Cardiovascular risks impact human brain N-acetylaspartate in regionally specific patterns

Joshua Chiappelli; Laura M. Rowland; S. Andrea Wijtenburg; Hongji Chen; Andrew A. Maudsley; Sulaiman Sheriff; Shuo Chen; Anya Savransky; Wyatt Marshall; Meghann C. Ryan; Heather A. Bruce; Alan R. Shuldiner; Braxton D. Mitchell; Peter Kochunov; L. Elliot Hong

doi:10.1073/pnas.1907730116

New Research In

Edited by Bruce S. McEwen, Rockefeller University, New York, NY, and approved October 21, 2019 (received for review May 3, 2019)

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Significance

We used a 3-dimensional whole-brain spectroscopic imaging technique to determine the relationship of the Framingham Cardiovascular Risk Score (FCVRS) to neurochemistry in a sample of Amish participants without neurologic or psychiatric disorders. Cardiovascular risk scores were inversely associated with N-acetylaspartate (NAA), especially in white matter regions. As NAA is a marker for neuronal integrity and serves as a reservoir for precursors to myelin lipid synthesis, the relationship to FCVRS implicates reduced NAA as a potential early marker and mechanistic clue for the contribution of cardiovascular risk factors to cognitive decline and neurodegenerative disorders.

Abstract

Cardiovascular risk factors such as dyslipidemia and hypertension increase the risk for white matter pathology and cognitive decline. We hypothesize that white matter levels of N-acetylaspartate (NAA), a chemical involved in the metabolic pathway for myelin lipid synthesis, could serve as a biomarker that tracks the influence of cardiovascular risk factors on white matter prior to emergence of clinical changes. To test this, we measured levels of NAA across white matter and gray matter in the brain using echo planar spectroscopic imaging (EPSI) in 163 individuals and examined the relationship of regional NAA levels and cardiovascular risk factors as indexed by the Framingham Cardiovascular Risk Score (FCVRS). NAA was strongly and negatively correlated with FCVRS across the brain, but, after accounting for age and sex, the association was found primarily in white matter regions, with additional effects found in the thalamus, hippocampus, and cingulate gyrus. FCVRS was also negatively correlated with creatine levels, again primarily in white matter. The results suggest that cardiovascular risks are related to neurochemistry with a predominantly white matter pattern and some subcortical and cortical gray matter involvement. NAA mapping of the brain may provide early surveillance for the potential subclinical impact of cardiovascular and metabolic risk factors on the brain.

Footnotes

↵¹J.C. and L.M.R. contributed equally to this work.
↵²To whom correspondence may be addressed. Email: jchiappe{at}som.umaryland.edu or lrowland{at}som.umaryland.edu.

Author contributions: L.M.R., S.A.W., P.K., and L.E.H. designed research; H.C., A.S., W.M., and P.K. performed research; A.A.M. and S.S. contributed new reagents/analytic tools; J.C., L.M.R., S.A.W., H.C., S.C., M.C.R., P.K., and L.E.H. analyzed data; and J.C., L.M.R., S.A.W., A.A.M., S.S., S.C., A.S., W.M., M.C.R., H.A.B., A.R.S., B.D.M., P.K., and L.E.H. wrote the paper.
Competing interest statement: L.E.H. has received or plans to receive research funding or consulting fees from Mitsubishi, Your Energy Systems LLC, Neuralstem, Taisho Pharmaceutical, Luye Pharma, Sound Pharma, Heptares, Takeda, and Pfizer. L.M.R. has received or plans to receive consulting fees from Otsuka America Pharmaceutical, Inc. A.R.S. is a full-time employee of Regeneron Pharmaceuticals, Inc. All other authors declare no competing interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1907730116/-/DCSupplemental.

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