Large differences in adiponectin levels have no clear effect on multiple sclerosis risk: A Mendelian randomization study.

BACKGROUND: Mendelian randomization (MR) studies have demonstrated strong support for an association between genetically increased body mass index and risk of multiple sclerosis (MS). The adipokine adiponectin may be a potential mechanism linking body mass to risk of MS. OBJECTIVE: To evaluate whether genetically increased adiponectin levels influence risk of MS. METHODS: Using genome-wide significant single nucleotide polymorphisms (SNPs) for adiponectin, we undertook an MR study to estimate the effect of adiponectin on MS. This method prevents bias due to reverse causation and minimizes bias due to confounding. Sensitivity analyses were performed to evaluate the assumptions of MR. RESULTS: MR analyses did not support a role for genetically elevated adiponectin in risk of MS (odds ratio (OR) = 0.93 per unit increase in natural-log-transformed adiponectin, equivalent to a two-standard deviation increase in adiponectin on the absolute scale; 95% confidence interval (CI) = 0.66-1.33; p = 0.61). Further MR analysis suggested that genetic variation at the adiponectin gene, which influences adiponectin level, does not impact MS risk. Sensitivity analyses, including MR-Egger regression, suggested no bias due to pleiotropy. CONCLUSION: Lifelong genetically increased adiponectin levels in humans have no clear effect on risk of MS. Other biological factors driving the association between body mass and MS should be investigated.

Cellular and Molecular Inflammatory Profile of the Choroid Plexus in Depression and Suicide.

The inflammatory hypothesis of depression is one of the main theories that endeavors to explain and describe the underlying biological mechanisms of depression and suicide. While mounting evidence indicates altered peripheral and central inflammatory profiles in depressed patients and suicide completers, little is known about how peripheral and central inflammation might be linked in these contexts. The choroid plexus (ChP), a highly vascularized tissue that produces cerebrospinal fluid (CSF) and lacks a blood-brain-barrier, is an interface between peripheral and central immune responses. In the present study, we investigated the cellular and molecular inflammatory profile of the ChP of the lateral ventricle in depressed suicides and psychiatrically healthy controls. Gene expression of macrophages, pro- and anti-inflammatory cytokines, and various factors implicated in immune cell trafficking were measured; and density of ionized calcium-binding adaptor molecule 1-positive (Iba1+) macrophages associated with the ChP epithelial cell layer (ECL) was examined. Significant downregulations of the genes encoding interleukin 1ß (IL1ß), a pro-inflammatory acute-phase protein; intercellular cell adhesion molecule 1 (ICAM1), a protein implicated in immune cell trafficking in the ChP; and IBA1, a monocyte/macrophage marker; were detected in depressed suicides as compared to controls. No difference in the density of Iba1+ macrophages associated with the ChP ECL was observed. While interpretation of these findings is challenging in the absence of corroborating data from the CSF, peripheral blood, or brain parenchyma of the present cohort, we hypothesize that the present findings reflect a ChP compensatory mechanism that attenuates the detrimental effects of chronically altered pro-inflammatory signaling caused by elevated levels of pro-inflammatory cytokines, such as IL-1ß, peripherally and/or centrally. Together, these findings further implicate neuroimmune processes in the etiology of depression and suicide.

Increased doublecortin (DCX) expression and incidence of DCX-immunoreactive multipolar cells in the subventricular zone-olfactory bulb system of suicides.

Postmortem studies have confirmed the occurrence of adult hippocampal neurogenesis in humans and implicated this process in antidepressant response, yet neurogenesis in other regions remains to be examined in the context of depression. Here we assess the extent of subventricular zone-olfactory bulb (SVZ-OB) neurogenesis in adult humans having died by suicide. Protein expression of proliferative and neurogenic markers Sox2, proliferating cell nuclear antigen, and doublecortin (DCX) were examined in postmortem SVZ and OB samples from depressed suicides and matched sudden-death controls. In the SVZ, DCX-immunoreactive (IR) cells displayed phenotypes typical of progenitors, whereas in the olfactory tract (OT), they were multipolar with variable size and morphologies suggestive of differentiating cells. DCX expression was significantly increased in the OB of suicides, whereas SVZ DCX expression was higher among unmedicated, but not antidepressant-treated, suicides. Although very few DCX-IR cells were present in the control OT, they were considerably more common in suicides and correlated with OB DCX levels. Suicides also displayed higher DCX-IR process volumes. These results support the notion that OB neurogenesis is minimal in adult humans. They further raise the possibility that the differentiation and migration of SVZ-derived neuroblasts may be altered in unmedicated suicides, leading to an accumulation of ectopically differentiating cells in the OT. Normal SVZ DCX expression among suicides receiving antidepressants suggests a potentially novel mode of action of antidepressant medication. Given the modest group sizes and rarity of DCX-IR cells assessed here, a larger-scale characterization will be required before firm conclusions can be made regarding the identity of these cells.