title: Age of Childhood Onset in Type 1 Diabetes and Functional Brain Connectivity in Midlife.
abstract: OBJECTIVE
  The development of Type 1 diabetes mellitus (T1DM) within the first 7 years of life has been linked to poorer cognitive performance. Adults with T1DM have altered functional brain connectivity, but no studies have examined whether earlier age of T1DM onset is associated with functional connectivity later in life. Accordingly, we tested the relationship between age of onset and resting state functional connectivity in a cohort of middle-aged adults with childhood-onset T1DM.
  
  
  METHODS
  Participants were from a subsample of the Pittsburgh Epidemiology of Diabetes Complications cohort and included 66 adults (mean age = 47.54 years, 32 men). Resting state blood oxygen level-dependent activity was used to calculate mean connectivity for eight functional brain networks. A multivariate analysis of variance examined associations between age of onset and network connectivity. Diffusion tensor and fluid-attenuated inversion recovery images were analyzed to identify microstructural alterations and white-matter hyperintensity volumes.
  
  
  RESULTS
  Later childhood onset of T1DM was associated with lower connectivity (F(8,57) = 2.40, p = .026). A significant interaction was present for current age such that an inverse association with age of onset for functional connectivity was present in older individuals (F(8,55) = 2.88, p = .035). Lower connectivity was associated with older age, increased white-matter hyperintensity volume, and lower microstructural integrity.
  
  
  CONCLUSIONS
  Diagnosis of T1DM later in childhood may be associated with lower brain functional connectivity, particularly in those surviving into older ages. These alterations may be an early marker for subsequent cognitive decrements. Future studies are warranted to understand the pathways underlying these associations.
authors.affiliation: From the Departments of Psychiatry (J.P. Ryan, Aizenstein, C.M. Ryan, Fine) and Neurology (Saxton), University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and Departments of Epidemiology (Orchard) and Epidemiology (Nunley, Rosano), University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania.
authors.forename: John P
authors.initials: JP
authors.lastname: Ryan
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Aizenstein
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Orchard
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Ryan
authors.forename: Judith A
authors.initials: JA
authors.lastname: Saxton
authors.forename: David F
authors.initials: DF
authors.lastname: Fine
authors.forename: Karen A
authors.initials: KA
authors.lastname: Nunley
authors.forename: Caterina
authors.initials: C
authors.lastname: Rosano
mesh_terms: D000328:Adult; D017668:Age of Onset; D001921:Brain / Q000473:pathology / Q000503:physiopathology*; D063132:Connectome / Q000379:methods*; D003922:Diabetes Mellitus, Type 1; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods*; D008297:Male; D008875:Middle Aged; D009415:Nerve Net / Q000473:pathology / Q000503:physiopathology*