Abstract
Midlife obesity is a risk factor of late onset Alzheimer's disease (LOAD) but why this is the case remains unknown. As systemic inflammation is involved in both conditions, obesity-related neuroinflammation may contribute to damage in limbic structures important in LOAD. Here, we investigated the hypothesis that systemic inflammation would mediate central obesity related effects on limbic tissue microstructure in 166 asymptomatic individuals (38–71 years old). We employed MRI indices sensitive to myelin and neuroinflammation [macromolecular proton fraction (MPF) and kf] from quantitative magnetization transfer (qMT) together with indices from neurite orientation dispersion and density imaging (NODDI) to investigate the effects of central adiposity on the fornix, parahippocampal cingulum, uncinate fasciculus (compared with whole brain white matter and corticospinal tract) and the hippocampus. Central obesity was assessed with the Waist Hip Ratio (WHR) and abdominal visceral and subcutaneous fat area fractions (VFF, SFF), and systemic inflammation with blood plasma concentrations of leptin, adiponectin, C-reactive protein and interleukin 8. Men were significantly more centrally obese and had higher VFF than women. Individual differences in WHR and in VFF were negatively correlated with differences in fornix MPF and kf, but not with any differences in neurite microstructure. In women, age mediated the effects of VFF on fornix MPF and kf, whilst in men differences in the leptin and adiponectin ratio fully mediated the effect of WHR on fornix MPF. These results suggest that visceral fat related systemic inflammation may damage myelin-related properties of the fornix, a key limbic structure known to be involved in LOAD.
Highlights
Obesity is globally on the rise (World Health Organisation, 2018; Alzheimer's Research UK, 2014) and has become an epidemic in many Western countries
Midlife obesity is a risk factor of late onset Alzheimer's disease (LOAD) but the biological mechanisms underpinning this link remain poorly understood. Both conditions are associated with systemic inflammation, and it is increasingly recognised that microglia-mediated immune responses play an important role in LOAD (Dansokho and Heneka, 2018; Heneka et al, 2015; Sarlus and Heneka, 2017; Tejera and Heneka, 2016)
It has been proposed that obesity induced gut dysbiosis may trigger microglia mediated neuroinflammation, and in turn may contribute to the development of LOAD pathology (Bartzokis, 2011; Sochocka et al, 2018; Venegas et al, 2017)
Summary
Obesity is globally on the rise (World Health Organisation, 2018; Alzheimer's Research UK, 2014) and has become an epidemic in many Western countries. As midlife obesity is a risk factor of LOAD, and LOAD pathology is proposed to spread from the hippocampal formation via limbic white matter pathways such as the fornix (Plowey and Ziskin, 2016) to the neocortex (Braak and Del Trecidi, 2015), we hypothesised that obesity-related differences would disproportionally affect limbic white and grey matter regions, i.e. the fornix, parahippocampal cinguli, uncinate fasciculi, and the hippocampi, relative to whole brain and cortico-spinal-motor white matter (Kullmann et al, 2015; Metzler-Baddeley et al, 2013) To test this hypothesis, mean values of qMT and NODDI indices were extracted from all regions (Fig. 1B). Principal component analysis (PCA) was used i) to assess the relationships between the different microstructural indices in white and grey matter and ii) to reduce the dimensionality of the data for further correlational analyses of obesity-brain relationships
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