title: Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study.
abstract: OBJECTIVE
  Brain imaging and fluid biomarkers are characterized in children at risk for autosomal dominant Alzheimer disease (ADAD).
  
  
  OBJECTIVE
  To characterize and compare structural magnetic resonance imaging (MRI), resting-state and task-dependent functional MRI, and plasma amyloid-β (Aβ) measurements in presenilin 1 (PSEN1) E280A mutation-carrying and noncarrying children with ADAD.
  
  
  METHODS
  Cross-sectional measures of structural and functional MRI and plasma Aβ assays were assessed in 18 PSEN1 E280A carriers and 19 noncarriers aged 9 to 17 years from a Colombian kindred with ADAD. Recruitment and data collection for this study were conducted at the University of Antioquia and the Hospital Pablo Tobon Uribe in Medellín, Colombia, between August 2011 and June 2012.
  
  
  METHODS
  All participants had blood sampling, structural MRI, and functional MRI during associative memory encoding and resting-state and cognitive assessments. Outcome measures included plasma Aβ1-42 concentrations and Aβ1-42:Aβ1-40 ratios, memory encoding-dependent activation changes, resting-state connectivity, and regional gray matter volumes. Structural and functional MRI data were compared using automated brain mapping algorithms and search regions related to AD.
  
  
  RESULTS
  Similar to findings in adult mutation carriers, in the later preclinical and clinical stages of ADAD, mutation-carrying children were distinguished from control individuals by significantly higher plasma Aβ1-42 levels (mean [SD]: carriers, 18.8 [5.1] pg/mL and noncarriers, 13.1 [3.2] pg/mL; P < .001) and Aβ1-42:Aβ1-40 ratios (mean [SD]: carriers, 0.32 [0.06] and noncarriers, 0.21 [0.03]; P < .001), as well as less memory encoding task-related deactivation in parietal regions (eg, mean [SD] parameter estimates for the right precuneus were -0.590 [0.50] for noncarriers and -0.087 [0.38] for carriers; P < .005 uncorrected). Unlike carriers in the later stages, mutation-carrying children demonstrated increased functional connectivity of the posterior cingulate cortex with medial temporal lobe regions (mean [SD] parameter estimates were 0.038 [0.070] for noncarriers and 0.190 [0.057] for carriers), as well as greater gray matter volumes in temporal regions (eg, left parahippocampus; P < . 049, corrected for multiple comparisons).
  
  
  CONCLUSIONS
  Children at genetic risk for ADAD have functional and structural brain changes and abnormal levels of plasma Aβ1-42. The extent to which the underlying brain changes are either neurodegenerative or developmental remains to be determined. This study provides additional information about the earliest known biomarker changes associated with ADAD.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston2Department of Psychiatry, Massachusetts General Hospital, Boston3Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston4Harvard Medical School, Boston, Ma.
authors.forename: Yakeel T
authors.initials: YT
authors.lastname: Quiroz
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston4Harvard Medical School, Boston, Massachusetts.
authors.forename: Aaron P
authors.initials: AP
authors.lastname: Schultz
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona7Arizona Alzheimer's Consortium, Phoenix8Department of Mathematics and Statistics, Arizona State University, Tempe.
authors.forename: Kewei
authors.initials: K
authors.lastname: Chen
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona7Arizona Alzheimer's Consortium, Phoenix.
authors.forename: Hillary D
authors.initials: HD
authors.lastname: Protas
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston4Harvard Medical School, Boston, Massachusetts9Frontotemporal Dementia Unit, Department of Neurology, Massachusetts General Hospital, Boston.
authors.forename: Michael
authors.initials: M
authors.lastname: Brickhouse
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona10Eli Lilly and Company, Indianapolis, Indiana11Department of Neurosciences, University of California, San Diego.
authors.forename: Adam S
authors.initials: AS
authors.lastname: Fleisher
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona7Arizona Alzheimer's Consortium, Phoenix.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Langbaum
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona7Arizona Alzheimer's Consortium, Phoenix.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Thiyyagura
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Fagan
authors.affiliation: Department of Neurology, Washington University School of Medicine, St Louis, Missouri.
authors.forename: Aarti R
authors.initials: AR
authors.lastname: Shah
authors.affiliation: Psychology Department, Boston University, Boston, Massachusetts.
authors.forename: Martha
authors.initials: M
authors.lastname: Muniz
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston15Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts.
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Arboleda-Velasquez
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Claudia
authors.initials: C
authors.lastname: Munoz
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Gloria
authors.initials: G
authors.lastname: Garcia
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Acosta-Baena
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Margarita
authors.initials: M
authors.lastname: Giraldo
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Victoria
authors.initials: V
authors.lastname: Tirado
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Dora L
authors.initials: DL
authors.lastname: Ramírez
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona7Arizona Alzheimer's Consortium, Phoenix16Department of Psychiatry, University of Arizona, Phoenix.
authors.forename: Pierre N
authors.initials: PN
authors.lastname: Tariot
authors.affiliation: Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston4Harvard Medical School, Boston, Massachusetts9Frontotemporal Dementia Unit, Department of Neurology, Massachusetts General Hospital, Boston.
authors.forename: Bradford C
authors.initials: BC
authors.lastname: Dickerson
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Boston3Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston4Harvard Medical School, Boston, Massachusetts17Center for Alzheimer Research and Treatment, Departm.
authors.forename: Reisa A
authors.initials: RA
authors.lastname: Sperling
authors.affiliation: Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia.
authors.forename: Francisco
authors.initials: F
authors.lastname: Lopera
authors.affiliation: Banner Alzheimer's Institute, Phoenix, Arizona7Arizona Alzheimer's Consortium, Phoenix16Department of Psychiatry, University of Arizona, Phoenix18Division of Neurogenomics, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Reiman
mesh_terms: D000293:Adolescent; D000544:Alzheimer Disease / Q000097:blood* / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D001921:Brain / Q000473:pathology; D001931:Brain Mapping; D002648:Child; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D009154:Mutation; D009929:Organ Size; D010446:Peptide Fragments / Q000097:blood*; D053764:Presenilin-1 / Q000235:genetics*
chemical_list: D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; D053764:Presenilin-1; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)