High “Normal” Blood Glucose Is Associated with Decreased Brain Volume and Cognitive Performance in the 60s: The PATH through Life Study

Moyra E Mortby,Perminder S Sachdev,Kaarin J Anstey,Andrew L Janke,Nicolas Cherbuin,Friedemann Paul

doi:10.1371/journal.pone.0073697

Abstract

ContextType 2 diabetes is associated with cerebral atrophy, cognitive impairment and dementia. We recently showed higher glucose levels in the normal range not to be free of adverse effects and to be associated with greater hippocampal and amygdalar atrophy in older community-dwelling individuals free of diabetes.ObjectiveThis study aimed to determine whether blood glucose levels in the normal range (<6.1 mmol/L) were associated with cerebral volumes in structures other than the hippocampus and amygdale, and whether these glucose-related regional volumes were associated with cognitive performance.Design, Setting and Participants210 cognitively healthy individuals (68–73 years) without diabetes, glucose intolerance or metabolic syndrome were assessed in the large, community-based Personality and Total Health Through Life (PATH) study.Main Outcome MeasureBaseline blood glucose levels in the normal range (3.2–6.1 mmol/l) were used to determine regional brain volumes and associated cognitive function at wave 3.ResultsHigher blood glucose levels in the normal range were associated with lower grey/white matter regional volumes in the frontal cortices (middle frontal gyrus, inferior frontal gyrus precentral gyrus). Moreover, identified cerebral regions were associated with poorer cognitive performance and the structure-function associations were gender specific to men.ConclusionThese findings stress the need to re-evaluate what is considered as healthy blood glucose levels, and consider the role of higher normal blood glucose as a risk factor for cerebral health, cognitive function and dementia. A better lifetime management of blood glucose levels may contribute to improved cerebral and cognitive health in later life and possibly protect against dementia.

Highlights

It is well established that type 2 diabetes is associated with ‘accelerated brain ageing’ [1], white matter lesions [2], atrophy [3,4] and the presence of infarcts [5], which in turn relate to reduced cognitive functioning [1,4], an increased risk of Alzheimer’s disease [6,7] and vascular damage [8]
Higher blood glucose levels in the normal range were associated with lower grey/white matter regional volumes in the frontal cortices
These findings stress the need to re-evaluate what is considered as healthy blood glucose levels, and consider the role of higher normal blood glucose as a risk factor for cerebral health, cognitive function and dementia

Summary

Introduction

It is well established that type 2 diabetes is associated with ‘accelerated brain ageing’ [1], white matter lesions [2], atrophy [3,4] and the presence of infarcts [5], which in turn relate to reduced cognitive functioning [1,4], an increased risk of Alzheimer’s disease [6,7] and vascular damage [8]. We have recently shown that higher glucose levels in the normal range (,6.1 mmol/L) are not necessarily free of adverse effects, and are associated with greater hippocampal and amygdalar atrophy in older community-dwelling individuals free of diabetes [12]. These findings are in accordance with animal studies demonstrating higher plasma glucose levels in rats to be associated with hippocampal neuronal loss, decreased neurogenesis, impaired spatial learning, reduced hippocampal dendritic spine density, and reduced long-term potentiation [13,14,15]. In nondiabetics, experimentally raised plasma glucose levels have been associated with increased systemic inflammation [16,17], abnormal coagulation function [18], chronic stress and activation of the Hypothalamus-Pituitary-Adrenal axis [19], which are possible mechanisms that may explain these findings

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