Peripheral Inflammation and Cognitive Performance in Middle-Aged Adults With and Without Type 2 Diabetes: Results From the ENBIND Study.

Adam H Dyer,Desmond O’Neill,Isabella Batten,Sean P Kennelly,Conor P Woods,Niall Conlon,Richard Reilly,Karen Jones,James Gibney,Jean Dunne,Nollaig M Bourke,Louise Mckenna,Matthew Widdowson

doi:10.3389/fnagi.2020.605878

Abstract

Midlife Type 2 Diabetes Mellitus (T2DM) is associated with a greater risk of dementia in later life. Peripheral inflammation and its impact on cognition is proposed as one of the pathological mechanisms mediating this link. However, studies have primarily focused on older individuals with established cognitive impairment and a long duration of T2DM. Importantly, knowledge of which individuals with midlife T2DM who are at greatest risk of later cognitive decline is lacking. We examined the cross-sectional relationship between serum levels of 8 pro-inflammatory markers (IL-1β, IL-6, TNF-α, IL-8, MCP-1, CXCL10, IL-12p70, CRP) and performance on a detailed neuropsychological assessment battery in middle-aged adults with uncomplicated T2DM (N = 89; 52 ± 8.1 years, 47% female) and matched healthy controls (N = 50; 52 ± 8.3 years, 59% female). Linear regression was used to analyze associations between serum markers and cognitive performance in the overall cohort, followed by a T2DM∗protein concentration interaction analysis to identify any T2DM-specific effects. We observed a significant T2DM-specific association between serum TNF-α levels and scores on the Paired Associates Learning (PAL) task (β: −3.16, SE: 1.32, p = 0.01, Std. Beta: −0.94), a task with significant working memory demands previously implicated in T2DM-related cognitive dysfunction. However, this did not persist on controlling for multiple testing. We provide exploratory evidence for a significant T2DM-specific relationship between serum TNF-α and memory performance. These findings require further replication and longitudinal analysis with the aim of selecting-out individuals with midlife T2DM at risk of future cognitive decline for potential preventative interventions.

Highlights

Type 2 Diabetes Mellitus (T2DM) in midlife is associated with a greater risk of dementia in later life (Liebson et al, 1997a,b; Ott et al, 1999; Gudala et al, 2013; Jan Biessels and Despa, 2018)
Of 140 participants screened, a single participant with T2DM was excluded for a Montreal Cognitive Assessment (MoCA) score below the cut-off
139 participants (52.3 ± 8.1 years of age, 50% female; 69/139) meeting the inclusion criteria were recruited to the current study, 89 of whom had a diagnosis of T2DM free from any diabetesrelated complications in addition to 50 healthy controls

Summary

Introduction

Type 2 Diabetes Mellitus (T2DM) in midlife is associated with a greater risk of dementia in later life (Liebson et al, 1997a,b; Ott et al, 1999; Gudala et al, 2013; Jan Biessels and Despa, 2018). In T2DM, localized inflammation in the pancreas, glucotoxicity, lipotoxicity, oxidative stress and endoplasmic reticulum stress results in activation of the innate immune system and proinflammatory macrophages (Donath and Sholeson, 2011) Such changes result in the secretion of pro-inflammatory cytokines such as Tumor Necrosis Factor α (TNF-α), Interleukin-1β (IL-1β), Interleukin-6 (IL-6) and Monocyte Chemoattractant Protein 1 (MCP-1) which are detectable at greater levels in the serum of those with T2DM in comparison to their nondiabetic counterparts (Donath and Sholeson, 2011; Donath, 2014). The relationship between peripheral inflammation and cognitive dysfunction has never been studied in those with midlife T2DM, at the exact age when T2DM is acting as a risk factor for later cognitive decline

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