title: Reorganization of Functional Networks in Verbal Working Memory Circuitry in Early Midlife: The Impact of Sex and Menopausal Status.
abstract: Converging preclinical and human evidence indicates that the decline in ovarian estradiol production during the menopausal transition may play a mechanistic role in the neuronal changes that occur early in the aging process. Here, we present findings from a population-based fMRI study characterizing regional and network-level differences in working memory (WM) circuitry in midlife men and women (N = 142; age range 46-53), as a function of sex and reproductive stage. Reproductive histories and hormonal evaluations were used to determine menopausal status. Participants performed a verbal WM task during fMRI scanning. Results revealed robust differences in task-evoked responses in dorsolateral prefrontal cortex and hippocampus as a function of women's reproductive stage, despite minimal variance in chronological age. Sex differences in regional activity and functional connectivity that were pronounced between men and premenopausal women were diminished for postmenopausal women. Critically, analyzing data without regard to sex or reproductive status obscured group differences in the circuit-level neural strategies associated with successful working memory performance. These findings underscore the importance of reproductive age and hormonal status, over and above chronological age, for understanding sex differences in the aging of memory circuitry. Further, these findings suggest that early changes in working memory circuitry are evident decades before the age range typically targeted in cognitive aging studies.
authors.affiliation: Division of Women's Health, Department of Medicine.|Department of Psychiatry, Brigham and Women's Hospital, Boston, MA 02120, USA.|Harvard Medical School, Boston, MA 02120, USA.|Athinoula A. Martinos Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Emily G
authors.initials: EG
authors.lastname: Jacobs
authors.affiliation: Department of Psychiatry, Brigham and Women's Hospital, Boston, MA 02120, USA.
authors.forename: Blair
authors.initials: B
authors.lastname: Weiss
authors.affiliation: Harvard Medical School, Boston, MA 02120, USA.|Athinoula A. Martinos Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Nikos
authors.initials: N
authors.lastname: Makris
authors.affiliation: Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Sue
authors.initials: S
authors.lastname: Whitfield-Gabrieli
authors.affiliation: Department of Epidemiology, Brown University School of Public Health, Providence, RI, USA.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Buka
authors.affiliation: Neuroendocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Klibanski
authors.affiliation: Division of Women's Health, Department of Medicine.|Department of Psychiatry, Brigham and Women's Hospital, Boston, MA 02120, USA.|Harvard Medical School, Boston, MA 02120, USA.|Athinoula A. Martinos Center, Massachusetts General Hospital, Charlestown, MA 02129, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Goldstein
mesh_terms: D000367:Age Factors; D005260:Female; D006062:Gonadotropins / Q000378:metabolism; D006624:Hippocampus / Q000000981:diagnostic imaging / Q000502:physiology*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008570:Memory, Short-Term / Q000502:physiology*; D008593:Menopause / Q000502:physiology*; D008875:Middle Aged; D009483:Neuropsychological Tests; D010100:Oxygen / Q000097:blood; D017397:Prefrontal Cortex / Q000000981:diagnostic imaging / Q000502:physiology*; D011247:Pregnancy; D012727:Sex Characteristics; D013256:Steroids / Q000378:metabolism; D014706:Verbal Learning / Q000502:physiology*
chemical_list: D006062:Gonadotropins; D013256:Steroids; D010100:Oxygen
keywords: cognitive aging; estradiol; fMRI; prefrontal cortex; sex steroid hormones