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

Abstract

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.

Figure 1. Plasma Amyloid-β Concentrations in Presenilin 1 (PSEN1) E280A Mutation Carriers and Noncarriers

Shown are between-group cross-sectional comparisons between PSEN1 mutation carriers and noncarriers. P values were calculated using Mann-Whitney U tests. The red lines indicate means.

Figure 2. Functional Brain Measures in Presenilin 1 (PSEN1) E280A Mutation Carriers Compared With Noncarriers

Statistical maps were projected onto the medial surfaces of a spatially standardized brain. The color scale represents the between-group difference significance in the postulated search regions. A, Results show main effect of mutation during the contrast novel face-name pairs vs repeated face-name pairs. Compared with non-carriers, carriers had significantly less deactivation bilaterally in the precuneus and parietal regions (P = .005, uncorrected for multiple regional comparisons). B, Parameter estimates extracted as a sphere with a radius of 5 mm and centered at the coordinate 6, −49, 71 from the right precuneus for the contrast novel pairs vs repeated pairs for PSEN1 mutation carriers and noncarriers. For the novel greater than repeated contrast, the mean (SD) parameter estimates in this region were −0.590 (0.502) for noncarriers and −0.087 (0.372) for PSEN1 carriers. C, Map displays group differences in functional default-mode network connectivity for carriers vs noncarriers. PSEN1 mutation carriers showed increased functional connectivity between the posterior cingulate cortex and bilateral medial temporal lobe regions (P = .005, uncorrected for multiple regional comparisons). D, Mean functional connectivity of the posterior cingulate cortex region with an anatomical mask of bilateral medial temporal lobe regions. The mean (SD) parameter estimates were 0.038 (0.070) for noncarriers and 0.190 (0.057) for carriers.

Figure 3. Structural Brain Measures in PSEN1 E280A Mutation Carriers Compared With Noncarriers

Compared with noncarriers, PSEN1 mutation carriers had significantly greater gray matter volume in the bilateral parietal and temporal regions and the posterior cingulate cortex (P < .005, uncorrected for multiple regional comparisons). Differences in the parahippocampal gyrus and temporal pole remained significant after correcting for multiple comparisons. A, Statistical maps were projected onto the lateral and medial surfaces of a spatially standardized brain. B, The peak gray matter difference between carriers and noncarriers in the temporal pole at 40, 11, −21 (Talairach) is also displayed. The mean (SD) parameter estimates were 0.57 (0.07) for noncarriers and 0.66 (0.06) for carriers.