Abstract
Neuropsychiatric disorders overlap in symptoms and share genetic risk factors, challenging their current classification into distinct diagnostic categories. Novel cross-disorder approaches are needed to improve our understanding of the heterogeneous nature of neuropsychiatric diseases and overcome existing bottlenecks in their diagnosis and treatment. Here we employ high-content multi-parameter phospho-specific flow cytometry, fluorescent cell barcoding and automated sample preparation to characterize ex vivo signaling network responses (n = 1764) measured at the single-cell level in B and T lymphocytes across patients diagnosed with four major neuropsychiatric disorders: autism spectrum condition (ASC), bipolar disorder (BD), major depressive disorder (MDD), and schizophrenia (SCZ; n = 25 each), alongside matched healthy controls (n = 100). We identified 25 nodes (individual cell subtype-epitope-ligand combinations) significantly altered relative to the control group, with variable overlap between different neuropsychiatric diseases and heterogeneously expressed at the level of each individual patient. Reconstruction of the diagnostic categories from the altered nodes revealed an overlapping neuropsychiatric spectrum extending from MDD on one end, through BD and SCZ, to ASC on the other end. Network analysis showed that although the pathway structure of the epitopes was broadly preserved across the clinical groups, there were multiple discrete alterations in network connectivity, such as disconnections within the antigen/integrin receptor pathway and increased negative regulation within the Akt1 pathway in CD4+ T cells from ASC and SCZ patients, in addition to increased correlation of Stat1 (pY701) and Stat5 (pY694) responses in B cells from BD and MDD patients. Our results support the "dimensional" approach to neuropsychiatric disease classification and suggest potential novel drug targets along the neuropsychiatric spectrum.
Highlights
Epitope-specific responses were observed for JAK-Stat cytokines (IL-6, IL-10, and IFN-α2c) across different Stat isotypes (Stat1, Stat3, Stat4, Stat5) [51, 52], for mechanistic target of rapamycin complex 1 (mTORC1) inhibitor at mTORC1 substrate 4EBP1 [53] and for cAMP pathway ligands at PKA RIIα [54, 55]
We apply high-content functional screening of primary peripheral blood mononuclear cells (PBMCs) from neuropsychiatric patients and typical controls to functionally interrogate the underlying cell signaling structure of different diseases across the neuropsychiatric spectrum
Clustering of individual patient readouts across clinically associated nodes (Fig. 1a) displayed a spectral arrangement (Fig. 1b) of primary peak densities ranging from major depressive disorder (MDD), through bipolar disorder (BD) and SCZ, to autism spectrum condition (ASC)
Summary
These authors contributed : S.G. Lago, J. Neuropsychiatric diagnoses do not fall into discrete clinical groups. They represent a spectrum of conditions with overlapping symptoms shared across different clinical dimensions [1, 2].
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