Background: No studies have examined whether interactions between the apolipoprotein E4 (ApoE4) allele and peripheral biomarkers, hypertension, and type 2 diabetes mellitus (T2DM) may impact the neurocognitive, behavioral and social dysfunctions in amnestic mild cognitive impairment (aMCI) and Alzheimer disease (AD). Aims: To clinically define and biologically validate a subgroup of aMCI subjects that take up an intermediate position between controls and AD patients. Methods: In 61 healthy controls, 60 subjects with aMCI, and 60 AD patients we measured the features of aMCI/AD using the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). A composite BIORISK score was computed using the ApoE4 allele, serum folate, albumin, white blood cells, fasting blood glucose (FBG), atherogenic index of plasma (AIP), T2DM and hypertension. Results: Clustering and nearest neighbour analyses were unable to validate the aMCI subgroup. We constructed two z unit-based composite scores, the first indicating overall burden of cognitive, social, and behavioural deterioration (OBD), and a second reflecting the interactions between ApoE4, all other biomarkers, hypertension and T2DM (BIORISK). We found that 40.2% of the variance in the OBD score was explained by BIORISK, ApoE4, age and education. The OBD index was used to construct three subgroups (normal, medium, and high OBD) with the medium group (n=45) showing mild cognitive dysfunctions (MCD) in memory, language, orientation, and ADL. People with MCD show OBD and BIORISK scores that are significantly different from controls and AD.Conclusions: Petersen’s aMCI criteria cannot be validated and should be replaced by the more restrictive, biologically validated MCD class.
Abstract Background Major depression comprises two discrete subtypes, major (MDMD) and simple (SDMD) dysmood disorder. MDMD, but not SDMD, patients were identified to have highly sensitized cytokine/growth factor networks using stimulated whole blood cultures. However, no information regarding serum cytokines/chemokines/growth factors in SDMD is available. Objectives This case-control study compares 48 serum cytokines/chemokines/growth factors in academic students with SDMD (n=64) and first episode (FE)-SDMD (n=47) to those of control students (n=44) using a multiplex assay. Findings Both FE-SDMD and SDMD exhibit a notable inhibition of immune profiles, such as the compensatory immunoregulatory response system (CIRS) and alternative M2 macrophage and T helper-2 (Th-2) profiles. We observed a substantial reduction in the serum concentrations of five proteins: interleukin (IL)-4, IL-10, soluble IL-2 receptor (sIL-2R), IL-12p40, and macrophage colony-stimulating factor. A significant proportion of the variability observed in suicidal behaviors (26.7%) can be accounted for by serum IL-4, IL-10, and sIL-2R (all decreased), and CCL11 (eotaxin) and granulocyte CSF (both increased). The same biomarkers (except for IL-10), accounted for 25.5% of the variance in SDMS severity. A significant correlation exists between decreased levels of IL-4 and elevated ratings of the brooding type of rumination. Conclusions The immune profile of SDMD and FE-SDMD exhibits a significant deviation from that observed in MDMD, providing additional evidence that SDMD and MDMD represent distinct phenotypes. SDMD is characterized by the suppression of the CIRS profile, which signifies a disruption of immune homeostasis and tolerance, rather than the presence of an inflammatory response.
Depts of Psychiatry of 1) Erasme Hospital, Free University of Brussels, and 2) University Hospital of Antwerpen, Belgium.
Current case definitions of schizophrenia (DSM-5, ICD), made through a consensus among experts, are not cross-validated and lack construct reliability validity. The aim of this paper is to explain how to use bottom-up pattern recognition approaches to construct a reliable and replicable nomothetic network reflecting the direct effects of risk resilience (RR) factors, and direct and mediated effects of both RR and adverse outcome pathways (AOPs) on the schizophrenia phenome. This study was conducted using data of 40 healthy controls and 80 patients with schizophrenia. Using partial least Squares (PLS) analysis, we found that 39.7% of the variance in the phenomenome (lowered self-reported quality of life) was explained by the unified effects of AOPs (IgA to tryptophan catabolites, LPS, and the paracellular pathway, cytokines, and oxidative stress biomarkers), the cognitome (memory and executive deficits), and symptomatome (negative symptoms, psychosis, hostility, excitation, mannerism, psychomotor retardation, formal thought disorders); 55.8% of the variance in the symptomatome was explained by a single trait extracted from AOPs and the cognitome; and 22.0% of the variance in the latter was explained by the RR (Q192R polymorphism and CMPAaase activity, natural IgM, and IgM levels to zonulin). There were significant total effects (direct + mediated) of RR and AOPs on the symptomatome and phenomenome. In the current study, we built a reliable nomothetic network that reflects the associations between RR, AOPs, and the phenome of schizophrenia and discovered new diagnostic subclasses of schizophrenia based on unified RR, AOPs, and phenome scores.
Summary The relationship between myocardial infarction (MI), depression and cardiac death is not well understood. There is evidence that poly unsaturated fatty acid (PUFA) metabolism and composition in phospholipids and cholesterylesters are involved in the pathophysiology of affective disorders and cardiac dysregulation. In this paper the relationship of PUFAs with 1) cardiac events 2) depressive disorder and 3) the inflammatory response system (IRS) will be reviewed. The underlying pathophysiologic mechanisms relate to the effects of dietary fatty acids on the IRS, the HPA-axis, serotonin metabolism and platelet reactivity. These effects are the result of the important effects of PUFAs on the structure and function of localized membrane domains, their involvement in eicosanoid synthesis and their influence on intra-cellular signalling pathways and gene expression. Antidepressive treatment has been shown to have immunosuppressive effects in healthy volunteers. In patients with bipolar disorder or schizophrenia, PUFA supplementation resulted in significant symptom reduction. In the ongoing substudy of the MIND-IT, the effects of antidepressive treatment on immune status, PUFA composition in serum phospholipids and cholesterylesters and whole blood serotonin in depressive post-MI patients will be investigated. More knowledge on the relationships between PUFAs in diet, IRS parameters and serotonin metabolism may alter treatment strategies in the prevention of both cardiac death and the occurrence of depressive disorder in cardiac patients.
This Special Section of the International Journal of Neuropsychopharmacology presents papers which review the current status of the relationship between the inflammatory response system (IRS) and major 'endogenous' and 'organic' (due to a medical condition) depression. Studies published over the last 11 years and reviewed in this Special Section begin to test the necessary conditions which are needed to accept the hypothesis that an activation of the IRS is involved in the pathophysiology and aetiology of 'endogenous' and 'organic' depression. This hypothesis suggests that some types of 'endogenous' and 'organic' depression may be related to IRS activation, such as an increased production of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), IL-6, tumour necrosis factor-α (TNF-α) and interferon-γ (IFN)-γ. These cytokines are stress-sensitive, may cause depression, they have specific effects on brain systems involved in the pathogenesis of major depression, such as the serotonergic system and the hypothalamic–pituitary–adrenal (HPA) axis, and their production may be suppressed by antidepressants. Future research should examine whether anti-inflammatory drugs are effective in the treatment of depression and whether naturally occurring variants of the 'IRS' genes confer susceptibility to the development of the depressive phenotype through altered function of the respective gene products.
