TY - JOUR
T1 - Brain imaging and blood biomarker abnormalities in children with autosomal dominant Alzheimer disease a cross-sectional study
AU - Quiroz, Yakeel T.
AU - Schultz, Aaron P.
AU - Chen, Kewei
AU - Protas, Hillary D.
AU - Brickhouse, Michael
AU - Fleisher, Adam S.
AU - Langbaum, Jessica B.
AU - Thiyyagura, Pradeep
AU - Fagan, Anne M.
AU - Shah, Aarti R.
AU - Muniz, Martha
AU - Arboleda-Velasquez, Joseph F.
AU - Munoz, Claudia
AU - Garcia, Gloria
AU - Acosta-Baena, Natalia
AU - Giraldo, Margarita
AU - Tirado, Victoria
AU - Ramírez, Dora L.
AU - Tariot, Pierre N.
AU - Dickerson, Bradford C.
AU - Sperling, Reisa A.
AU - Lopera, Francisco
AU - Reiman, Eric M.
N1 - Publisher Copyright:
© 2015 American Medical Association. All rights reserved.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2015/8/1
Y1 - 2015/8/1
N2 - 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 Medellin, 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.
AB - 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 Medellin, 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.
UR - http://www.scopus.com/inward/record.url?scp=84938907794&partnerID=8YFLogxK
U2 - 10.1001/jamaneurol.2015.1099
DO - 10.1001/jamaneurol.2015.1099
M3 - Article
C2 - 26121081
AN - SCOPUS:84938907794
VL - 72
SP - 912
EP - 919
JO - JAMA Neurology
JF - JAMA Neurology
SN - 2168-6149
IS - 8
ER -