Blood-Brain Barrier Dysfunction and CSF Immunoglobulin Synthesis in Down Syndrome Regression Disorder
Jonathan Santoro1, Neetha Eduthan2, Mellad Khoshnood3, Saba Jafarpour4, Natalie Boyd3, Benjamin Vogel3, Lina Nguyen3, Lilia Kazerooni3, Eleanor Britton2, Hannah Lyford5, Matthew Galbraith2, Angela Rachubinski2, Joaquin Espinosa2
1Department of Neurology, Children's Hospital Los Angeles, 2Linda Crnic Institute, University of Colorado, 3Children's Hospital Los Angeles, 4Children’s Hospital of Los Angeles, 5University of California Sana Barbara
Objective:
This study sought to evaluate proteomic, metabolomic, and immune signatures in the cerebrospinal fluid of individuals with Down Syndrome Regression Disorder (DSRD).
Background:
Down Syndrome Regression Disorder (DSRD) is an acute/subacute onset neuropsychiatric condition affecting individuals with Down syndrome. This condition has been previously noted to have abnormalities on multiple neurodiagnostic tests including EEG, MRI and lumbar puncture which are associated with marked responses to immunotherapy when present.
Design/Methods:
A prospective case-control study comparing proteomic, metabolomic, and immune profiles in individuals with DSRD was performed. Samples were obtained from a biorepository of affected individuals and compared to clinically available data and previously obtained neurodiagnostic studies. Individuals with DSRD were compared to individuals with established neuroinflammatory conditions (e.g., multiple sclerosis), and neurotypical controls undergoing a lumbar puncture for headaches. Samples underwent high-throughput proteomic, metabolomic, and immune marker profiling. Data was compared across groups and clinical phenotypes. Gene set enrichment analysis and pathway analyses were utilized to analyze the data.
Results:
In total, 34 individuals with DSRD, 22 neuroinflammatory controls, and 27 neurotypical controls were enrolled in the study. We observed a highly significant concordance in dysregulated proteomics signatures in DSRD and neuroinflammatory controls versus healthy controls, most prominently upregulation of many immunoglobulin sequences. In addition, individuals with DSRD displayed strong upregulation of liver-derived plasma proteins and erythrocyte proteins in the CSF, indicating poor blood-brain barrier integrity. The immune marker profile of DSRD is clearly similar to other neuroimmunological conditions, including strong elevation of MIP3-a, eotaxin, and IFN-g.
Conclusions:
Individuals with DSRD have unique CSF proteomic and metabolomic signatures consistent with neuroinflammation and increased blood-brain barrier permeability. The CSF of individuals with DSRD was more comparable to individuals with neuroinflammatory disorders than neurotypical controls, indicating the potential for an immune etiology of disease.
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