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Principal Investigator: FEI DU
Organization: MCLEAN HOSPITAL
Fiscal Year: 2024
Award: $844,822
Funding agency: National Institute of Mental Health
Project Summary
Schizophrenia (SZ) is a devastating psychiatric disorder that brings heavy burden to health care systems. A
large literature indicates that individuals with SZ show markers of early aging, such as faster decline in cognitive
functioning, increased risk for dementia, and significantly shorter life expectancies. Interestingly, the increased
rate of dementia in SZ cannot be fully accounted for by the established dementia risk factors or the pathology of
neurodegenerative disorders, suggesting additional pathological causes of cognitive impairment and increased
mortality in older SZ patients. Additionally, many SZ patients develop medical conditions such as diabetes,
metabolic syndrome, and cardiovascular disease, conditions often exacerbated by side effects of antipsychotic
medications. However, it is unclear whether these phenomena reflect premature aging early in life, accelerated
pace of aging later, toxic effects of chronic psychosis with antipsychotic therapy, or a mixture of all three. Recent
advances in the field of early psychosis including our own work suggest that an “immuno-oxidative” pathway,
including NMDA receptor hypofunction/glutamatergic dysfunction, bioenergetic impairment/redox dysregulation,
and neuroinflammation, form a “central hub” of brain pathology in SZ. These biochemical abnormalities result in
neuronal dysfunction that eventually might disrupt the long distance and large-scale neuronal communication,
thereby leading to cognitive dysfunction. To study these phenomena, we have developed novel neuroimaging
approaches to measure the redox ratio (NAD+/NADH) in vivo, as well as other markers of mitochondrial function,
including creatine kinase (CK)/ATPase activity and the antioxidant glutathione (GSH)—a molecule essential for
cellular repair that has functional ties to NAD. Research has shed some light on these mechanisms in early
phases of SZ and transition to chronic illness. However, little progress has been made in understanding their
role across the lifespan in SZ, despite the fact that these abnormalities are closely linked with the diverse early
aging phenomena seen in SZ. In this application, we propose to extend our previous research on the early stage
of SZ to older populations to examine the trajectory of biochemical abnormalities in SZ. Our overarching
hypothesis is that metabolic and redox abnormalities continue to unfold over the lifespan and are associated
with additional sequelae for impaired brain function in SZ. To capture the full aging trajectory, we propose an
accelerated longitudinal design where we recruit patients with SZ and age/sex-matched healthy controls (HC)
between the ages of 40-70. We will collect a broad neurochemical profile as described above, but also structural,
functional, and vascular neuroimaging, as well as comprehensive cognitive and clinical assessments. This rich
dataset will enable us to explore dynamic mental illness trajectories. It may provide targets for future interventions
to slow down abnormal aging, reduce risk of dementia, and delay mortality among people with SZ.
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