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Brain insulin signaling and cerebrovascular disease in human postmortem brain

  • Arvanitakis, Zoe1
  • Capuano, Ana W.1
  • Wang, Hoau-Yan2, 3
  • Schneider, Julie A.1
  • Kapasi, Alifiya1
  • Bennett, David A.1
  • Ahima, Rexford S.4
  • Arnold, Steven E.5
  • 1 Rush University Medical Center, 1750 W. Harrison Street, Suite 1000, Chicago, IL, 60612, USA , Chicago (United States)
  • 2 City University of New York School of Medicine, 160 Convent Avenue, New York, NY, 10031, USA , New York (United States)
  • 3 Graduate School of The City University of New York, 365 Fifth Avenue, New York, NY, 10061, USA , New York (United States)
  • 4 Johns Hopkins University School of Medicine, 333 East Monument Street, Baltimore, MD, 21205, USA , Baltimore (United States)
  • 5 Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Charlestown, MA, 02129, USA , Charlestown (United States)
Published Article
Acta Neuropathologica Communications
Springer (Biomed Central Ltd.)
Publication Date
Apr 15, 2021
DOI: 10.1186/s40478-021-01176-9
Springer Nature


Insulin is an important hormone for brain function, and alterations in insulin metabolism may be associated with neuropathology. We examined associations of molecular markers of brain insulin signaling with cerebrovascular disease. Participants were enrolled in the Religious Orders Study (ROS), an ongoing epidemiologic community-based, clinical-pathologic study of aging from across the United States. Using cross-sectional analyses, we studied a subset of ROS: 150 persons with or without diabetes, matched 1:1 by sex on age-at-death and education. We used ELISA, immunohistochemistry, and ex vivo stimulation with insulin, to document insulin signaling in postmortem midfrontal gyrus cortex tissue. Postmortem neuropathologic data identified cerebrovascular disease including brain infarcts, classified by number (as none for the reference; one; and more than one), size (gross and microscopic infarcts), and brain region/location (cortical and subcortical). Cerebral vessel pathologies were assessed, including severity of atherosclerosis, arteriolosclerosis, and amyloid angiopathy. In separate regression analyses, greater AKT1 phosphorylation at T308 following ex vivo stimulation with insulin (OR = 1.916; estimate = 0.650; p = 0.007) and greater pS616IRS1 immunolabeling in neuronal cytoplasm (OR = 1.610; estimate = 0.476; p = 0.013), were each associated with a higher number of brain infarcts. Secondary analyses showed consistent results for gross infarcts and microinfarcts separately, but no other association including by infarct location (cortical or subcortical). AKT S473 phosphorylation following insulin stimulation was associated with less amyloid angiopathy severity, but not with other vessel pathology including atherosclerosis and arteriolosclerosis. In summary, insulin resistance in the human brain, even among persons without diabetes, is associated with cerebrovascular disease and especially infarcts. The underlying pathophysiologic mechanisms need further elucidation. Because brain infarcts are known to be associated with lower cognitive function and dementia, these data are relevant to better understanding the link between brain metabolism and brain function.

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