# Aging and Disease Course: Contributions to Lifespan Neurobiology of Schizophrenia

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2021 · $698,784

## Abstract

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 ...

## Key facts

- **NIH application ID:** 10278892
- **Project number:** 1R01MH127317-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Elena Ivanovna Ivleva
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $698,784
- **Award type:** 1
- **Project period:** 2021-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10278892

## Citation

> US National Institutes of Health, RePORTER application 10278892, Aging and Disease Course: Contributions to Lifespan Neurobiology of Schizophrenia (1R01MH127317-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10278892. Licensed CC0.

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