title: Higher glucose levels associated with lower memory and reduced hippocampal microstructure.
abstract: OBJECTIVE
  For this cross-sectional study, we aimed to elucidate whether higher glycosylated hemoglobin (HbA1c) and glucose levels exert a negative impact on memory performance and hippocampal volume and microstructure in a cohort of healthy, older, nondiabetic individuals without dementia.
  
  
  METHODS
  In 141 individuals (72 women, mean age 63.1 years ± 6.9 SD), memory was tested using the Rey Auditory Verbal Learning Test. Peripheral levels of fasting HbA1c, glucose, and insulin and 3-tesla MRI scans were acquired to assess hippocampal volume and microstructure, as indicated by gray matter barrier density. Linear regression and simple mediation models were calculated to examine associations among memory, glucose metabolism, and hippocampal parameters.
  
  
  RESULTS
  Lower HbA1c and glucose levels were significantly associated with better scores in delayed recall, learning ability, and memory consolidation. In multiple regression models, HbA1c remained strongly associated with memory performance. Moreover, mediation analyses indicated that beneficial effects of lower HbA1c on memory are in part mediated by hippocampal volume and microstructure.
  
  
  CONCLUSIONS
  Our results indicate that even in the absence of manifest type 2 diabetes mellitus or impaired glucose tolerance, chronically higher blood glucose levels exert a negative influence on cognition, possibly mediated by structural changes in learning-relevant brain areas. Therefore, strategies aimed at lowering glucose levels even in the normal range may beneficially influence cognition in the older population, a hypothesis to be examined in future interventional trials.
authors.affiliation: From the Departments of Neurology (L.K., A.V.W., A.W., A.F.) and Biostatistics and Clinical Epidemiology (U.G.), NeuroCure Cluster of Excellence (A.V.W., A.F.), and Center for Stroke Research Berlin (U.G., A.F.), Charité-University Medicine, Berlin; and Department of Psychiatry (D.R.), University of Halle, Germany.
authors.forename: Lucia
authors.initials: L
authors.lastname: Kerti
authors.forename: A Veronica
authors.initials: AV
authors.lastname: Witte
authors.forename: Angela
authors.initials: A
authors.lastname: Winkler
authors.forename: Ulrike
authors.initials: U
authors.lastname: Grittner
authors.forename: Dan
authors.initials: D
authors.lastname: Rujescu
authors.forename: Agnes
authors.initials: A
authors.lastname: Flöel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D001057:Apolipoproteins E / Q000235:genetics; D001786:Blood Glucose; D005215:Fasting / Q000097:blood; D005260:Female; D005838:Genotype; D006442:Glycated Hemoglobin / Q000378:metabolism; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008569:Memory Disorders / Q000097:blood* / Q000473:pathology*; D008875:Middle Aged; D009483:Neuropsychological Tests; D012044:Regression Analysis
chemical_list: D001057:Apolipoproteins E; D001786:Blood Glucose; D006442:Glycated Hemoglobin