title: Age-modulated association between prefrontal NAA and the BDNF gene.
abstract: Brain-derived neurotrophic factor (BDNF) has been implicated in the pathophysiology of psychiatric and neurological disorders and in the mechanisms of antidepressant pharmacotherapy. Psychiatric and neurological conditions have also been associated with reduced brain levels of N-acetyl-aspartate (NAA), which has been used as a putative marker of neural integrity. However, few studies have explored the relationship between BDNF polymorphisms and NAA levels directly. Here, we present data from a single-voxel proton magnetic resonance spectroscopy study of 64 individuals and explore the relationship between BDNF polymorphisms and prefrontal NAA level. Our results indicate an association between a single nucleotide polymorphism (SNP) within BDNF, known as rs1519480, and reduced NAA level (p = 0.023). NAA levels were further predicted by age and Asian ancestry. There was a significant rs1519480 × age interaction on NAA level (p = 0.031). Specifically, the effect of rs1519480 on NAA level became significant at age ⩾34.17 yr. NAA level decreased with advancing age for genotype TT (p = 0.001) but not for genotype CT (p = 0.82) or CC (p = 0.34). Additional in silico analysis of 142 post-mortem brain samples revealed an association between the same SNP and reduced BDNF mRNA expression in the prefrontal cortex. The rs1519480 SNP influences BDNF mRNA expression and has an impact on prefrontal NAA level over time. This genetic mechanism may contribute to inter-individual variation in cognitive performance seen during normal ageing, as well as contributing to the risk for developing psychiatric and neurological conditions.
authors.affiliation: Psychiatric University Hospital, University of Bern, Bern, Switzerland.
authors.forename: Basira
authors.initials: B
authors.lastname: Salehi
authors.forename: Nora
authors.initials: N
authors.lastname: Preuss
authors.forename: Jan Willem
authors.initials: JW
authors.lastname: van der Veen
authors.forename: Jun
authors.initials: J
authors.lastname: Shen
authors.forename: Alexander
authors.initials: A
authors.lastname: Neumeister
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Drevets
authors.forename: Colin
authors.initials: C
authors.lastname: Hodgkinson
authors.forename: David
authors.initials: D
authors.lastname: Goldman
authors.forename: Jens R
authors.initials: JR
authors.lastname: Wendland
authors.forename: Andrew
authors.initials: A
authors.lastname: Singleton
authors.forename: Jesse R
authors.initials: JR
authors.lastname: Gibbs
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.forename: Gregor
authors.initials: G
authors.lastname: Hasler
mesh_terms: D000293:Adolescent; D000328:Adult; D000375:Aging / Q000235:genetics* / Q000378:metabolism*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D003863:Depression / Q000235:genetics / Q000473:pathology; D003865:Major Depressive Disorder / Q000235:genetics / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D055815:Young Adult
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger; D001224:Aspartic Acid; C000179:N-acetylaspartate