revelando efeitos positivos nos sintomas psicológicos e comportamentais em estádios moderados-graves da Doença de Alzheimer, embora o grupo de controlo também beneficiasse da atividade a que foi sujeito. / ABSTRACT: The purpose of this study was to analyse the effects that a musical program held for 12 weeks had in neuropsychiatric and depressive symptoms and emotional expressions in participants with Alzheimer's disease (AD). There were 13 participants with Alzheimer's disease diagnosis in a moderate to severe stadium of the disease, 8 of them were integrated in a musical program and 5 of them constituted the control group. ln order to identify the dementia stadiums, the Global Deterioration Scale was used. ln order to evaluate the symptoms, before and after, the Neuropsychiatric lnventory, the Cornell Scale for Depression in Dementia and Observed Emotion Rating Scale were used. Without significant results, the participation in the musical program improved the scores in the performed tasks, becoming a program with positive effects regarding behaviour and psychological symptoms in moderate to severe stadiums of Alzheimer's disease, although the control group also profited from doing the task that they were exposed to.
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Ioshimoto, Gabriela Lourençon. "Estudo da eletrorretinografia do camundongo modelo de alzheimer (3xTg-AD)." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/47/47135/tde-28042011-155725/.
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Objetivo: Avaliar eletrofisiologicamente a função da retina do camundongo modelo de Alzheimer (3xTg-AD) comparando com seu controle (b6;129-PS1) em um estudo longitudinal com seis idades (2, 4, 6, 8, 10 e 12 meses). Métodos: Eletrorretinogramas (ERGs) foram registrados em 44 camundongos 3xTg-AD e em 23 controles, após administrada anestesia. Para o registro foi colocado um eletrodo de lente de contato sobre a córnea, um eletrodo de referência na cabeça e um terra na cauda. Em sessão de 30-40min de duração foram expostos ao seguinte protocolo de estimulação: 1) Adaptação ao escuro seguida de flashes nas intensidades: 0,003; 0,03; 0,3; 3 e 30 cd.s/m2; 2) Estimulação periódica (30 cd.s/m2) nas freqüências de 12, 18, e 30 Hz, sob luz de fundo (30 cd/m2). Resultados: Os ERGs mostraram dois tipos de respostas escotópicas tanto no grupo dos camundongos controles (b6;129- PS1) quanto nos modelos de Alzheimer. 13% dos camundongos controles e 72% dos modelos de AD apresentaram ERGs com potenciais oscilatórios presentes e tempo implícito da onda-b dentro da faixa esperada (45,31 ± 6,74 ms), enquanto no restante dos grupos, o ERG apresentou latência da onda-b muito aumentada (111,73 ± 22,56 ms) e potenciais oscilatórios ausentes. Devido a estes resultados, os grupos controle e experimental foram subdivididos em: b6;129 com OP, b6;129 sem OP; 3xTg-AD com OP e 3xTg-AD sem OP. Também foi incluído um grupo controle adicional constituído por 9 camundongos C57/B6. Comparando os cinco grupos, nenhuma diferença foi encontrada em relação à amplitude e à latência da onda-a. A amplitude da onda-b também foi semelhante para todos, ao contrário da latência para atingir o pico da onda-b dos grupos b6;129 sem OP e 3xTg-AD sem OP, que se apresentou duas vezes maior do que nos grupos com OP. As amplitudes dos cinco potenciais oscilatórios foram medidas individualmente e não mostraram diferenças entre os controles e os 3xTg-AD. Para o estímulo periódico, a amplitude do 1º harmônico dos grupos com OP mostrou clara diferença entre os grupos controle e o 3xTg-AD, tanto em 12 Hz como em 18 Hz. Os resultados dos dois grupos controle b6;129 e C57/B6 mantiveram-se muito próximos. Os grupos sem OP mantiveram-se sempre próximos a 10 V para as três freqüências de estimulação e mostraram atraso na diferença de fase média do 1º harmônico em 18 e 30 Hz, indicando maior lentidão de resposta, quando comparados aos primeiros. Conclusão: O camundongo 3xTg-AD e seu controle (b6;129) apresentam uma variante lenta e sem OPs do ERG escotópico em parte da população. Células bipolares, amácrinas e ganglionares podem estar alteradas nesses subgrupos (b6;129 sem OP e 3xTg-AD sem OP). Os grupos controle e 3xTg-AD com OPs diferiram quanto à amplitude de resposta à estimulação intermitente, diferença essa que implica em menor capacidade de processamento temporal para o modelo de AD. Sugerimos que as células bipolares de cones podem estar alteradas nos modelos de AD devido às amplitudes mais baixas dos 1os harmônicos desse grupo<br>Objective: To evaluate electrophysiologically the function of the retina of the Alzheimer model mouse (3xTg-AD) comparing it with its control (b6;129-PS1) in a longitudinal study at six ages (2, 4, 6, 8, 10 e 12 months) Methods: Electroretinograms (ERGs) were recorded in 44 anesthetized mice 3xTg-AD and in 23 controls, with a contact lens electrode placed on the cornea, a reference electrode on the head and a ground on the tail. During a 30-40min duration session the mice were exposed to the following stimulation protocol: 1) Scotopic response Dark adaptation followed by flashes at the following intensities: 0,003; 0,03; 0,3; 3 e 30 cd.s/m2; 2) Periodic stimulation (30 cd.s/m2) at the temporal frequencies of 12, 18, e 30 Hz, under background light (30 cd/m2). Results: The ERGs showed two types of scotopic responses, which ocurred in both the control mice (b6;129- PS1) and the Alzheimer´s models (3xTg-AD). 13% of the controls and 72% of the Alzheimer´s models mice presented ERGs with oscillatory potentials (OPs) and b-wave implicit times within the expected range (45,31 ± 6,74 ms), while for the other groups the ERG presented a very delayed b-wave latency (111,73 ± 22,56 ms) and absence of OPs. Given these results, the control and experimental groups were subdivided into: b6;129 with OPs, b6;129 without OPs; 3xTg-AD with OPs e 3xTg-AD without OPs. An additional control group with 9 mice C57/B6 was included. Comparing the five groups, no difference was found in a-wave amplitude and latency. The b-wave amplitude also did not differ among the groups, but the latency of the b-wave for the groups b6;129 without OPs and 3xTg-AD without OPs, was twice as long as in the groups with OPs. The amplitudes of the five OPs, measured individually, did not show differences between controls and 3xTg-AD groups. For the periodic stimulation the amplitude of the first harmonic of the Fourier transform of the groups with OPs showed a clear difference between the control and the 3xTg-AD groups, both for the 12 Hz and for the 18 Hz stimuli. The results of the two control groups (b6;129 and C57/B6) were very close. The groups without OPs had responses always close to 10 V for the three frequencies of stimulation and showed phase delay for the first harmonic, indicating response slowing, compared to the other groups. Conclusions: We found that a sub-group of both triple transgenic (3xTg-AD) and control mice (b6;129) manifest strikingly slow scotopic ERGs that lack OPs. We hypothesize that these response feature may reflect alterations in bipolar, amacrine and ganglion cells. The sub-group of triple transgenic and control mice that exhibited OPs differed in their response to flicker. Alzheimer model had significantly lower flicker-response amplitudes than the controls, suggesting impaired retinal temporal processing. We propose that the flicker results are consistent with alteration in cone bipolar cells in the Alzheimer model mice
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Kinoshita, Denise. "Análise temporal de mediadores inflamatórios no tecido neuronal e na periferia em camundongos 3xTg-AD, um modelo animal para a Doença de Alzheimer." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/10/10133/tde-26092012-140403/.
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A Doença de Alzheimer é a causa mais freqüente de demência senil e os gastos com pacientes com demência já supera os de pacientes com câncer ou com doenças cardiovasculares. As lesões características dessa doença são as placas amilóides e os emaranhados neurofibrilares. A neuroinflamação também está presente na maioria dos pacientes com Alzheimer, e parece contribuir para o dano no tecido neuronal. Adicionalmente, estudos vêm demonstrando que pacientes com Alzheimer também apresentam alterações sistêmicas, e, dessas, a mais relatada é o estado pró-inflamatório em tecidos periféricos, permitindo que a Doença de Alzheimer seja estudada em um contexto neuroimunológico. Utilizando um modelo murino para a Doença de Alzheimer, o camundongo 3xTg-AD (que desenvolve ambas as patologias β-amilóide e tau), investigamos se aumento de mediadores inflamatórios também pode ser detectado nesse modelo, tanto no hipocampo (estrutura relevante para os sintomas da doença) como no sangue. Alterações cognitivas e comportamentais e a presença do precursor da proteína amilóide (APP) e/ ou peptídeo β-amilóide em estruturas cerebrais relevantes para a doença (córtex, hipocampo, subículo e amígdala) permitiram validar o camundongo 3xTg-AD como um modelo murino da Doença de Alzheimer. Análises da expressão de mediadores inflamatórios no hipocampo demonstraram que a presença de APP e/ ou peptídeo β-amilóide no cérebro não induz um estado pró-inflamatório no hipocampo ou no sangue, até os 12 meses de idade. Porém, a expressão de APP e/ ou peptídeo β-amilóide no cérebro parece induzir distúrbios sistêmicos, já que algumas alterações periféricas foram encontradas. Como a resposta ao LPS envolve tanto tecidos periféricos, como o Sistema Nervoso Central, avaliou-se os efeitos da administração periférica de LPS nesse camundongo, aos 12 meses de idade. A resposta inflamatória ao LPS diferiu entre camundongos Wild Type (grupo controle) e 3xTg-AD. No sangue, menor aumento de IL-6 e MCP-1 e maior aumento de IFN-γ foram encontrados nos camundongos 3xTg-AD. As conseqüências deste perfil de citocinas séricas no Sistema Nervoso Central foram distintas, dependendo da resposta avaliada: enquanto que a ativação do eixo HPA foi semelhante, a produção de citocinas inflamatórias no hipocampo foi atenuada. Portanto, no camundongo 3xTg-AD, a diferente resposta inflamatória ao LPS no sangue promoveu menor produção de mediadores inflamatórios no hipocampo.<br>Alzheimer\'s Disease is the most frequent cause of senil dementia and the costs with demented patients already exceeds that of patients with cancer or cardiovascular diseases. The characteristic lesions of this disease are amyloid plaques and neurofibrillary tangles. Neuroinflammation is also present in most of Alzheimer\'s patients, and seems to contribute to neuronal tissue damage. In addition, studies have demonstrated that patients with Alzheimer also display systemic alterations, and of those, the most reported is the pro-inflammatory state in peripheral tissues, allowing Alzheimer\'s Disease to be studied in a neuroimmunology context. Using a murine model of Alzheimer\'s Disease, the 3xTg-AD mice (which develops both amyloid-βand tau pathologies), we investigated whether enhancement of inflammatory mediators can also be detected in this model, in both hippocampus (a relevant structure for the symptoms of the disease) and in blood. Cognitive and behavioral alterations and the presence of amyloid precursor protein (APP) and/ or amyloid-β peptide in relevant brain structures for the disease (cortex, hippocampus, subiculum and amigdala) allowed the validation of 3xTg-AD mice as a murine model of Alzheimer\'s Disease. Analysis of inflammatory mediators expression in hippocampus demonstrated that the presence of APP and/ or amyloid-β peptide in the brain does not induce a pro-inflammatory state in hippocampus or in the blood, until 12 months of age. Nevertheless, APP and/or amyloid-β peptide expression in the brain seems to induce systemic disturbances, once peripheral alterations were detected. As LPS response includes both peripheral tissues and the Central Nervous System, we evaluated peripheral administration effects of LPS in these mice, at 12 months of age. The inflammatory response to LPS differed between Wild Type (control group) and 3xTg-AD. In the blood, smaller enhancement of IL-6 and MCP-1 and higher enhancement of IFN-γ were found in 3xTg-AD mice. The consequences of this serum cytokine profile on the Central Nervous System were distinct, depending on the response evaluated: while HPA axis activation was similar, production of inflammatory cytokines in hippocampus was attenuated. Therefore, in the 3xTg-AD mice, a different inflammatory response to LPS in blood promoted lesser inflammatory mediators production in hippocampus.
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Kanyenda, Limbikani J. "The role of luteinising hormone (LH)/human chorionic gonadotropin (hCG) in regulating the production of beta amyloid (Aβ), a protein central to Alzheimer's disease (AD)". Thesis, Edith Cowan University, Research Online, Perth, Western Australia, 2006. https://ro.ecu.edu.au/theses/358.
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Alzheimer's disease (AD), a progressive neurodegenerative disorder of the brain, is the most common form of dementia among the elderly which is clinically characterised by memory complaints and personality changes. AD is classified broadly into early on set AD (EOAD, occurringyrs) and late on set (LOAD, occurring >65 yrs). Hormonal changes following menopause/andropause have been implicated in AD development and pathogenesis. Currently high levels of the gonadotropins LH and FSH have been associated with increased risk of AD development; however the exact role of LH in AD pathogenesis remains unknown. Interestingly LH and hCG have similar structure and function, thus effects of hCG on Aβ production were assessed in vivo and in vitro models. Additionally the link between pregnancy and cognitive function were also assed.
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White, Paul. "An immersive virtual reality navigational tool for diagnosing and treating neurodegeneration." Libertas, 2016. http://hdl.handle.net/1993/31979.
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One of the earliest symptoms of Alzheimer’s Disease (AD) is a loss of spatial navigation. In this work, we improved an existing screening test for AD that analyzed a patient’s spatial navigation ability. The existing screening test was made more immersive, and therefore more reliable, by integrating support for a leading-edge consumer-targeted Head-Mounted Display (HMD). This integration brought some technical and usability challenges, that were addressed. Furthermore, we investigated the rehabilitative potential of Virtual Reality Navigational (VRN) activities in two case studies: an Early Stage AD (ESA) participant and a Late Stage AD (LSA) participant. We found that the ESA participant was able to significantly improve his navigation skills, and we observed some qualitative improvements in memory and navigation in his personal life. The LSA participant did not improve noticeably at the VRN tasks, but his mood improved after participating in the treatment sessions. These case studies suggested that VRN treatment may be beneficial for people with AD, especially at the onset stage.<br>February 2017
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Itkin, Anna. "Multidisniplinary study of Alzheimer's disease-related peptides : from amyloid precursor protein (APP) to amyloid β-oligomers and γ-secretase modulators". Thesis, Strasbourg, 2012. http://www.theses.fr/2012STRAF051/document.
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Une des caractéristiques histopathologiques de la maladie d'Alzheimer (AD) est la présence de plaques amyloïdes formées par les peptides amyloïdes β (Aβ) de 40 et 42 résidus, qui sont les produits de clivage par des protéases de l'APP. Afin de comprendre le rôle des variations structurelles du TM dans le traitement de l'APP, les peptides APP_TM4K ont été étudiés dans la bicouche lipidique en utilisant l’ATR-FTIR et ssNMR. Tandis que la structure secondaire globale du peptide APP_TM4K est hélicoidale, hétérogénéité de conformation et d'orientation a été observée pour le site de clivage γ et , que peuvent avoir des implications dans le mécanisme de clivage et donc dans la production d’Aβ. Les peptides Aβ s'agrègent pour produire des fibrilles et aussi de manière transitoire d'oligomères neurotoxiques. Nous avons constaté qu'en présence de Ca2+, l’Aβ (1-40) forme de préférence des oligomères, tandis qu'en absence de Ca2+ l'Aβ (1-40) s’agrège sous forme de fibrilles. Dans les échantillons sans Ca2+, l’ATR-FTIR révèle la conversion des oligomères en feuillets β antiparallèles en la conformation caractéristique des fibrilles en feuillets β parallèles. Ces résultats nous ont amené à conclure que les Ca2+ stimulent la formation d'oligomères d'Aβ (1-40), qui sont impliqués dans l’AD. Les positions et une orientation précise de deux nouveaux médicaments puissants modulateurs de la γ-sécrétase - le benzyl-carprofen et le sulfonyl-carprofen dans la bicouche lipidique, ont été obtenus à partir des expériences des ssNMR. Ces résultats indiquent que le mécanisme probable de modulation du clivage par la y-sécrétase est une interaction directe avec le domaine TM de l’APP<br>A histopathological characteristic of Alzheimer’s disease (AD) is the presence of amyloid plaques formed by amyloid β(A) peptides of 40 and 42 residues-long, which are the cleavage products of APP by proteases. To understand the role of structural changes in the TM domain of APP, APP_TM4K peptides were studied in the lipid bilayer using ATR-FTIR and ssNMR. While the overall secondary structure of the APP_TM4K peptide is helical, conformational and orientational heterogeneity was observed for the y- and for the -cleavage sites, which may have implications for the cleavage mechanism and therefore the production of Aβ. Starting from its monomeric form, Aβ peptides aggregate into fibrils and / or oligomers, the latter being the most neurotoxic. We found that in the presence of Ca2 +, Aβ (1-40) preferably forms oligomers, whereas in the absence of a2 + Aβ (1-40) aggregates into fibrils. In samples without Ca2 +, ATR-FTIR shows conversion from antiparallel β sheet conformation of oligomers into parallel β sheets, characteristic of fibrils. These results led us to conclude that Ca2 +stimulates the formation of oligomers of Aβ (1-40), that have been implicated in the pathogenesis of AD. Position and precise orientation of two new drugs powerful modulators of γ-secretase benzyl-carprofen and carprofen sulfonyl in the lipid bilayer were obtained from neutron scattering and ssNMR experiments. These results indicate that carprofen-derivatives can directly interact with APP. Such interaction would interfere with proper APP-dimer formation, which is necessary for the sequential cleavage by β -secretase, diminishing or greatly reducing Aβ42 production
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Borra, Davide. "Sviluppo ed applicazione di reti neurali convoluzionali con dati di neuroimaging." Master's thesis, Alma Mater Studiorum - Università di Bologna, 2018.
Find full textAbstract:
La malattia di Alzheimer (AD) è un disordine neurodegenerativo che rappresenta la forma più comune di demenza negli adulti sopra i 65 anni, mentre la compromissione cognitiva lieve (MCI) è una condizione che in alcuni casi può rappresentare una fase prodromica della malattia di Alzheimer, mentre in altri, è comune in pazienti con la malattia dei piccoli vasi cerebrali (SVD). In questo elaborato sono state sviluppate due reti neurali convoluzionali 2-D, NeuroNet-1 e NeuroNet-2 (o NeuroNet), ed applicate alla classificazione a 2 vie di: a) MCI con SVD (40 pazienti in totale) con dati di diffusione come gli indici di diffusività media (MD), anisotropia frazionaria (FA) e moda del tensore di diffusione (MO); b) AD (200 pazienti in totale) con dati MRI T1-pesati. NeuroNet-2 è basata su NeuroNet-1, attraverso considerazioni frutto di una fase preliminare di studio. I risultati sui dati di diffusione suggeriscono che, l'utilizzo di un approccio multi-modalità e di un numero di fette analizzate in relazione al numero di soggetti, comportino risultati migliori. Infatti, l'accuratezza sui dati di test ottenuta nello studio multi-modalità su 6 fette è di 0.97±0.08 (media±deviazione standard). Inoltre, l'utilizzo di tecniche di interpretazione dell'apprendimento, come Gradient-weighted Class Activation Mapping (Grad-CAM) e test di occlusione, ha permesso di valutare le regioni cerebrali più importanti nella predizione e dimostrare che, oltre ai lobi frontali, alcune regioni di sostanza bianca come il corpo calloso, il tapetum, le radiazioni talamiche posteriori ed il braccio anteriore della capsula interna, sono molto importanti nella predizione delle funzioni esecutive. Infine, nello studio che riporta risultati migliori, l'ordinamento secondo importanza delle mappe di indici di diffusione considerate risulta MD>MO>FA. Invece, sui dati MRI T1-pesati è stata ottenuta un'accuratezza sui dati di test di 0.97±0.01.
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Boman, Erik. "Olfactory and cognitive abilities in two strains of Alzheimer`s disease model mice." Thesis, Linköping University, Department of Physics, Chemistry and Biology, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-19200.
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<p>The present study assessed olfactory and cognitive abilities in two strains of Alzheimer’s disease (AD) model mice and in healthy control mice over a four month time period. To this end an operant conditioning paradigm using an automated olfactometer and a spatial learning test with non-olfactory cues were employed and data on olfactory learning and memory, discrimination, and sensitivity as well as spatial learning and memory were collected. The mice were between 6 to 7 month old at the beginning of the study and 9 to 10 months old at the end of the data collection, that is, in the age range when the animals are supposed to display marked neuroanatomical changes typical of AD. The results demonstrate that there were no systematic differences in olfactory performance and spatial learning and memory abilities of AD model mice and the control mice up to the age they were tested. Further, there was no indication of an age-related decline in performance in any of the mouse strains across the testing period. Several reasons might account for the observed lack of difference in olfactory and cognitive performance between the mouse strains tested here: the AD model mice might not develop amyloid plaques and neurofibrillary tangles at all or they might develop them later than stated by the supplier. Alternatively, the AD model mice may have developed AD-typical neuroanatomical changes but these do not, or not yet, affect their olfactory performance and/or spatial learning and memory capabilities. Ongoing data collection will help to evaluate which of these explanations holds true.</p>
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Wang, Xinglong. "Impaired Balance of Mitochondria Fission and Fusion in Alzheimer Disease." Case Western Reserve University School of Graduate Studies / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=case1228318762.
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Puig, Parnau Irene. "Electrical stimulation of the medial forebrain bundle as a potential therapy for Alzheimer's disease: effects on molecular markers in rodent model." Doctoral thesis, Universitat de Girona, 2021. http://hdl.handle.net/10803/672300.
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Electrical stimulation of deep brain areas has been suggested as a novel approach to restore memory circuits in Alzheimer’s disease (AD). Previous studies from our group have demonstrated that rewarding stimulation of the medial forebrain bundle (MFB-ICSS) facilitates learning and memory in healthy and brain-lesioned rats. This thesis assesses for the first time the effect of MFB-ICSS on AD-associated molecules and its relation with cognitive outcome in rats, including amyloid-β and streptozotocin sporadic AD models.
Results confirmed that MFB-ICSS modulates AD-related molecules and facilitates memory in this condition. Specifically, amyloid precursor protein (APP), phosphorylated tau and key gene expression regulators like SIRT1 and particular microRNAs are modulated by MFB-ICSS in the hippocampus of treated rats. Moreover, effects on miR-132 and SIRT1 were also observed in blood, suggesting a potential use of these molecules as non-invasive biomarkers.
Altogether, these data sustain the MFB as a promising stimulation target for AD treatment.<br>L’estimulació elèctrica de regions cerebrals profundes s’ha proposat com una estratègia per reparar els circuits de la memòria en la malaltia d’Alzheimer (AD). Estudis previs del nostre grup demostren que l’estimulació reforçant del feix prosencefàlic medial (MFB-ICSS) facilita l’aprenentatge i la memòria en rates sanes o amb determinades lesions cerebrals. En aquesta tesi, s’avalua per primera vegada l’efecte de la MFB-ICSS sobre molècules associades amb l’AD i la relació amb la millora cognitiva en rates, incloent els models d’AD esporàdic de β-amiloide i d'estreptozotocina.
Els resultats confirmen que la MFB-ICSS afecta molècules relacionades amb l’AD i facilita la memòria en aquest context. Concretament, modula els nivells de les proteïnes APP, tau fosforilada, SIRT1 i determinats microARNs a l’hipocamp. A més, els efectes sobre miR-132 i SIRT1 també s’observen en sang, suggerint un potencial biomarcador d’aquestes molècules.
Globalment, aquests resultats situen el MFB com a diana d’estimulació prometedora per tractar l’AD<br>Programa de Doctorat en Biologia Molecular, Biomedicina i Salut
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Padilla, Cerezo Berizohar. "Computer-Aided Diagnoses (CAD) System: An Artificial Neural Network Approach to MRI Analysis and Diagnosis of Alzheimer’s Disease (AD)." DigitalCommons@CalPoly, 2017. https://digitalcommons.calpoly.edu/theses/1837.
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Alzheimer’s disease (AD) is a chronic and progressive, irreversible syndrome that deteriorates the cognitive functions. Official death certificates of 2013 reported 84,767 deaths from Alzheimer’s disease, making it the 6th leading cause of death in the United States. The rate of AD is estimated to double by 2050. The neurodegeneration of AD occurs decades before symptoms of dementia are evident. Therefore, having an efficient methodology for the early and proper diagnosis can lead to more effective treatments.
Neuroimaging techniques such as magnetic resonance imaging (MRI) can detect changes in the brain of living subjects. Moreover, medical imaging techniques are the best diagnostic tools to determine brain atrophies; however, a significant limitation is the level of training, methodology, and experience of the diagnostician. Thus, Computer aided diagnosis (CAD) systems are part of a promising tool to help improve the diagnostic outcomes. No publications addressing the use of Feedforward Artificial Neural Networks (ANN), and MRI image attributes for the classification of AD were found.
Consequently, the focus of this study is to investigate if the use of MRI images, specifically texture and frequency attributes along with a feedforward ANN model, can lead to the classification of individuals with AD. Moreover, this study compared the use of a single view versus a multi-view of MRI images and their performance. The frequency, texture, and MRI views in combination with the feedforward artificial neural network were tested to determine if they were comparable to the clinician’s performance. The clinician’s performances used were 78 percent accuracy, 87 percent sensitivity, 71 percent specificity, and 78 percent precision from a study with 1,073 individuals.
The study found that the use of the Discrete Wavelet Transform (DWT) and Fourier Transform (FT) low frequency give comparable results to the clinicians; however, the FT outperformed the clinicians with an accuracy of 85 percent, precision of 87 percent, sensitivity of 90 percent and specificity of 75 percent. In the case of texture, a single texture feature, and the combination of two or more features gave results comparable to the clinicians. However, the Gray level co-occurrence matrix (GLCOM), which is the combination of texture features, was the highest performing texture method with 82 percent accuracy, 86 percent sensitivity, 76 percent specificity, and 86 percent precision. Combination CII (energy and entropy) outperformed all other combinations with 78 percent accuracy, 88 percent sensitivity, 72 percent specificity, and 78 percent precision. Additionally, a combination of views can increase performance for certain texture attributes; however, the axial view outperformed the sagittal and coronal views in the case of frequency attributes. In conclusion, this study found that both texture and frequency characteristics in combinations with a feedforward backpropagation neural network can perform at the level of the clinician and even higher depending on the attribute and the view or combination of views used.
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Lindberg, Hanna. "Engineering of Affibody molecules targeting the Alzheimer’s-related amyloid β peptide". Doctoral thesis, KTH, Proteinteknologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-173864.
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Wang, Dongdong. "Natural Product Chemical Probe Discovery against Parkinson’s Disease." Thesis, Griffith University, 2016. http://hdl.handle.net/10072/367616.
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Parkinson’s disease (PD) is the second most common neurodegenerative disease, affecting over five million patients worldwide. Like Alzheimer’s disease (AD), it mostly affects the elderly and causes considerable disability and suffering. Unfortunately, the molecular mechanism of PD is still poorly understood, and there are no drugs available to treat the disease. Our overall aim was to identify natural products to probe PD by phenotypic assay using human olfactory neurosphere-derived (hONS) cells from PD patients. The research presented in this thesis exemplifies the importance of natural products as chemical probes for further investigation of PD as well as lead compounds for future PD-drug development.
The thesis begins with an introduction of PD and the chemotherapeutics for PD. It also covers a review on the natural origin anti-PD compounds and the analysis of their physicochemical properties using Lipinski’s rule of five. As part of a research program aiming to identify anti-PD chemical probes, a high throughput screening assay was developed to screen 4224 fractions. Twenty fractions were confirmed to display neuroprotective effects of the PD cells against rotenone. Seven prioritized fractions, representing one Australian marine sponge Jaspis splendens (subject 1) and two Australian terrestrial plants Gloriosa superba (subject 2) and Alangium villosum (subject 3), were selected for large scale extraction and isolation. The results were presented in Chapter 2 to 5.<br>Thesis (PhD Doctorate)<br>Doctor of Philosophy (PhD)<br>School of Natural Sciences<br>Science, Environment, Engineering and Technology<br>Full Text