Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study | Dementia and Cognitive Impairment | JAMA Network
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Original Investigation
August 2015

Brain Imaging and Blood Biomarker Abnormalities in Children With Autosomal Dominant Alzheimer Disease: A Cross-Sectional Study

Author Affiliations
  • 1Department of Neurology, Massachusetts General Hospital, Boston
  • 2Department of Psychiatry, Massachusetts General Hospital, Boston
  • 3Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston
  • 4Harvard Medical School, Boston, Massachusetts
  • 5Grupo de Neurociencias, Universidad de Antioquia, Medellín, Colombia
  • 6Banner Alzheimer’s Institute, Phoenix, Arizona
  • 7Arizona Alzheimer’s Consortium, Phoenix
  • 8Department of Mathematics and Statistics, Arizona State University, Tempe
  • 9Frontotemporal Dementia Unit, Department of Neurology, Massachusetts General Hospital, Boston
  • 10Eli Lilly and Company, Indianapolis, Indiana
  • 11Department of Neurosciences, University of California, San Diego
  • 12Department of Neurology, Washington University School of Medicine, St Louis, Missouri
  • 13Psychology Department, Boston University, Boston, Massachusetts
  • 14Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston
  • 15Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
  • 16Department of Psychiatry, University of Arizona, Phoenix
  • 17Center for Alzheimer Research and Treatment, Department of Neurology, Brigham & Women’s Hospital, Boston, Massachusetts
  • 18Division of Neurogenomics, Translational Genomics Research Institute, Phoenix, Arizona
JAMA Neurol. 2015;72(8):912-919. doi:10.1001/jamaneurol.2015.1099

Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.