Previous studies have suggested that depression and suicide are related to alterations in total cholesterol serum concentrations, and that an altered distribution of haptoglobin (Hp) phenotypes in major depression indicates that variation on chromosome 16 may be associated with that illness. Lecithin:cholesterol acyl transferase (LCAT, EC 2.3.1.43), the enzyme that catalyzes the esterifying reaction of cholesterol in serum, is located close to the Hp gene. This study examined the serum concentrations of total and free cholesterol and the esterified cholesterol ratio in 26 healthy controls, 47 unipolar depressed subjects (16 minor, 14 simple major and 17 melancholic depressed subjects) and 12 relatives of melancholic subjects. Depressed subjects (regardless of subtype) and relatives of depressed subjects had a significantly lower esterified cholesterol ratio than normal controls. No significant differences in total or free cholesterol concentrations were found between the above study groups. In depressed subjects, there were no significant relationships between the esterified cholesterol ratio, total or free cholesterol and postdexamethasone adrenocorticotropic or cortisol values, Hp phenotypes, severity of illness or suicidal symptoms. It is hypothesized that lower esterification in serum cholesterol may constitute a vulnerability factor for depression through alterations in cell membrane microviscosity.
The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.
Objective Somatization is a symptom cluster characterized by ‘psychosomatic’ symptoms, that is, medically unexplained symptoms, and is a common component of other conditions, including depression and myalgic encephalomyelitis/chronic fatigue syndrome ( ME / CFS ). This article reviews the data regarding the pathophysiological foundations of ‘psychosomatic’ symptoms and the implications that this has for conceptualization of what may more appropriately be termed physio‐somatic symptoms. Method This narrative review used papers published in PubMed, Scopus, and Google Scholar electronic databases using the keywords: depression and chronic fatigue, depression and somatization, somatization and chronic fatigue syndrome, each combined with inflammation, inflammatory, tryptophan, and cell‐mediated immune ( CMI ). Results The physio‐somatic symptoms of depression, ME / CFS , and somatization are associated with specific biomarkers of inflammation and CMI activation, which are correlated with, and causally linked to, changes in the tryptophan catabolite ( TRYCAT ) pathway. Oxidative and nitrosative stress induces damage that increases neoepitopes and autoimmunity that contribute to the immuno‐inflammatory processes. These pathways are all known to cause physio‐somatic symptoms, including fatigue, malaise, autonomic symptoms, hyperalgesia, intestinal hypermotility, peripheral neuropathy, etc. Conclusion Biological underpinnings, such as immune‐inflammatory pathways, may explain, at least in part, the occurrence of physio‐somatic symptoms in depression, somatization, or myalgic encephalomyelitis/chronic fatigue syndrome and thus the clinical overlap among these disorders.
