The physio-affective phenome of major depression is strongly associated with biomarkers of astroglial and neuronal projection toxicity which in turn are associated with peripheral inflammation, insulin resistance and lowered calcium

Abstract

Background. Major depressive disorder (MDD) is characterized by elevated activity of peripheral neuro-immune and neuro-oxidative pathways, which may cause neuro-affective toxicity by disrupting neuronal circuits in the brain. No study has explored peripheral indicators of neuroaxis damage in MDD in relation to serum inflammatory and insulin resistance (IR) biomarkers, calcium, and the physio-affective phenome consisting of depressive, anxious, chronic fatigue, and physiosomatic symptoms. Methods. Serum levels of phosphorylated tau protein 217 (P-tau217), platelet-derived growth factor receptor beta (PDGFR), neurofilament light chain (NF-L), glial fibrillary acidic protein (GFAP), C-reactive protein (CRP), calcium and the HOMA2-insulin resistance (IR) index were measured in 94 MDD patients and 47 controls. Results. 61.1% of the variance in the physio-affective phenome (conceptualized as a factor extracted from depression, anxiety, fatigue and physiosomatic symptoms) is explained by the regression on GFAP, NF-L, P-tau2017, PDGFRβ and HOMA2-IR (all positively associated), and decreased calcium. In addition, CRP and HOMA2-IR predicted 28.9% of the variance in the neuroaxis index. We observed significant indirect effects of CRP and calcium on the physio-affective phenome which were partly mediated by the four neuroaxis biomarkers. Annotation and enrichment analysis revealed that the enlarged GFAP, P-tau217, PDGFR, and NF-L network was enriched in glial cell and neuronal projections, the cytoskeleton and axonal transport, including a mitochondrion. Conclusions: Peripheral inflammation and IR may damage the astroglial and neuronal projections thereby interfering with mitochondrial transport. This toxicity, combined with inflammation, IR and lowered calcium, may, at least in part, induce the phenome of MDD.

Lowered Quality of Life in Long COVID Is Predicted by Affective Symptoms, Chronic Fatigue Syndrome, Inflammation and Neuroimmunotoxic Pathways

“…According to the theory summarized in this work, activated neuro-immune and neuro-oxidative pathways cause dysfunctions in peripheral and central neuronal cells as well as central circuits that mediate affection, sleep, pain, cognition, and memory. Recently, we discovered that in MDD, the effects of peripheral inflammation (as measured by CRP), lower calcium, and insulin resistance on the physio-affective phenome of depression (as measured by HAMD, HAMA, and FF scores) were mediated by neuronal injury indicators indicating damage to astroglial and neuronal (axonal) projections [ 47 ]. In patients with unstable angina, we discovered that activation of immune-inflammatory pathways (CRP and cytokines including IL-6) affects the physio-affective phenome of unstable angina, and that these effects are mediated by increased atherogenicity and insulin resistance [ 48 ].…”

“…Previously, we discussed the neurotoxic effects of increased insulin resistance, including increased permeability of the blood-brain barrier, decreased levels of brain-derived neurotrophic factor, impaired synaptic plasticity and dendritic spine damage, and decreased hippocampal volume and metabolic activity in the prefrontal cortex [ 47 ]. Lower serum calcium is not only an indicator of an inflammatory response [ 47 ], but it is also associated with physiosomatic symptoms including muscle spasms and cramps, neuromuscular irritability, paresthesia, circumoral numbness, neurocognitive and memory impairments, fatigue, and depression and anxiety [ 50 , 51 , 52 ]. Recent meta-analysis findings indicate that low calcium in COVID-19 patients is associated with increased severity, higher mortality, and more complications [ 53 ].…”

Increased insulin resistance due to Long COVID is associated with depressive symptoms and partly predicted by the inflammatory response during acute infection

“…Our results suggest that IR in Long COVID may contribute to the overall neurotoxicity which comprises effects of IO&NS mechanisms (25,73) . Recently, we have described the mechanism that may explain these IR-associated neurotoxic effects on the physio-affective phenomenon of MDD (74) . For example, IR is associated with a decrease in metabolic activity in the medial prefrontal cortex and hippocampal volume, dysfunctions in the medial prefrontal cortex and hippocampal connectome, and neurocognitive impairments including in executive functions and memory (75)(76)(77) .…”

Increased galanin-galanin receptor 1 signaling, inflammation, and insulin resistance are associated with affective symptoms and chronic fatigue syndrome due to Long COVID

“…In addition, in acute COVID-19 populations, S100B concentration correlated significantly with organ injury indicators and inflammation markers, including C-reactive protein (CRP) 44 . In patients with acute COVID-19 infection, elevated serum NSE concentrations are correlated with disease severity 43 In patients with MDD and end-stage renal disease, various neuronal damage biomarkers are associated with increased levels of depression, anxiety, and CFS symptoms 45, 46 . However, the precise mechanisms underlying the connections between neuropsychiatric symptoms due to Long COVID and biomarkers of inflammation such as PGE2, GAL-GALR1 signaling, PAI1, IGF-1, and neuronal biomarkers remain unknown.…”

“…In addition, in acute COVID-19 populations, S100B concentration correlated significantly with organ injury indicators and inflammation markers, including C-reactive protein (CRP) 44 . In patients with acute COVID-19 infection, elevated serum NSE concentrations are correlated with disease severity 43 In patients with MDD and end-stage renal disease, various neuronal damage biomarkers are associated with increased levels of depression, anxiety, and CFS symptoms 45,46 .…”