Multidimensional aging trajectories in mid to late-life psychosis (MAP)

Even though schizophrenia spectrum disorders (SSD) are generally considered to be neurodevelopmental in origin, emerging evidence supports the idea that aberrant brain aging may also occur. Because this concept has only recently reemerged, data on characteristic phenotypical and brain age-related trajectories in SSD and their underlying mechanisms remain sparse. These critical knowledge gaps constitute major obstacles in identifying actionable treatment targets for aberrant aging in SSD. Our proposal has two overarching goals: (1) address existing knowledge gaps in age-related changes in SSD and (2) identify actionable targets for novel interventions designed to ameliorate, or even prevent, aberrant aging in SSD. A considerable body of work in geroscience suggests that normal aging phenomena are present at multiple levels. Specifically, age-related declines in brain structures and cognitive function are well established. Recent findings also suggest that energy metabolism (bioenergetics) in the brain, which is critical for brain plasticity and cognition, is negatively affected by aging. Emerging data further supports the idea that these phenomena are intricately connected and point towards bioenergetic aging as a potentially driving force behind structural brain aging and cognitive aging. These principles of aging in the general population provide the conceptual framework of our project. We propose to leverage state-of-the-art multimodal neuroimaging techniques and tailored cognitive tasks to systematically evaluate age-related changes in brain structure, function, and bioenergetics in the dorsal anterior cingulate cortex (dACC), which is considered a hallmark brain region implicated in the pathophysiology of SSD and plays a critical role in nonsocial and social cognition. Over a period of 5 years, we will enroll 120 individuals with SSD and 120 demographically matched controls. We will quantify (1) cortical thickness deviations in the dACC using novel normative reference models, (2) social cognition and nonsocial cognition with a tailored behavioral battery and task fMRI, and (3) in vivo spectroscopic indices of bioenergetics in the dorsal ACC (dACC) using ultra-high-field MR spectroscopy (MRS). We will determine if these measures of patients differ from those of healthy volunteers (Aim 1) and if the effect of age on these measures differs between patients and controls (Aim 2). We will also explore whether age trajectories converge across measures in an exploratory aim. The findings of this project could offer mechanistic insights into aging process in SSD by focusing on multiple units of analysis and provide actionable treatment targets for aberrant aging in SSD.