RESUMO
Improvements have been made in the diagnosis of Alzheimer's disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by magnetic resonance imaging (MRI) and positron emission tomography (PET) scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques-species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid ß oligomers (AßOs), rather, are now widely accepted as the Aß species most germane to AD onset and progression. Here we report evidence further supporting the role of AßOs as pathological instigators of AD and introduce promising anti-AßO diagnostic probes capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, Aß oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase of AßOs is prominent in the subiculum and correlates with concomitant development of reactive astrocytosis. The impact of these AßOs on memory is in harmony with findings that intraventricular injection of synthetic AßOs into wild type mice induced hippocampal dependent memory dysfunction within 24 h. Compelling support for the conclusion that endogenous AßOs cause memory loss was found in experiments showing that intranasal inoculation of AßO-selective antibodies into 5xFAD mice completely restored memory function, measured 30-40 days post-inoculation. These antibodies, which were modified to give MRI and PET imaging probes, were able to distinguish 5xFAD mice from wild type littermates. These results provide strong support for the role of AßOs in instigating memory loss and salient AD neuropathology, and they demonstrate that AßO selective antibodies have potential both for therapeutics and for diagnostics.
RESUMO
BACKGROUND: Children who spent time in territories formerly controlled by the Islamic State of Iraq and Syria (ISIS) and who are now being reintegrated into their countries of origin have experienced significant trauma and may present with adjustment or mental health problems. OBJECTIVE: In this paper we describe how Emotional Security Theory (EST; Davies & Cummings, 1994) and its more recent formulation, EST-reformulated (EST-R; Davies & Martin, 2013, 2014), provide a theoretical lens to aid in understanding the ways in which traumatic experiences under ISIS may have an enduring impact on a child's development and well-being. METHODS & RESULTS: The core assumption of EST is that maintaining safety and security is a central goal for a child growing up in the context of conflict. Children living in conflict zones under ISIS rule may have developed emotional insecurity, which in turn is theorized to lead to developmental cascades across multiple domains of functioning and at times result in clinically significant distress. This theoretical understanding can guide intervention, as it suggests that the foci of intervention must (1) minimize social signals indicative of threat while also (2) reducing behavioral response patterns that limit opportunities for exploration and prosocial affiliation. Trauma Systems Therapy is a multidisciplinary child trauma treatment model that addresses both stressors in the social environment and related emotional dysregulation. CONCLUSIONS: Challenges and considerations related to implementing such a comprehensive treatment approach in low- and middle-income countries are discussed.
