Background: Despite substantial research and development investment in Alzheimer's disease (AD), effective therapeutics remain elusive. Significant emerging evidence has linked cholesterol, beta-amyloid and AD, and several studies have shown a reduced risk for AD and dementia in populations treated with statins. However, while some clinical trials evaluating statins in general AD populations have been conducted, these resulted in no significant therapeutic benefit. By focusing on subgroups of the AD population, it may be possible to detect endotypes responsive to statin therapy. Methods: Here we investigate the possible protective and therapeutic effect of statins in AD through the analysis of datasets of integrated clinical trials, and prospective observational studies. Results: Re-analysis of AD patient-level data from failed clinical trials suggested by trend that use of simvastatin may slow the progression of cognitive decline, and to a greater extent in ApoE4 homozygotes. Evaluation of continual long-term use of various statins, in participants from multiple studies at baseline, revealed better cognitive performance in statin users. These findings were supported in an additional, observational cohort where the incidence of AD was significantly lower in statin users, and ApoE4/ApoE4-genotyped AD patients treated with statins showed better cognitive function over the course of 10-year follow-up. Conclusions: These results indicate that the use of statins may benefit all AD patients with potentially greater therapeutic efficacy in those homozygous for ApoE4.

Background Traumatic brain injury (TBI) is a complex disease with a spectrum of symptoms and disabilities. Over the past decade TBI has become the focus of research due to growing epidemiological and clinical evidences that TBI incidences are strong risk factors for Alzheimer’s disease (AD). Major pathological hallmarks of AD are massive accumulations of amyloid-β peptide (Aβ) toxic oligomers and plaques. Neuroinflammation is also considered as a common denominator in AD and aging. The epidemiological and experimental studies have supported that non-steroidal anti-inflammatory drugs markedly reduce the age-related prevalence of AD and can slow amyloid deposition by mechanisms that still remain elusive. S100A9 is a multifunctional cytokine with diverse roles in the cell signaling pathways associated with inflammation and cancers. A widespread expression of S100A9 was also reported in many other ailments involving inflammatory processes, such as AD, malaria, cerebral ischemia and TBI, implying that S100A9 may be a universal biomarker of inflammation. The distinctive feature of S100A9 compared to other pro-inflammatory cytokines is its ability to self-assemble into amyloids, which may lead to the loss of its signaling functions and acquired amyloid cytotoxicity, exceeding that of Aβ. Methods S100A9 properties was studied under various ex vivo and in vitro conditions. First, human and mouse tissues with TBI and AD were subjected to microscopic, immunohistochemical and immunofluorescent techniques. Then, aged mouse treated with native, oligomeric and fibrillary S100A9 was also studied by using behavioral and neurochemical analysis. Moreover, S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ42 and tau proteins, by studying cerebrospinal fluid (CSF) samples from different stages of dementia. Finally, in vitro experiments on S100A9 amyloidogenesis, co-aggregation with Aβ40 and Aβ42, digestion and cytotoxicity were also performed by using spectroscopic, atomic force microscopy and cell biology methods. Results S100A9-driven amyloid-neuroinflammatory cascade serves as a link between TBI and AD. We have found that S100A9 contributes to the plaque formation and intraneuronal responses in AD, being a part of the amyloid-neuroinflammatory cascade. In TBI we have found that extensive S100A9 neuronal production and amyloid self-assembly is triggered immediately after injury, leading to apoptotic pathways and neuronal loss. S100A9 is an integral component of both TBI precursor-plaques, formed prior to Aβ deposition, and AD plaques, characterized by different degree of amyloid maturation, indicating that all plaques are associated with inflammation. Both intra- and extracellular amyloid-neuroinflammatory cascades are intertwined and showed similar tendencies in human and mouse tissues in TBI and AD. Ex vivo findings are further supported by in vitro experiments on S100A9 amyloidogenesis, digestion and cytotoxicity. Importantly, being highly amyloidogenic itself, S100A9 can trigger and aggravate Aβ amyloid self-assembly and significantly contribute to amyloid cytotoxicity. Moreover, the CSF dynamics of S100A9 levels matches very closely the content of Aβ42 in AD, vascular dementia and mild cognitive impairment due to AD, emphasizing the involvement of S100A9 together with Aβ in the amyloid-neuroinflammatory cascade in these ailments. Conclusions The conclusions of this thesis is that the inflammatory pathways and S100A9 specifically represent a potential target for the therapeutic interventions during various post-TBI stages and far prior AD development to halt and reverse these damaging processes. / Role of pro-inflammatory S100A9 protein in amyloid-neuroinflammatory cascade in Alzheimer’s disease and traumatic brain injury

Background: Alzheimer’s disease (AD) is the most common form of dementia and is characterized by a progressive loss of memory, judgment, and thinking in older adults. The current treatment is cholinesterase inhibitors, which increase acetylcholine at the synapse. Medications with anticholinergic (AC) activity are given for a variety reasons including for the treatment of comorbid conditions or side effects of cholinesterase inhibitors (ChEIs). These drugs inhibit acetylcholine in the brain. Studies have shown the detrimental outcomes of using AC medications with ChEIs in older adults. Moreover, older patients take more medications and have an increased risk of developing AC toxicity as these effects are additive. The association between AC burden with functional, cognitive, and behavioral outcomes bears further evaluation. Methods: This study is a retrospective observational study that investigated the effect of AC medications on function, cognition, and behavior. Data was collected from charts on dementia patients who resided at Piedmont Geriatric Hospital. Descriptive statistics and GEE regression were performed using MS Excel 2007 and SPSS 18.0. Results: There were a total of 83 subjects included in this study with a median age of 77 years old and with a median length of stay of 536 days. 33.7% of the patients were taking cognitive-enhancing medications. The analysis found that AC burden was not a significant predictor of functional, cognitive or behavioral decline. Conclusion: The minimal amount of literature on this association, suggests that AC burden may have negative consequences on function, cognition and behavior in dementia patients. The study results provided inconclusive evidence about the association of AC burden on poorer functional, cognitive and behavioral outcomes. Future research in this field is needed to determine if there is a true association between worsening outcomes and AC burden.

This correlational study explored the knowledge, perceived seriousness, and willingness to seek medical help for Alzheimer’s Disease (AD) among Ghanaian Immigrants currently residing in the Unites States. Study participants were 163 Ghanaian Immigrants between the ages of 45 and 90, attending Ghanaian community churches in Virginia and Maryland. Significant results include a positive correlation between knowledge and perceived seriousness of the disease, perceived seriousness of the disease was negatively correlated with caregiving experience. These results as well as several seemingly counterintuitive findings are discussed in terms of the Health Disparities and Psychometric challenges. Specifically, these results points to the necessity for future research and implication for action in the following areas: 1) Further qualitative exploration to develop a deep, rich understandings of the phenomenon of AD among Ghanaian Immigrants, 2) Improved cultural sensitivity in psychometric assessment with immigrant populations of AD knowledge, perceptions, and willingness to seek assistance, 3) Person Centeredness and Cultural Humility in Educational Interventions to empower individuals and parallel existing cultural beliefs rather than displacing them.

In this series of essays about professional burnout, a veteran teacher seeks a way to continue her work and enthusiasm in it, for the sake of both her and her students. To that end, she explores her relationships with her father and mother, and how the practices of teaching and learning she brought from home have affected her present classroom experiences. A complicating factor is the presence of chronic illness and its demands both primary and secondary: her father's Alzheimer's, her mother's bi-polar disorder, and the demands of eldercare for her mother. She also explores her own habitual practice of being a student, in a reflective inquiry into the mind and situation of students from inside her own experiences. Interleaved vignettes of student interaction illustrate the kinds of difficulty that the speaker has with her teaching. They appear chronologically to suggest a developmental movement.

Microglia are essential to the brain’s innate immune response and play a vital role in neuropathology related to tauopathies. Understanding how microglia change in response to differential expression of RNA binding protein T-cell intracellular antigen 1 (TIA1) will lend insight to microglial function in tauopathy. In preliminary studies our laboratory has shown that decreasing the expression of TIA1 has an inverse and dose dependent effect on activated microglial density in the dentate gyrus of the P301S mouse (PhD Candidate Chelsey LeBlang, 2018). Here, we utilized serial sectioning electron microscopy to define whether this relationship between TIA1 level and microglia remains consistent in the hilus and granule cell layer (GCL) of the dentate gyrus. Our analyses of microglial volume and microglial interactions within the neuropil have yielded four conclusions. First, the hilus, but not the GCL, exhibited a significant decrease in microglial volume per volume of tissue with the knock out and heterozygous expression of TIA1. Second, the number of appositions on microglia steadily increased on AT8+ and AT8- presynaptic and postsynaptic appositions in the hilus with decreasing TIA1 expression. Third, with the exception of one AT8- somatic apposition, the surface area of microglia apposing AT8+ somata is greater than any other structure and exhibits a dose dependent decrease with decreasing TIA1 expression. Fourth, in the GCL there is a larger fractional surface area of AT8- presynaptic and AT8+ postsynaptic structures when compared to their respective synaptic counterparts. Though not entirely consistent with previous data, this study has important implications for microglial function in tauopathy and related diseases.

Cette thèse porte sur les relations entre mémoire et conscience du trouble dans la maladie d'Alzheimer. La maladie d'Alzheimer touche 5% de la population âgée de plus de 65 ans. Dans les faits, 880 000 personnes sont concernées en France en 2011 parmi lesquelles 30 000 sont âgées de moins de 35 ans. A l’heure actuelle, de nombreux progrès ont été faits permettant de mieux comprendre les déficits mnésiques chez ces patients et leur évolution au cours de la maladie. Toutefois, très peu de recherches ont évalué l’influence de ces troubles de mémoire sur la conscience du trouble et/ou de la maladie. L'axe principal de cette thèse sera donc d'évaluer comment les troubles de mémoire dans la maladie d'Alzheimer influencent la conscience du trouble. / Alzheimer's disease is characterized by memory deficits. However, only a few studies have explored how patients judge their memory difficulties. The main aim of this thesis is to determine in more details whether or not Alzheimer’s patients have impaired metamnesic abilities (knowledge about own memory). Indeed, previous studies showed a complex pattern of results and suggested a fractionation of metamemory in Alzheimer’s disease (Souchay, 2007). Therefore, the main aim of this thesis is to explore this fractionation in more details and to explore whether it can be observed (1) between long-term memory tasks and short-term memory tasks, (2) according to the type of response (judgment of learning or judgment of forgetting, or (3) with implicit measures).To study the fractionation hypothesis, 7 studies have been carried out comparing younger adults, older adults and patients with amnesic Mild Cognitive Impairment or Alzheimer's disease. Results first contradicted the existence of fractionation of metamemory, Alzheimer’s patients were as accurate as predicted their performance on short-term memory tasks than on long-term memory (yet failed). Furthermore, this work showed that implicit metamemory judgments are preserved in Alzheimer's disease (Mograbi and Morris, 2013) on both episodic and semantic memory tasks, contrary of the observation on explicit measures in literature (Souchay, 2000). Finally, patients were more inaccurate than elderly when asked to predict their remembering and their forgetting on both episodic and semantic memory tasks. In conclusion, results contradict the existence of a fractionation of metamemory in Alzheimer's disease. This finding will contribute to inform metamemory (Flavell, 1979 ; Nelson et Narens, 1990) and ansognosia models (Cognitive Awareness Model : Agnew et Morris,1998 ; Hannedotir et Morris, 2007 ; Morris et Hannesdotir, 2004 ; Morris et Mograbi, 2013).

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

Kate Zeller is nearly thirteen, with hair like a rat’s nest and the temperament of a dog chained up against its will: moody and likely to bite you. She lives in the small town of Brookford with her twenty-two year old brother Teddy and her grandfather, Tony, an acclaimed graphic novelist. As summer turns to autumn, two things barrel uninvited into Kate’s life: one is Raleigh, a strange new girl with a head full of Shakespeare and a secret knowledge of ghosts. The other is the Alzheimer’s that sneaks itself into her grandfather’s head and begins to steal it away, piece by piece. The history and tragedy of the Zeller family begins to unwind as reality blurs with fantasy, creator with creations, all being watched by a man who lives deep in the forest that connects Kate’s house to Raleigh’s. A man with eyes that tick. / Includes bibliography. / Thesis (M.F.A.)--Florida Atlantic University, 2015. / FAU Electronic Theses and Dissertations Collection

A inclusão da eletroencefalografia nos protocolos de pesquisa diagnóstica para DA é plenamente justificada por sua larga disponibilidade, baixo custo, alta sensibilidade, o que possibilita a realização de exames seriados e o acompanhamento da evolução do estudo neurológico. Objetivo: Determinar um índice de corte, para utilizaçào na prática clínica, no auxilio diagnóstico da doença de Alzheimer. Metodologia: Avaliamos dois grupos de indivíduos compostos por 57 voluntários normais e idade superior a 50 anos comparados a 50 indivíduos com DA provável. Realizamos registros de EEG em vigília, olhos fechados e repouso por 30 minutos e computamos as potências espectrais das bandas de frequência alfa e teta, para todos os eletrodos, e calculamos a razão alfa/teta. Realizamos a regressão logística das variáveis razão alfa/teta da potência média do eletrodo C3 e do eletrodo O1e calculamos uma fórmula para o auxílio no diagnóstico da DA com um acerto cuja, sensibilidade para DA de 76, 4 % e especificidadede 84,6 % e a área sob a curva ROC 0.92. Conclusão: A regressão logística da razão alfa/teta do Espectro da potência média do EEG é um bom marcador para discriminar pacientes com doença de Alzheimer de controles normais / The inclusion of electroencephalography in diagnostic research protocols for AD is fully justified given EEG\'s wide availability, low cost and high sensitivity, allowing serial exams and neurological evolution follow-ups. Objective: To determine a screening index for use in routine clinical practice to aid the diagnosis of Alzheimer\'s disease. Methodology: Two groups of individuals older than 50 years, comprising a control group of 57 normal volunteers and a study group of 50 patients with probable AD, were compared. EEG recordings were performed of subjects in a wake state with eyes closed at rest for 30 mins. Spectral potentials of the alpha and theta bands were computed for all electrodes and the alpha/theta ratio calculated. Logistic regression of the variables alpha/theta of the mean potential of the C3 and O1 electrodes was carried out. A formula was calculated to aid the diagnosis of AD yielding 76.4 % sensitivity and 84.6 specificity for AD with an area under the ROC curve of 0.92. Conclusion: Logistic regression of the alpha/theta of the Spectrum of the mean potential of EEG represents a good marker for discriminating between AD patients and normal controls