Dementia is a major public health problem worldwide. Emerging research indicates that clinical infections and PTSD could be important risk factors for dementia. However, evidence for infections and the risk of dementia primarily examines central nervous system (CNS) infections. Extant epidemiological evidence for systemic bacterial infections and the risk for dementia is limited while that for PTSD and the risk for dementia did not account for psychotropic medications commonly used in management of PTSD and could affect cognitive function. The purpose of this study was to 1) review the evidence for CNS infections as possible causes of Alzheimer’s disease (AD) dementia, and 2) using nationwide Veterans Health Administration databases, conduct original retrospective cohort analyses in nationally representative samples of U.S. veterans aged 56 years and older to determine the associations between systemic bacterial infections, PTSD, and psychotropic PTSD medication use with the risk for developing dementia. Review of the research pertaining to an infectious AD etiology hypothesis including the various mechanisms through which different clinical and subclinical infections could cause or promote the progression of AD, and the concordance between putative infectious agents and the epidemiology of AD showed evidence linking AD to an infectious cause to be largely inconclusive; however, the amount of evidence suggestive of an association is too substantial to ignore. Analysis of the associations between systemic bacterial infections and the risk for dementia showed a significant association between exposure to any systemic bacterial infection and an increased risk for dementia (hazard ratio [HR] = 1.20; 95% confidence interval [CI] = 1.16-1.24) after adjustment for demographic characteristics, and medical and psychiatric comorbidity. In addition, septicemia (HR=1.39; 95%CI=1.16-1.66), bacteremia (HR=1.22; 95%CI=1.0-1.49), osteomyelitis (HR=1.20; 95%CI=1.06-1.37), pneumonia (HR=1.10; 95%CI=1.02-1.19), UTI (HR=1.13; 95%CI=1.08-1.18), and cellulitis (HR=1.14; 95%CI=1.09-1.20) were independently associated with significantly increased risk of developing dementia after adjustment for potential confounders. Analysis of the associations between PTSD and psychotropic PTSD medication use with the risk for dementia showed a significant association between PTSD and the risk for dementia (HR=1.35; 95%CI=1.27-1.43) after adjustment for demographic characteristics, medical and psychiatric comorbidity, and health care utilization. Analysis of the impact of psychotropic PTSD medications including selective serotonin reuptake inhibitors (SSRI), serotonin-norepinephrine reuptake inhibitors (SNRI), benzodiazepines (BZA), novel antidepressants (NA) and atypical antipsychotics (AA) on the association between PTSD and the risk for dementia showed significant interactions between PTSD and use of SSRIs (p<.0001), NAs (p=.0016), and AAs (p<.0001). Multivariate analysis showed a significant association between PTSD and an increased risk for dementia among individuals not using any psychotropic PTSD medications at baseline (HR=1.70; 95%CI=1.58-1.82). PTSD patients using SSRIs (HR=2.10; 95%CI=1.82-2.41), NAs (2.19; 95%CI=1.94-2.48) or AAs (4.56; 95%CI=4.04-5.15) were significantly more likely to develop dementia compared to those without PTSD and not using any psychotropic PTSD medications. PTSD patients using SSRIs (HR=1.24; 95%CI=1.08-1.42), NAs (HR=1.29; 95% CI=1.14-1.46) or AAs (HR=2.69; 95%CI=2.38-3.04) were also significantly more likely to develop dementia compared to those with PTSD and not using any psychotropic PTSD medications. SNRI (HR=1.35; 95%CI=1.26-1.46) and BZA drug use (HR=1.40; 95%CI=1.35-1.45) at baseline was associated with an increased risk for dementia regardless of PTSD diagnosis. These findings indicate; 1) evidence for an infectious AD etiology hypothesis in inconclusive, 2) both severe (e.g. sepsis), and less severe (e.g. cellulitis) systemic bacterial infections are collectively and independently associated with an increased risk of dementia among older U.S. veterans hence prevention of systemic bacterial infections could positively influence the risk for dementia among older adults, and 3) PTSD and psychotropic medication use are associated with an increased risk for dementia among U.S. veterans. Further epidemiologic, clinical, and basic science research is required to elucidate the mechanisms and the associations between infections and the risk for dementia and to determine if the independent and effect modifying impacts of psychotropic PTSD medication use on the risk for dementia are related to differences in PTSD severity, other psychiatric comorbidity, or whether psychotropic PTSD medication use is an independent risk factor for dementia.

Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-09-27T14:21:32Z No. of bitstreams: 1 osmarnascimentosilva.pdf: 5346948 bytes, checksum: c6c4bb9eae4172e04c4553f57d4e27d0 (MD5) / Approved for entry into archive by Diamantino Mayra (mayra.diamantino@ufjf.edu.br) on 2016-09-27T15:15:36Z (GMT) No. of bitstreams: 1 osmarnascimentosilva.pdf: 5346948 bytes, checksum: c6c4bb9eae4172e04c4553f57d4e27d0 (MD5) / Made available in DSpace on 2016-09-27T15:15:36Z (GMT). No. of bitstreams: 1 osmarnascimentosilva.pdf: 5346948 bytes, checksum: c6c4bb9eae4172e04c4553f57d4e27d0 (MD5) Previous issue date: 2015-04-28 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Com o aumento na incidência de infecções resistentes a múltiplos antibióticos, existe hoje um grande interesse pelos peptídeos antimicrobianos (PAMs) como modelos para a produção de novos antibióticos. Os PAMs são mediadores multifuncionais da resposta imune inata, com atividade antibacteriana direta. O uso de PAMs como agentes terapêuticos tem algumas limitações, como a estabilidade, a toxicidade e alta massa molecular. Apesar dessas limitações, eles apresentam propriedades compensatórias, como imunomodulatória e antitumoral bem como a capacidade de inibir β-lactamases. O desenho racional de PAMs tem sido usado para gerar análogos com atividade melhorada. No presente trabalho avaliamos a atividade antibacteriana in vitro e in vivo da clavanina A e através da modificação incremental criamos dois análogos dos peptídeos mostoparano-L e clavanina A (clavanina-MO e mastoparanoMO),além disso, utilizamos o desenho racional de peptídeos para a criação de dois inibidores de β-lactamase (dBLIPs 1 e 2). A clavanina A mostrou se eficiente na eliminação de S. aureus em um modelo de infecção de ferida e impediu o início da sepse e, assim, reduziu a mortalidade de camundongos infectados em um modelo de infecção bacteriana sistêmica. A clavanina-MO e mastoparano-MO impediram o crescimento de bactérias planctônicas e levaram à erradicação de biofilmes bacterianos maduros. Os peptídeos modificados mostram-se promissores como agentes terapêuticos contra infecções bacterianas sistêmicas e biofilmes causadas por uma variedade de bactérias. dBLIP-1 e dBLIP-2 em combinação com antibióticos convencionais foram eficazes na eliminação de Escherichia coli e Staphylococcus aureus que expressam β-lactamases em um modelo murino de infecção sistêmica. dBLIPs 1 e 2 fornecem pistas para superar a resistência à base de β-lactamase. / With the increased incidence of multiple antibiotic resistant infections, there is huge interesting in antimicrobial peptides (AMPs) as templates to produce novel antibiotics. The AMPs are multifunctional mediators of innate immune response with direct antibacterial activities. Nevertheless, the use of AMPs as therapeutic agents has certain limitations such as stability, toxicity and high molecular mass. Despite such limitations, they show additional properties such as antitumor and immunomodulatory as well as the ability to inhibit β-lactamases. Furthermore, the rational AMPs design has been used to produce analogues with improved activity. In the present study, we utilized the rational AMPs design for generation of two β-lactamase inhibitors (dBLIPs 1 and 2) and through two incremental modification created analogues of clavanin A and mostoparan-L (clavanin-MO and mastoparan-MO respectively) peptides. Both inhibitors in combination with conventional antibiotics were effective for control of Staphylococcus aureus and Escherichia coli expressing β-lactamase in a murine model of systemic infection. dBLIPs 1 and 2 provide clues to overcome resistance to β-lactamase base. The clavanin-MO and mastoparan-MO prevented the growth of planktonic bacteria, leading to the mature biofilm eradication of pathogenic Gram-negative and -positive. The clavanina-MO and mastoparan-MO are promising therapeutic agents against systemic infections and bacterial biofilms caused by a wide bacterial variety.