BDNF rs6265 Met carriers with alcohol use disorder show greater age-related decline of N-acetylaspartate in left dorsolateral prefrontal cortex

Abstract

Background: Brain-derived neurotrophic factor (BDNF) is implicated in neuronal and glial cell growth and differentiation, synaptic plasticity, and apoptotic mechanisms. A single-nucleotide polymorphism of the BDNF rs6265 gene may contribute to the pattern and magnitude of brain metabolite abnormalities apparent in those with an Alcohol Use Disorder (AUD). We predicted that methionine (Met) carriers would demonstrate lower magnetic resonance spectroscopy (MRS) measures of N-acetylaspartate level (NAA) and greater age-related decline in NAA than valine (Val) homozygotes.

Methods: Veterans with AUD (n=95; 46±12 years of age, min = 25, max = 71) were recruited from VA Palo Alto residential treatment centers. Single voxel MRS, at 3 Tesla, was used to obtain NAA, choline (Cho) and creatine (Cr) containing compounds from the left dorsolateral prefrontal cortex (DLPFC). Metabolite spectra were fit with LC Model and NAA and Cho were standardized to total Cr level and NAA was also standardized to Cho.

Results: Val/Met (n=35) showed markedly greater age-related decline in left DLPFC NAA/Cr level than Val/Val (n=60); no differences in mean metabolite levels were observed between Val/Met and Val/Val. Val/Met demonstrated greater frequency of history of MDD and higher frequency of cannabis use disorder over 12 months prior to study.

Conclusions: The greater age-related decline in left DLPFC NAA/Cr and the higher frequency of MDD history and Cannabis Use disorder in BDNF rs6265 Met carriers with AUD are novel and may have implications for non-invasive brain stimulation targeting the left DLFPC and other psychosocial interventions typically utilized in the treatment of AUD.

Trial registration: ClinicalTrials.gov NCT03191266 NCT03291431.

Keywords: Alcohol use disorder; Brain derived neurotrophic factor; Magnetic resonance spectroscopy; N-acetylaspartate.