title: Metabolic networks underlying cognitive reserve in prodromal Alzheimer disease: a European Alzheimer disease consortium project.
abstract: This project aimed to investigate the metabolic basis for resilience to neurodegeneration (cognitive reserve) in highly educated patients with prodromal Alzheimer disease (AD).
  
  
  METHODS
  Sixty-four patients with amnestic mild cognitive impairment who later converted to AD dementia during follow-up, and 90 controls, underwent brain (18)F-FDG PET. Both groups were divided into a poorly educated subgroup (42 controls and 36 prodromal AD patients) and a highly educated subgroup (48 controls and 28 prodromal AD patients). Brain metabolism was first compared between education-matched groups of patients and controls. Then, metabolism was compared between highly and poorly educated prodromal AD patients in both directions to identify regions of high education-related metabolic depression and compensation. The clusters of significant depression and compensation were further used as volumetric regions of interest (ROIs) in a brain interregional correlation analysis in each prodromal AD subgroup to explore metabolic connectivity. All analyses were performed by means of SPM8 (P < 0.001 uncorrected at peak level, P < 0.05 false discovery rate-corrected at cluster level; age, sex, Mini-Mental State Examination score, and center as nuisance).
  
  
  RESULTS
  Highly educated prodromal AD patients showed more severe hypometabolism than poorly educated prodromal AD patients in the left inferior and middle temporal gyri and the left middle occipital gyrus (ROI depression). Conversely, they showed relative hypermetabolism in the right inferior, middle, and superior frontal gyri (ROI compensation). The sites of compensation, mainly corresponding to the right dorsolateral prefrontal cortex (DLFC), showed wide metabolic correlations with several cortical areas in both hemispheres (frontotemporal cortex, parahippocampal gyrus, and precuneus) in highly educated prodromal AD patients but not in poorly educated prodromal AD patients. To provide evidence on whether these metabolic correlations represent preservation of the physiologic networks of highly educated control subjects (neural reserve) or rather the recruitment of alternative networks (neural compensation), or a combination of the two, we performed metabolic connectivity analysis of the DLFC in highly educated controls as well. The correlation sites of right DLFC partly overlapped those of highly educated prodromal AD patients but were less extended.
  
  
  CONCLUSIONS
  The present findings suggest that highly educated prodromal AD patients can cope better with the disease thanks to neural reserve but also to the recruitment of compensatory neural networks in which the right DLFC plays a key role.
authors.affiliation: Nuclear Medicine, Department of Internal Medicine, IRCCS AOU San Martino-IST, University of Genoa, Genoa, Italy. silviadaniela.morbelli@hsanmartino.it
authors.forename: Silvia
authors.initials: S
authors.lastname: Morbelli
authors.forename: Robert
authors.initials: R
authors.lastname: Perneczky
authors.forename: Alexander
authors.initials: A
authors.lastname: Drzezga
authors.forename: Giovanni B
authors.initials: GB
authors.lastname: Frisoni
authors.forename: Anna
authors.initials: A
authors.lastname: Caroli
authors.forename: Bart N M
authors.initials: BN
authors.lastname: van Berckel
authors.forename: Rik
authors.initials: R
authors.lastname: Ossenkoppele
authors.forename: Eric
authors.initials: E
authors.lastname: Guedj
authors.forename: Mira
authors.initials: M
authors.lastname: Didic
authors.forename: Andrea
authors.initials: A
authors.lastname: Brugnolo
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Naseri
authors.forename: Gianmario
authors.initials: G
authors.lastname: Sambuceti
authors.forename: Marco
authors.initials: M
authors.lastname: Pagani
authors.forename: Flavio
authors.initials: F
authors.lastname: Nobili
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology*; D058245:Cognitive Reserve; D015331:Cohort Studies; D004522:Educational Status; D005060:Europe; D005260:Female; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways; D062706:Prodromal Symptoms
keywords: Alzheimer’s disease; cognitive reserve; metabolic connectivity; mild cognitive impairment; positron emission tomography