👤 Mhd Rami Al Shweiki

Decreased cerebrospinal fluid (CSF) levels of synaptic proteins, possibly reflecting impaired synaptic function, have been observed in major depressive disorder (MDD). To investigate the diagnostic utility of the soluble N-ethylmaleimide-sensitive-factor attachment receptor (SNARE) complex protein, synaptosomal-associated protein of 25 kDa (SNAP-25), for MDD. Overall, 208 participants with one of MDD, schizophrenia (SCZ) or bipolar disorder (BD), and healthy controls (HCs) were retrospectively enrolled. CSF levels of SNAP-25 were assessed relative to MDD characteristics and the diagnostic potential was analysed. In subgroups of patients, CSF levels of presynaptic neurexin 3 (NRXN3), postsynaptic neurogranin (NRGN) and Alzheimer's disease biomarkers were measured for comparison. SNAP-25 levels, but not the levels of the other synaptic markers, were significantly decreased in MDD compared with HCs, allowing for discrimination with 68% sensitivity and 67% specificity. SNAP-25 was not associated with MDD severity or antidepressant medication. Compared with HCs, SCZ also displayed decreased SNAP-25 enabling discrimination with 64% sensitivity and 77% specificity. There were strong correlations between levels of synaptic proteins and established Alzheimer pathology markers, with subtle differences in the association pattern between disorders. Our data suggest that SNAP-25, NRXN3 and NRGN versus beta-amyloid and phosphorylated tau protein 181 (ptau) are regulated differentially across psychiatric disorders and that SNAP-25 has a moderate diagnostic potential for MDD and SCZ. We propose that CSF SNAP-25 level might represent an integrated readout of reduced synaptic function, rather than of synaptic degeneration, in MDD. Further studies are needed to analyse whether this potential can be increased by using multimarker measurements and whether it will be possible to subtype psychiatric disorders according to synaptic involvement in pathophysiology. SNAP-25 and other synaptic proteins in CSF might aid diagnosis and subtyping of MDD and SCZ. The current development of sensitive methods to also determine synaptic proteins in blood samples from patients will advance the validation of the biomarker potential and contribute to understanding of synaptic involvement in the pathophysiology of MDD and SCZ. Show less

Major depressive disorder (MDD) is a leading cause of morbidity with a lifetime prevalence of 10%. There is increasing evidence suggesting synaptic dysfunction and impaired integrity of certain brain circuits in MDD. Here we investigate the cerebrospinal fluid proteome of psychiatric patients focusing on MDD by deep proteomic profiling approach combined with a further validation step using targeted mass spectrometry. We demonstrate profound CSF proteomic changes during on-going depression episodes in MDD patients (n = 40) in comparison to controls (n = 27), schizophrenia spectrum disorder (n = 13), and bipolar disorder patients (n = 11). The discovery analysis with isobaric tags for relative and absolute quantitation (iTRAQ) reveals changes in proteins associated with synaptic transmission, myelination, and Wnt signaling in CSF of MDD. The multiple reaction monitoring (MRM) validation analysis confirms significantly decreased levels of eight proteins including the membrane synaptic proteins neurexin 3 (NRXN3), contactin-associated protein-like 4 (CNTNAP4), and glutamate ionotropic receptor AMPA type subunit 4 (GRIA4) in the CSF of MDD patients in comparison to the controls. Overall, the study demonstrates proteins that constitute an MDD biosignature for further validation studies and provides insight into the pathophysiology of MDD and other psychiatric disorders. Show less