Aging and Disease Course: Contributions to Lifespan Neurobiology of Schizophrenia

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PROJECT SUMMARY The 2020 NIMH Strategic Plan for Research calls for investigations targeting neurobiology of mental illness across the lifespan. Recent innovations in the field of early psychosis have established the critical importance of timely interventions. However, little progress has been made in broader lifespan approaches to schizophrenia (SZ) neurobiology and treatment. The lack of specific biomarkers capturing dynamic alterations along the SZ trajectory hinders progress in targeted treatment development. Growing evidence suggests that the SZ lifespan is the product of two distinct dimensions: aging and disease course. However, the exact trajectories of these dimensions remain unclear. Specific biomarkers capturing unique and/or overlapping aspects of their mechanisms are unavailable. Cognitive and broader clinical correlates of aging and SZ disease course, and their implications for treatment, are yet to be identified. We propose to investigate differential aspects of SZ neurobiology captured by aging and disease course, in order to develop specific biomarkers which may offer actionable targets for intervention. The proposal is predicated on a novel mechanistic Model of SZ Trajectories across the Adult Lifespan, positing distinct biological fingerprints within the anterior limbic circuit for aging and disease course in SZ: (1) alterations in the circuit’s function and structure that occur earlier in the lifespan and are larger in magnitude than the alterations expected with normal aging (accelerated aging dimension); and (2) regionally-specific anterior limbic “hyperactivity” in early SZ, with a subsequent transformation into “hypoactivity” in advanced SZ (disease course dimension). The proposed Model has a strong evidential basis; it is testable; and, if confirmed, it will provide important guidance for the development of future targeted therapeutics, e.g., reducing anterior limbic hyperactivity in early SZ vs. enhancing this same circuit’s function in advanced SZ and along the aging trajectory. In a sample of SZ and matched healthy controls (n=168, 84/group) aged 18-75 years we will ascertain a broad panel of biomarkers [via multimodal brain imaging: novel triple-refocusing 1H-MRS, high-resolution perfusion (Vascular Space Occupancy), and task-based fMRI], along with comprehensive cognitive and clinical characterization. All measures will be acquired at baseline and repeated at 2-year longitudinal follow-up. Using cutting-edge computational approaches, we will examine (i) effects of aging and SZ disease course on anterior limbic system biomarkers, and interactions between these effects; (ii) lifespan trajectories for different biomarkers; (iii) patterns of limbic system biomarkers in age- and SZ disease course-based subgroups (e.g., Younger vs. Older, Early-Course vs. Advanced SZ), as well as in data- driven subgroups (e.g., those with vs. without accelerated aging profiles); and (iv) associations between biomarkers and cognitive and clinical outcomes. This research will advance the field by providing novel biomarkers that capture unique neurobiological contributions of aging and disease course in SZ, and will motivate future studies on SZ mechanisms across the lifespan, and development of precision treatments.