Neuropsychiatric diseases constitute the single largest source of disability-adjusted life years in the US, accounting for 20% of disability from all causes. Despite the significant health threat and severe socioeconomic impact, there is a paucity of studies to guide novel treatment development and this has led to substantial reductions in the effort to discover new drugs by pharmaceutical agencies. The attrition rate of clinical trials is extremely high, with success rates of only about 8% for therapies related to the central nervous system. The vast differences in behavior, physiology, and biology between rodent models, which are traditionally the model of choice for preclinical studies, and humans, almost certainly contribute significantly to these high attrition rates. The ultimate goal of this research is to provide evidence for the utility of baboons as a preclinical model for neuropsychiatric diseases. To achieve this, the following Specific Aims will be addressed: 1. Identify variation in brain structure of 32 (16 male and 16 female) healthy and aged baboons 2. Determine a miRNA biomarker signature of structural variation in the brains of baboons. Using magnetic resonance imaging (MRI) and next-generation sequencing technologies, miRNA biomarkers will be identified that are associated with either volume or cortical thickness in seven brain regions implicated in multiple neuropsychiatric diseases in human studies - hippocampus, amygdala, thalamus, dorsal anterior cingulate cortex, insula, medial orbitofrontal cortex, and entorhinal cortex. Prior evidence already exists in support of a baboon model for neuroimaging studies, including significantly larger brains than other primates, which include all primary cortical structures found in humans, and a higher degree of gyrification. In order to capture the most relevant biomarker signature miRNA expression will be assessed in peripheral blood cells, cerebrospinal fluid (CSF), and in exosomes derived from plasma and CSF for association with neuroanatomical variation. To establish the potential importance of such biomarkers to neuropsychiatric disease, an independent group of baboons will be used to determine correlations between peripheral miRNA biomarkers and brain miRNA expression in those brain regions assessed via neuroimaging. By linking peripheral miRNA biomarkers to neuroanatomical variation and miRNA expression in brain regions important for neuropsychiatric disease, a more complete understanding of the biology of these diseases can be achieved. If similar biological relationships exist between humans and baboons with relation to brain structure, this lends support to the utility of baboons as a preclinical model for neuropsychiatric diseases, which may expedite the improvement of clinical trial success.
The proposed research is relevant to public health because it will identify peripheral miRNA biomarkers of neuroanatomical variation for brain regions important in neuropsychiatric disease using a baboon model. This is relevant to NIH's mission because the development of preclinical models, which resemble human physiology, behavior and biology will likely lead to improved clinical success in human trials of pharmacological agents.
