Evidence that complement and coagulation proteins are mediating the clinical response to omega-3 fatty acids: A mass spectrometry-based investigation in subjects at clinical high-risk for psychosis

Abstract

Preliminary evidence indicates beneficial effects of omega-3 polyunsaturated fatty acids (PUFAs) in early psychosis. The present study investigates the molecular mechanism of omega-3 PUFA-associated therapeutic effects in clinical high-risk (CHR) participants. Plasma samples of 126 CHR psychosis participants at baseline and 6-months follow-up were included. Plasma protein levels were quantified using mass spectrometry and erythrocyte omega-3 PUFA levels were quantified using gas chromatography. We examined the relationship between change in polyunsaturated PUFAs (between baseline and 6-month follow-up) and follow-up plasma proteins. Using mediation analysis, we investigated whether plasma proteins mediated the relationship between change in omega-3 PUFAs and clinical outcomes. A 6-months change in omega-3 PUFAs was associated with 24 plasma proteins at follow-up. Pathway analysis revealed the complement and coagulation pathway as the main biological pathway to be associated with change in omega-3 PUFAs. Moreover, complement and coagulation pathway proteins significantly mediated the relationship between change in omega-3 PUFAs and clinical outcome at follow-up. The inflammatory protein complement C5 and protein S100A9 negatively mediated the relationship between change in omega-3 PUFAs and positive symptom severity, while C5 positively mediated the relationship between change in omega-3 and functional outcome. The relationship between change in omega-3 PUFAs and cognition was positively mediated through coagulation factor V and complement protein C1QB. Our findings provide evidence for a longitudinal association of omega-3 PUFAs with complement and coagulation protein changes in the blood. Further, the results suggest that an increase in omega-3 PUFAs decreases symptom severity and improves cognition in the CHR state through modulating effects of complement and coagulation proteins.

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

“…A long-term goal of these studies is to better understand if the complement system can be harnessed to serve as a biomarker of neuroinflammation, synaptic pruning or even if complement pathways can be modulated for therapeutic use. Recent evidence, for example, supports a complement and coagulation protein pathway mechanism by which omega-3 polyunsaturated fatty acids might contribute to cognitive and symptom improvements in individuals with early psychosis [41]. A role for C4 in neuroinflammation is based on positive, negative, and mixed associations of C4 levels with markers of white matter integrity, CSF biochemistry, cortical thinning, and patterns of expression with postmortem brain structures and functions [31,32,42,51,52,54,[90][91][92][93][94][95][96][97].…”

“…Such functional endpoints that could be linkable to a plasma C4 biomarker include abnormal synaptic pruning, cortical thinning, neuropil contraction, and dendritic spine deficiencies [28][29][30][31][32][33][34][35][36][37]. Future potential biomarker goals might include detection of neuroinflammation, more rapid identification of early psychoses, identification of cognitive deficits and other symptomatology, choice of treatment, and monitoring of treatment efficacies [38][39][40][41][42][43]. Interrogations of peripheral C4, however, have produced remarkably mixed results, with peripheral C4 sometimes elevated, sometimes reduced and sometimes unchanged in schizophrenia versus comparison groups [33,36,38,40,[44][45][46][47][48][49][50].…”

Membrane Lipids in Ultra-High-Risk Patients: Potential Predictive Biomarkers of Conversion to Psychosis

“…Interestingly, the levels of alphalinolenic acid (C18:3n3) at baseline were significantly different between responders and non-responders to omega-3 supplementation (0.21% vs. 0.16%, p = 0.001) in the NEURO-PRO study [65]. Another study on the NEURAPRO cohort found that complement and coagulation proteins mediate the clinical response to omega-3 PUFA and suggested that an omega-3 increase decreased symptom severity and improved cognition [66].…”

An analysis of omega-3 clinical trials and a call for personalized supplementation for dementia prevention

“…Notably, supplementation with omega-3 PUFAs has been shown to interact with the key components of the complement cascade, including complement 5 (C5), S100 Calcium Binding Protein A9 (S100A9), Complement C1q B Chain (C1QB), and coagulation Factor V (F5). For example, omega-3 and cognition are positively associated with F5 and C1QB, suggesting its potential role in modifying cognition through complement-mediated synaptic pruning [ 22 ]. In AD, the prolonged activation of microglia results in significant neuronal damage due to the accumulation of Aβ peptide.…”