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Original Investigation
December 2017

Association Between Brain Gene Expression, DNA Methylation, and Alteration of Ex Vivo Magnetic Resonance Imaging Transverse Relaxation in Late-Life Cognitive Decline

Author Affiliations
  • 1Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, Illinois
  • 2Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois
  • 3Department of Diagnostic Radiology and Nuclear Medicine, Rush University Medical Center, Chicago, Illinois
  • 4Department of Behavioral Sciences, Rush University Medical Center, Chicago, Illinois
  • 5Department of Pathology, Rush University Medical Center, Chicago, Illinois
  • 6Department of Biomedical Engineering, Illinois Institute of Technology, Chicago
  • 7Center for Translational and Computational Neuroimmunology, Columbia University Medical Center, New York, New York
  • 8Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts
JAMA Neurol. 2017;74(12):1473-1480. doi:10.1001/jamaneurol.2017.2807
Key Points

Question  What are the associations between brain gene expression, DNA methylation, and alteration of ex vivo magnetic resonance imaging transverse relaxation in late-life cognitive decline above and beyond common neuropathologic conditions?

Findings  From analysis of data from longitudinal clinicopathologic cohort studies of aging, 4 genes were identified (ie, PADI2, ZNF385A, PSD2, and A2ML1), of which higher expression was associated with a slower transverse relaxation rate. Furthermore, an anticorrelation pattern between the transverse relaxation rate and DNA methylation in many of the cytosine-guanine dinucleotides was observed.

Meaning  Gene expression and DNA methylation are implicated in the alteration of brain tissue properties associated with cognitive decline.

Abstract

Importance  Alteration of ex vivo magnetic resonance imaging transverse relaxation is associated with late-life cognitive decline even after controlling for common neuropathologic conditions. However, the underlying neurobiology of this association is unknown.

Objective  To investigate the association between brain gene expression, DNA methylation, and alteration of magnetic resonance imaging transverse relaxation in late-life cognitive decline.

Design, Setting, and Participants  Data came from 2 community-based longitudinal cohort studies of aging and dementia, the Religious Orders Study, which began in 1993, and the Rush Memory and Aging Project, which began in 1997. All participants agreed to undergo annual clinical evaluations and to donate their brains after death. By October 24, 2016, a total of 1358 individuals had died and had brain autopsies that were approved by board-certified neuropathologists. Of those, 552 had undergone ex vivo imaging. The gene expression analysis was limited to 174 individuals with both imaging and brain RNA sequencing data. The DNA methylation analysis was limited to 225 individuals with both imaging and brain methylation data.

Main Outcomes and Measures  Maps of ex vivo magnetic resonance imaging transverse relaxation were generated using fast spin echo imaging. The target was a composite measure of the transverse relaxation rate (R2) that was associated with cognitive decline after controlling for common neuropathologic conditions. Next-generation RNA sequencing and DNA methylation data were generated using frozen tissue from the dorsolateral prefrontal cortex. Genome-wide association analysis was used to investigate gene expression and, separately, DNA methylation for signals associated with the R2 measure.

Results  Of the 552 individuals with ex vivo imaging data, 394 were women and 158 were men, and the mean (SD) age at death was 90.4 (6.0) years. Four co-expressed genes (PADI2 [Ensembl ENSG00000117115], ZNF385A [Ensembl ENSG00000161642], PSD2 [Ensembl ENSG00000146005], and A2ML1 [Ensembl ENSG00000166535]) were identified, of which higher expressions were associated with slower R2. The association of R2 with cognitive decline was attenuated when the gene expression signals were added to the model, such that the mean (SE) coefficient of association was reduced from 0.028 (0.008) (P < .001) to 0.019 (0.009) (P = .03). The DNA methylation scan did not detect a genome-wide significant signal, but it revealed an anticorrelation between R2 and DNA methylation in many of the cytosine-guanine dinucleotides.

Conclusions and Relevance  Brain gene expression and DNA methylation dysregulations are implicated in the alteration of brain tissue properties associated with late-life cognitive decline above and beyond the influence of common neuropathologic conditions.

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