The relationship of serum macrophage inhibitory cytokine-1 levels with gray matter volumes in community-dwelling older individuals.

Jiyang Jiang,Wei Wen,Evelyn Smith,John Crawford,Perminder S Sachdev,David A Brown,Julian N Trollor,Tao Liu,Anbupalam Thalamuthu,Bernhard T Baune,Samuel N Breit,Henry Brodaty,Wanlin Zhu,Mara Cercignani

doi:10.1371/journal.pone.0123399

Abstract

Using circulating inflammatory markers and magnetic resonance imaging (MRI), recent studies have associated inflammation with brain volumetric measures. Macrophage Inhibitory Cytokine–1 (MIC-1/GDF15) is a divergent transforming growth factor – beta (TGF-β) superfamily cytokine. To uncover the underlying mechanisms of the previous finding of a negative association between MIC-1/GDF15 serum levels and cognition, the present study aimed to examine the relationship of circulating MIC-1/GDF15 levels with human brain gray matter (GM) volumes, in a community-dwelling sample aged 70–90 years over two years (Wave 1: n = 506, Wave 2: n = 327), of which the age-related brain atrophy had been previously well defined. T1-weighted MRI scans were obtained at both waves and analyzed using the FMRIB Software Library and FreeSurfer. The results showed significantly negative associations between MIC-1/GDF15 serum levels and both subcortical and cortical GM volumes. GM volumes of the whole brain, cortex, temporal lobe, thalamus and accumbens showed significant mediating effects on the associations between MIC-1/GDF15 serum levels and global cognition scores. Increases in MIC-1/GDF15 serum levels were associated with decreases in cortical and subcortical GM volume over two years. In conclusion, MIC-1/GDF15 serum levels were inversely associated with GM volumes both cross-sectionally and longitudinally.

Highlights

Inflammation is associated with neuropsychiatric disorders, such as Alzheimer’s disease [1], schizophrenia [2], bipolar disorder [3], and major depressive disorder [4]
A recent study from our group revealed that serum Macrophage Inhibitory Cytokine—1 (MIC-1/GDF15) levels were associated with cognitive decline [16]
Our findings were similar to those from some benchmark longitudinal studies [35,36,37,38]. In this well-defined sample, our current study aimed at investigating the associations between MIC-1/GDF15 serum levels and brain gray matter (GM) volumes, in order to 1) examine the contribution of peripheral inflammation and/or MIC-1/GDF15 itself to the age-related brain decline, and 2) elucidate the mechanisms that may underlie the relationship between MIC-1/ GDF15 and cognitive decline

Summary

Introduction

Inflammation is associated with neuropsychiatric disorders, such as Alzheimer’s disease [1], schizophrenia [2], bipolar disorder [3], and major depressive disorder [4]. It is likely that MIC-1/GDF15 serum levels reflect the activity of cellular processes not sampled by the more commonly studied inflammation associated cytokines. Our findings were similar to those from some benchmark longitudinal studies [35,36,37,38] In this well-defined sample, our current study aimed at investigating the associations between MIC-1/GDF15 serum levels and brain gray matter (GM) volumes, in order to 1) examine the contribution of peripheral inflammation and/or MIC-1/GDF15 itself to the age-related brain decline, and 2) elucidate the mechanisms that may underlie the relationship between MIC-1/ GDF15 and cognitive decline. Based on the findings from previous studies, we hypothesize that an elevated level of systemic MIC-1/GDF15 serum levels would correlate with GM atrophy in cortical and subcortical regions, and that the GM volume is a mediator of the previously observed relationships between MIC-1/GDF15 serum levels and cognition

Participants

Results

Discussion