title: Impaired default network functional connectivity in autosomal dominant Alzheimer disease.
abstract: OBJECTIVE
  To investigate default mode network (DMN) functional connectivity MRI (fcMRI) in a large cross-sectional cohort of subjects from families harboring pathogenic presenilin-1 (PSEN1), presenilin-2 (PSEN2), and amyloid precursor protein (APP) mutations participating in the Dominantly Inherited Alzheimer Network.
  
  
  METHODS
  Eighty-three mutation carriers and 37 asymptomatic noncarriers from the same families underwent fMRI during resting state at 8 centers in the United States, United Kingdom, and Australia. Using group-independent component analysis, fcMRI was compared using mutation status and Clinical Dementia Rating to stratify groups, and related to each participant's estimated years from expected symptom onset (eYO).
  
  
  RESULTS
  We observed significantly decreased DMN fcMRI in mutation carriers with increasing Clinical Dementia Rating, most evident in the precuneus/posterior cingulate and parietal cortices (p < 0.001). Comparison of asymptomatic mutation carriers with noncarriers demonstrated decreased fcMRI in the precuneus/posterior cingulate (p = 0.014) and right parietal cortex (p = 0.0016). We observed a significant interaction between mutation carrier status and eYO, with decreases in DMN fcMRI observed as mutation carriers approached and surpassed their eYO.
  
  
  CONCLUSIONS
  Functional disruption of the DMN occurs early in the course of autosomal dominant Alzheimer disease, beginning before clinically evident symptoms, and worsening with increased impairment. These findings suggest that DMN fcMRI may prove useful as a biomarker across a wide spectrum of disease, and support the feasibility of DMN fcMRI as a secondary endpoint in upcoming multicenter clinical trials in Alzheimer disease.
authors.affiliation: Department of Neurology, Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jasmeer P
authors.initials: JP
authors.lastname: Chhatwal
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Schultz
authors.forename: Keith
authors.initials: K
authors.lastname: Johnson
authors.forename: Tammie L S
authors.initials: TL
authors.lastname: Benzinger
authors.forename: Clifford
authors.initials: C
authors.lastname: Jack
authors.forename: Beau M
authors.initials: BM
authors.lastname: Ances
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sullivan
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Salloway
authors.forename: John M
authors.initials: JM
authors.lastname: Ringman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Koeppe
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Marcus
authors.forename: Paul
authors.initials: P
authors.lastname: Thompson
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
authors.forename: Stephen
authors.initials: S
authors.lastname: Correia
authors.forename: Peter R
authors.initials: PR
authors.lastname: Schofield
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Rowe
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.forename: Adam M
authors.initials: AM
authors.lastname: Brickman
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
authors.forename: Eric
authors.initials: E
authors.lastname: McDade
authors.forename: Randall
authors.initials: R
authors.lastname: Bateman
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.forename: Allison M
authors.initials: AM
authors.lastname: Goate
authors.forename: Chengjie
authors.initials: C
authors.lastname: Xiong
authors.forename: Virginia D
authors.initials: VD
authors.lastname: Buckles
authors.forename: John C
authors.initials: JC
authors.lastname: Morris
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000453:epidemiology / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics*; D001921:Brain / Q000503:physiopathology*; D063132:Connectome; D005260:Female; D005799:Genes, Dominant / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000453:epidemiology / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D038622:Internationality; D008297:Male; D009415:Nerve Net / Q000503:physiopathology*; D053764:Presenilin-1 / Q000235:genetics*; D053766:Presenilin-2 / Q000235:genetics*; D015995:Prevalence
chemical_list: D016564:Amyloid beta-Protein Precursor; D053764:Presenilin-1; D053766:Presenilin-2