MicroRNAs in neural-derived extracellular vesicles as biomarkers in first episode schizophrenia

About This Grant

Project Summary Schizophrenia (SZ), a major chronic psychiatric illness, is characterized by psychotic symptoms, negative symptoms (e.g., lack of motivation, social withdrawal), cognitive deficits, and impaired social and occupational functioning. Despite advances in understanding the illness, diagnosis still relies on psychiatric interviews and the exclusion of medical or substance-induced psychosis. Likewise, treatment response, typically taking several weeks, is assessed via interviews without reliable biomarkers to guide treatment decisions. This lack of clinically relevant biomarkers represents a significant gap in the field. MicroRNAs (miRNAs), small non-coding RNAs crucial for gene expression regulation, can target hundreds of messenger RNAs and have been implicated in complex diseases like schizophrenia. MiRNA dysregulation in schizophrenia has been demonstrated in genome-wide association studies, human post-mortem brain tissue analyses, and biological fluid studies. Most miRNA studies in biological fluids related to SZ have focused on miRNAs in blood, either as circulating free cell or within peripheral blood mononuclear cells. A new approach being tested in depression and other neurological illnesses involves measuring miRNAs contained in neural-derived extracellular vesicles (NDE) isolated from plasma. NDEs, isolated using brain-specific surface markers, carry an enriched cargo of brain-predominant miRNAs, offering a less invasive window into central nervous system processes. This study will investigate plasma NDE miRNAs as diagnostic and treatment response biomarkers in first-episode schizophrenia (FES) using two approaches. The first approach involves a mechanistic clinical trial with first- episode schizophrenia (FES) participants. This population was specifically chosen to minimize confounding effects associated with prolonged antipsychotic exposure and extended illness duration. Aim 1 will compare plasma NDE miRNA profiles between 80 acutely psychotic FES participants before initiation of controlled treatment and 80 healthy volunteers. Aim 2 will assess baseline and change scores of plasma NDE miRNAs as predictors of response to 12 weeks of controlled treatment with aripiprazole or risperidone. Our second approach will leverage our participation in the Psychiatric Biomarkers Network (PBN), a multi-site consortium focused on fluid biomarkers in psychosis spectrum disorders. We will analyze blood and cerebrospinal fluid (CSF) samples from 60 early-phase schizophrenia participants and 60 healthy volunteers from the PBN to validate our findings in an independent sample and correlate plasma NDE miRNAs with CSF extracellular vesicle miRNAs (Aim 3). This will assess the ability of NDE miRNAs to reflect central nervous system abnormalities as measured in CSF. Successful completion of these aims will provide preliminary evidence for the utility of plasma NDE miRNAs as biomarkers in schizophrenia, paving the way for future refinement, validation, and clinical implementation.