Journal article

Neuroepigenetic signatures of age and sex in the living human brain

Tonya M Gilbert, Nicole R Zurcher, Mary C Catanese, Chieh-En J Tseng, Maria A Di Biase, Amanda E Lyall, Baileigh G Hightower, Anjali J Parmar, Anisha Bhanot, Christine J Wu, Matthew L Hibert, Minhae Kim, Umar Mahmood, Steven M Stufflebeam, Frederick A Schroeder, Changning Wang, Joshua L Roffman, Daphne J Holt, Douglas N Greve, Ofer Pasternak Show all

Nature Communications | NATURE PUBLISHING GROUP | Published : 2019

Abstract

Age- and sex-related alterations in gene transcription have been demonstrated, however the underlying mechanisms are unresolved. Neuroepigenetic pathways regulate gene transcription in the brain. Here, we measure in vivo expression of the epigenetic enzymes, histone deacetylases (HDACs), across healthy human aging and between sexes using [11C]Martinostat positron emission tomography (PET) neuroimaging (n = 41). Relative HDAC expression increases with age in cerebral white matter, and correlates with age-associated disruptions in white matter microstructure. A post mortem study confirmed that HDAC1 and HDAC2 paralogs are elevated in white matter tissue from elderly donors. There are also sex-..

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University of Melbourne Researchers

Grants

Awarded by National Institute on Drug Abuse


Awarded by National Institute of Mental Health


Awarded by Harvard/MGH Nuclear Medicine Training Program from the Department of Energy


Awarded by Center for Functional Neuroimaging Technologies


Awarded by Neuroimaging Analysis Center


Awarded by National Institutes of Health (NIH)


Awarded by NIH-NeuroBiobank


Awarded by NATIONAL INSTITUTE OF BIOMEDICAL IMAGING AND BIOENGINEERING


Awarded by NATIONAL INSTITUTE OF MENTAL HEALTH


Awarded by NATIONAL INSTITUTE ON DRUG ABUSE


Funding Acknowledgements

We thank B. Dickerson, A. Kendall, M. Wentworth, O. Johnson-Akeju, M. Albers, and N. Nortelus for consenting subjects and/or medical coverage; E. Pierce and O. Johnson-Akeju for arterial-line placement; J. Sore and the radiopharmacy team for radiotracer synthesis; G. Arabasz, S. Hsu, and R. Butterfield for assistance with MR-PET imaging; and A. Zhu for imaging data collection. We are grateful to C. Catana, D. Izquierdo, and D. Chonde for PET image analysis advice and A. Harikumar for advice on cognitive metrics. We thank M. Loggia, D. Albrecht, and M. Riley for helpful comments. This research received funding from the National Institute on Drug Abuse (R01DA030321 to J.M.H. and R00DA037928 to H-Y.W.), National Institute of Mental Health (R21 MH11197101A1 to J.M.H., R01 MH102377 and K24 MH110807 to M.K., R03 MH110745 to A.E.L., and R01MH108574 to O.P.), Harvard/MGH Nuclear Medicine Training Program from the Department of Energy (DE-SC0008430 to H-Y.W., T.M.G., and C.W.), Brain and Behavior Foundation Independent Investigator Award (J.M.H.) and Young Investigator Award (T.M.G.), American Federation for Aging Research (AFAR) New Investigator Award in Alzheimer's Disease (H-Y.W.), MGH Research Scholar's Program (J.M.H.), MGH ECOR Fund for Medical Discovery (T.M.G.), and Athinoula A. Martinos Center Postdoctoral Pilot Funding (T.M.G.). This research was carried out at the Athinoula A. Martinos Center for Biomedical Imaging at MGH, using resources provided by the Center for Functional Neuroimaging Technologies, P41EB015896, a P41 Biotechnology Resource Grant supported by the National Institute of Biomedical Imaging and Bioengineering (NIBIB), and the Neuroimaging Analysis Center, P41EB015902, a P41 supported by NIBIB. This work also involved the use of instrumentation supported by the National Institutes of Health (NIH) Shared Instrumentation Grant Program; specifically, S10RR017208-01A1, S10RR026666, S10RR022976, S10RR019933, S10RR023043, and S10RR023401. Human tissue was obtained from the NIH Neurobiobank at the University of Maryland, Baltimore, MD. Tissue was also obtained through the Harvard Brain Tissue Resource Center, funded through the NIH-NeuroBiobank HHSN-271-2013-00030C [The National Institute of Mental Health (NIMH), National Institute of Neurological Diseases and Stroke (NINDS), and Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)].