title: Association of metabolic dysregulation with volumetric brain magnetic resonance imaging and cognitive markers of subclinical brain aging in middle-aged adults: the Framingham Offspring Study.
abstract: OBJECTIVE
  Diabetic and prediabtic states, including insulin resistance, fasting hyperglycemia, and hyperinsulinemia, are associated with metabolic dysregulation. These components have been individually linked to increased risks of cognitive decline and Alzheimer's disease. We aimed to comprehensively relate all of the components of metabolic dysregulation to cognitive function and brain magnetic resonance imaging (MRI) in middle-aged adults.
  
  
  METHODS
  Framingham Offspring participants who underwent volumetric MRI and detailed cognitive testing and were free of clinical stroke and dementia during examination 7 (1998-2001) constituted our study sample (n = 2,439; 1,311 women; age 61 ± 9 years). We related diabetes, homeostasis model assessment of insulin resistance (HOMA-IR), fasting insulin, and glycohemoglobin levels to cross-sectional MRI measures of total cerebral brain volume (TCBV) and hippocampal volume and to verbal and visuospatial memory and executive function. We serially adjusted for age, sex, and education alone (model A), additionally for other vascular risk factors (model B), and finally, with the inclusion of apolipoprotein E-ε4, plasma homocysteine, C-reactive protein, and interleukin-6 (model C).
  
  
  RESULTS
  We observed an inverse association between all indices of metabolic dysfunction and TCBV in all models (P < 0.030). The observed difference in TCBV between participants with and without diabetes was equivalent to approximately 6 years of chronologic aging. Diabetes and elevated glycohemoglobin, HOMA-IR, and fasting insulin were related to poorer executive function scores (P < 0.038), whereas only HOMA-IR and fasting insulin were inversely related to visuospatial memory (P < 0.007).
  
  
  CONCLUSIONS
  Metabolic dysregulation, especially insulin resistance, was associated with lower brain volumes and executive function in a large, relatively healthy, middle-aged, community-based cohort.
authors.affiliation: Veterans Administration Boston HealthcareSystem, Boston, MA, USA. ztan@hms.harvard.edu
authors.forename: Zaldy S
authors.initials: ZS
authors.lastname: Tan
authors.forename: Alexa S
authors.initials: AS
authors.lastname: Beiser
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Rhoda
authors.initials: R
authors.lastname: Au
authors.forename: Jayandra J
authors.initials: JJ
authors.lastname: Himali
authors.forename: Stephanie
authors.initials: S
authors.lastname: Debette
authors.forename: Charles
authors.initials: C
authors.lastname: Decarli
authors.forename: Ramachandran S
authors.initials: RS
authors.lastname: Vasan
authors.forename: Philip A
authors.initials: PA
authors.lastname: Wolf
authors.forename: Sudha
authors.initials: S
authors.lastname: Seshadri
mesh_terms: D000368:Aged; D000375:Aging / Q000502:physiology*; D001057:Apolipoproteins E / Q000378:metabolism; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002097:C-Reactive Protein / Q000378:metabolism; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged
chemical_list: D001057:Apolipoproteins E; D015850:Interleukin-6; D002097:C-Reactive Protein