Aging and Disease Course: Contributions to Lifespan Neurobiology of Schizophrenia

Specific Aims: In order to investigate aging and disease course dimensions in SZ, the study will ascertain a broad panel of biomarkers using multimodal brain imaging, along with comprehensive cognitive and clinical measures, which will allow integration of in vivo molecular; circuit structure and function; and clinical levels of system pathology. Aim 1. In vivo Molecular Biomarkers. Examine age- and disease course-dependent effects on excitatory and inhibitory 1H-MRS-based biomarkers in the anterior limbic system in SZ. SZ and CON (n=84/group) will undergo novel triple-refocusing 1H-MRS with Glutamate (Glu), GABA and broader metabolite measures from bilateral Hipp and mPFC. Hypothesis 1.1: SZ will show declines in Hipp-mPFC Glu and GABA along the lifespan, with significantly earlier and larger reductions than those observed in CON. Hypothesis 1.2: SZ will show distinct Hipp-mPFC Glu and GABA markers along the disease course, with significantly elevated or equivalent Glu, and reduced GABA levels, in early SZ, and reduced Glu and GABA in advanced SZ, compared to CON. Aim 2. Functional Circuit Biomarkers. Examine age- and disease course-dependent effects on intrinsic and task-based activation biomarkers in the anterior limbic circuit in SZ, using high resolution perfusion \[Vascular Space Occupancy\] and functional MRI with an episodic memory \[Pattern Separation\] task, respectively. Hypothesis 2.1: SZ will show declines in Hipp-mPFC intrinsic and task-based activity along the lifespan, with significantly earlier and larger reductions than those in CON. Hypothesis 2.2: SZ will show distinct Hipp-mPFC intrinsic and task-dependent activity signatures across the disease course, with significantly elevated or equivalent regional activation in early SZ, and reduced activation in advanced SZ, compared to CON. Aim 3. Structural Circuit Biomarkers. Examine age- and disease course-dependent effects on structural biomarkers in the anterior limbic system in SZ, using high resolution structural MRI. Hypothesis 3.1: SZ will show declines in cortical thickness and volume in Hipp, mPFC and broader fronto-temporal regions across the lifespan, with significantly earlier and larger reductions than those in CON. Hypothesis 3.2: SZ will show distinct fronto-temporal alterations along the disease course, with modestly reduced cortical thickness and volume measures in early SZ and larger reductions in advanced SZ, compared to CON. The investigators also predict that molecular, functional, and structural alterations in the anterior limbic system will be associated with impaired episodic memory and broader cognitive dysfunction in SZ, with declining cognition along both the lifespan and SZ course. 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 the development of relevant precision treatments.