BDNF Val66Met Polymorphism and Gamma Band Disruption in Resting State Brain Functional Connectivity: A Magnetoencephalography Study in Cognitively Intact Older Females.

Inmaculada C Rodríguez-Rojo,Pablo Cuesta,Ana Barabash,María Eugenia López,Jaisalmer De Frutos-Lucas,Fernando Maestú,Ricardo Bruña,Pedro Montejo,Alberto Fernández,Ramón López-Higes,Mercedes Montenegro-Peña,Alberto Marcos,Ernesto Pereda

doi:10.3389/fnins.2018.00684

Abstract

The pathophysiological processes undermining brain functioning decades before the onset of the clinical symptoms associated with dementia are still not well understood. Several heritability studies have reported that the Brain Derived Neurotrophic Factor (BDNF) Val66Met genetic polymorphism could contribute to the acceleration of cognitive decline in aging. This mutation may affect brain functional connectivity (FC), especially in those who are carriers of the BDNF Met allele. The aim of this work was to explore the influence of the BDNF Val66Met polymorphism in whole brain eyes-closed, resting-state magnetoencephalography (MEG) FC in a sample of 36 cognitively intact (CI) older females. All of them were ε3ε3 homozygotes for the apolipoprotein E (APOE) gene and were divided into two subgroups according to the presence of the Met allele: Val/Met group (n = 16) and Val/Val group (n = 20). They did not differ in age, years of education, Mini-Mental State Examination scores, or normalized hippocampal volumes. Our results showed reduced antero-posterior gamma band FC within the Val/Met genetic risk group, which may be caused by a GABAergic network impairment. Despite the lack of cognitive decline, these results might suggest a selective brain network vulnerability due to the carriage of the BDNF Met allele, which is linked to a potential progression to dementia. This neurophysiological signature, as tracked with MEG FC, indicates that age-related brain functioning changes could be mediated by the influence of particular genetic risk factors.

Highlights

Over the last two decades, the interest in exploring candidate genes related to cognitive and brain aging has significantly increased (Kennedy et al, 2014)
The network-based functional connectivity (FC) methodology pointed out the existence of an altered brain network composed by longrange connections between antero-posterior regions of interest (ROIs), showing a significant diminished FC in Val/Met participants when compared to Val/Val homozygotes
The lLSOcc connected with the right supplementary motor area, the right superior frontal gyrus, the left gyrus rectus, the left orbital superior frontal gyrus, and the left anterior cingulate cortex

Summary

Introduction

Over the last two decades, the interest in exploring candidate genes related to cognitive and brain aging has significantly increased (Kennedy et al, 2014). BDNF is related to the activity-dependent synaptic plasticity, which is crucial for the modulation of several cognitive domains such as learning, memory, and executive functions (Horch et al, 1999; Egan et al, 2003; Binder and Scharfman, 2004; Bath and Lee, 2006). It is well-known that BDNF production decreases with age (Mattson and Magnus, 2006) and more importantly, with the emergence of Alzheimer’s Disease (AD)-related neuropathology (Qin et al, 2017). With this background in mind, recent literature (Matyi et al, 2017) has focused on exploring the association between several BDNF single nucleotide polymorphisms (SNPs) and this neurodegenerative disorder, providing additional evidence in support of the interest of further studying this relationship

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