Brain morphology links systemic inflammation to cognitive function in midlife adults

Abstract

Background Inflammation is linked to cognitive decline in midlife, but the neural basis for this link is unclear. One possibility is that inflammation associates with adverse changes in brain morphology, which accelerates cognitive aging and later dementia risk. Clear evidence is lacking, however, regarding whether inflammation relates to cognition in midlife via changes in brain morphology. Accordingly, the current study examines whether associations of inflammation with cognitive function are mediated by variation in cortical gray matter volume among midlife adults. Methods Plasma levels of interleukin (IL)-6 and C-reactive protein (CRP), relatively stable markers of peripheral systemic inflammation, were assessed in 408 community volunteers aged 30–54 years. All participants underwent structural neuroimaging to assess global and regional brain morphology and completed neuropsychological tests sensitive to early changes in cognitive function. Measurements of brain morphology (regional tissue volumes and cortical thickness and surface area) were derived using Freesurfer. Results Higher peripheral inflammation was associated with poorer spatial reasoning, short term memory, verbal proficiency, learning and memory, and executive function, as well as lower cortical gray and white matter volumes, hippocampal volume and cortical surface area. Mediation models with age, sex and intracranial volume as covariates showed cortical gray matter volume to partially mediate the association of inflammation with cognitive performance. Exploratory analyses of body mass suggested that adiposity may be a source of the inflammation linking brain morphology to cognition. Conclusions Inflammation and adiposity might relate to cognitive decline via influences on brain morphology.

Body mass and cognitive decline are indirectly associated via inflammation among aging adults

“…Once a robust link between a biometric risk factor, such as body mass, and an outcome of clinical interest is established, it essential to test the more proximal potential biological mechanisms that might help explain this association using mediation models that integrate the relevant biological intermediary into the pathways from risk factor to outcome (Miller et al, 2009). Our measure of circulating inflammation, CRP (a measure of systemic inflammation in the periphery), evidenced a significant indirect effect that accounted for the association between body mass and cognition; circulating levels of systemic inflammation are associated neuro-inflammation (Marsland et al, 2015, Perry, 2004and Perry, 2010). Although we were unable to include measures of neuro-inflammation in our current study, our results match well with neurodegenerative models of cognitive decline and suggest that inflammation is one biologically plausible mechanism through which body mass might affect cognition.…”

“…Systemic inflammation in the periphery is tied to neuro-inflammation in neurodegenerative disorders (Perry, 2004), as well as in aging populations more generally (Perry, 2010). For example, IL-6 and C-reactive protein (CRP) assessed in the periphery are associated with changes in brain morphology and cognitive decline in midlife (Marsland et al, 2015). As a result, individual differences in systemic inflammation may explain a portion of the variability in cognitive decline among aging adults.…”

Circulating inflammatory biomarkers in relation to brain structural measurements in a non-demented elderly population

“…Only three studies (32-34) investigated white matter microstructure and showed that systemic inflammation was associated with reduced fractional anisotropy (FA), an indicator of white matter integrity. CRP or IL6 was associated with reduced total brain volume (TBV)(35), total gray matter volume (TGMV)(36-38), total white matter volume (TWMV)(37), and hippocampal volume(36, 37, 39). However, CRP and IL6 were not associated with brain volumes in other studies (32, 33, 40-42).…”

“…However, CRP and IL6 were not associated with brain volumes in other studies (32, 33, 40-42). Only two studies examined whether inflammatory biomarkers were associated with cortical thickness (CT) and they found inconsistent results(37, 43). In one study of elderly adults, higher IL-6 was associated with accelerated annual rates of cortical thinning in the inferior temporal poles bilaterally(43), while another study found no cross-sectional associations of IL6 or CRP with CT in adults aged 30–54 years(37).…”

“…Only two studies examined whether inflammatory biomarkers were associated with cortical thickness (CT) and they found inconsistent results(37, 43). In one study of elderly adults, higher IL-6 was associated with accelerated annual rates of cortical thinning in the inferior temporal poles bilaterally(43), while another study found no cross-sectional associations of IL6 or CRP with CT in adults aged 30–54 years(37). Thus, inconsistency remains regarding the relationship between peripheral inflammatory biomarkers and brain volume; some brain measures such as microstructural white matter integrity(32-34), CT (37, 43), as well as regional brain volumes(37) were rarely examined.…”