Neurodiagnostic, Proteomic, and Metabolomic Investigations into Down Syndrome Regression Disorder

Dr. Jonathan D. Santoro is a physician-scientist focused on exploring the interface between neuroinflammation and neuropsychiatric disease in persons with Down syndrome (DS). Dr. Santoro is an international expert in Down Syndrome Regression Disorder (DSRD), a neuropsychiatric condition in persons with DS which causes acute or subacute onset bradykinesia, catatonia, delusions, hallucinations, mutism and the loss of ability to perform activities of daily living. This disease is devasting to both the patient and their caregivers given the high degree of disability associated with it. Dr. Santoro has spent the last five years identifying the potential role of neuroinflammation in individuals with this disease and has led multiple successful initiatives to treat this disease with immunotherapy. This five-year proposal will be the first comprehensive assessment utilizing neurodiagnostic studies (EEG, MRI, TCD, and lumbar puncture) and “multi-omics” analysis of the serum and cerebrospinal fluid to directly compare individuals with DSRD to individuals with DS without Regression (DSwR). Preliminary data has found that individuals with DSRD have significantly higher rates of neurodiagnostic abnormalities compared to individuals with DSwR and this is associated with higher rates of response to immunotherapeutics. Further, early stage “multi-omics” analysis has identified that upregulated immunoglobulin production and increased permeability of the blood-brain barrier may be a potential pathologic mechanism for this condition. This study will also employ advanced machine-based learning techniques to determine if advanced neurodiagnostic profiling can predict responses to treatments and potentially yield a unifying mechanism for this dreadful condition. By combining a multidisciplinary team of experts in DS, neuroradiology, multi-omics, and machine-based learning, the PI hopes to yield critically important data on the role of neuroinflammation in DSRD with the hopes of expanding investigations to autism spectrum disorder, epilepsy and moyamoya disease in the future. Project Number: 1R01HD119010-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Jonathan Santoro | Institution: CHILDREN'S HOSPITAL OF LOS ANGELES, LOS ANGELES, CA | Award Amount: $661,575 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 CN-S (81)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11901001